CN114805330A - HPK1 inhibitor, preparation method thereof, pharmaceutical composition and application thereof - Google Patents

HPK1 inhibitor, preparation method thereof, pharmaceutical composition and application thereof Download PDF

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Publication number
CN114805330A
CN114805330A CN202210069863.9A CN202210069863A CN114805330A CN 114805330 A CN114805330 A CN 114805330A CN 202210069863 A CN202210069863 A CN 202210069863A CN 114805330 A CN114805330 A CN 114805330A
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substituted
alkyl
heteroatoms
cycloalkyl
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吴予川
刘霄
钟起飞
陈曦
郝蕊
袁海涛
胡永韩
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Suzhou Sinoway Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Abstract

The invention discloses an HPK1 inhibitor, a preparation method thereof, a pharmaceutical composition and application thereof. Specifically disclosed is a compound represented by the formula I or IIA compound or a pharmaceutically acceptable salt thereof. The compound of the invention has novel structure and better activity and selectivity.

Description

HPK1 inhibitor, preparation method thereof, pharmaceutical composition and application thereof
Technical Field
The invention relates to an HPK1 inhibitor, a preparation method thereof, a pharmaceutical composition and application thereof.
Background
Hematopoietic progenitor kinase 1(HPK1, also known as MAP4K1) is a member of the MAP4K family, a serine/threonine kinase. Mainly expressed in immune cells, and has the function of regulating the functions of the immune cells.
In T cells, activation of the T Cell Receptor (TCR) signaling pathway leads to recruitment of cytosolic HPK1 to the cell membrane, binding to and phosphorylating the adaptor protein SLP76, promoting SLP76 binding to E3 ligase 14-3-3, leading to degradation of SLP76/LAT signaler, which in turn down-regulates the T Cell Receptor (TCR) pathway, inhibiting T cell activation and effector T cell function. HPK1 knockout compared to wild type (HPK 1) -/- ) And HPK1 kinase inactivated (HPK1 KD) T cells exhibit enhanced proliferative capacity and higher cytokine expression levels. Systemic lupus erythematosus patients in CD4+ T cells in HPK1 mRNA and protein expression level also significantly reduced.
HPK1 controls anti-tumor immune mechanisms in a T cell-dependent manner, as in HPK1 -/- In the tumor-bearing mice with HPK1 KD, T cells have stronger tumor cell killing capability, and the tumor cells expressing the immunosuppressive molecules PGE2 are in HPK1 -/- It grew more slowly than the wild type in HPK1 KD mice. The tumor microenvironment of HPK1 KD mice is analyzed, and the main immune cell biomarkers involved in the anti-tumor immunity are obviously improved, such as CD4, CD8, IFN gamma, Granzyme B and the like, and the expression of genes related to proinflammatory pathways including chemokine CXCL14 and the like is also obviously increased, and the expression of genes related to Th2 and Treg is reduced.
In 25 human cancers, expression of HPK1 was significantly positively correlated with T cell depletion marker PD-1, and positively correlated with other T cell depletion markers TIGIT, CTLA-4, LAG3, etc. in various tumors. Decreased HPK1 expression in low-grade glioma (LGG) and renal clear cell carcinoma (KIRC) was associated with increased survival in patients, while HPK1 expansion in pancreatic cancer (PAAD) and invasive breast cancer (BRAC) was associated with poor prognosis in patients.
In addition, HPK1 is also a negative regulator of B cell and dendritic cell activation and plays an important role in maintaining Treg cell function. In conclusion, HPK1 has multiple anti-tumor immunity promoting effects and is a potential therapeutic target for tumor immunotherapy and autoimmune diseases.
Disclosure of Invention
The invention aims to solve the technical problem of single structure of the existing HPK1 inhibitor, and provides an HPK1 inhibitor, a preparation method thereof, a pharmaceutical composition and application thereof.
The invention provides a compound shown as a formula I or II or a pharmaceutically acceptable salt thereof:
Figure BDA0003481686850000021
w is NH or O;
X 1 and X 2 Independently is N or CH; y is N or CR 4 ；
R 1 Is H, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group;
R 4 、R 6 and R 7 Independently H, hydroxy, halogen, CH 3 Or OCH 3 ；
R 8 And R 9 Independently H, hydroxy, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy, C substituted by one or more OH 1 -C 4 An alkyl group; or, R 8 、R 9 Together with the carbon atom to which they are attached form C 3 -C 8 A cycloalkyl group;
R 2 is-CHR 2-1 R 2-2 By one or more R 2-3 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 2-4 Substituted "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", substituted with one or more R 2-5 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radicals, substituted by one or more R 2-6 Substituted "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S" or "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S";
R 2-1 is H or- (CH) 2 )n-R 2-1-1 (ii) a n is 0, 1, 2 or 3;
R 2-1-1 is represented by one or more R 2-7 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 2-8 Substituted "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", substituted with one or more R 2-9 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radicals, substituted by one or more R 2-10 Substituted "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S" or "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S";
R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 、R 2-8 、R 2-9 and R 2-10 Independently halogen, hydroxy, cyano, NR 2-11 R 2-12 By one or more R 2-13 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl, by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 An alkoxy group;
R 2-11 and R 2-12 Independently is H or C 1 -C 6 An alkyl group;
R 2-13 and R 2-14 Independently cyano, hydroxy, amino, or halogen;
R 2-2 is H, substituted by one or more R 2-15 Substituted C 1 -C 6 Alkyl or C 1 -C 6 An alkyl group;
R 2-15 independently cyano, hydroxy, amino or halogen;
R 3 is composed of
Figure BDA0003481686850000022
or-C (═ Z) 3 )-L 1 -L 2 -L 3 -L 4 -L 5 ；
Z 1 Is O, S, NH or-CR 1-1 ；
Z 2 Is N or-CR 1-2 ；
Z 3 Is NH, O or S;
R 1-1 and R 1-2 Independently H, halogen, C substituted by one or more halogens 1 -C 4 Alkyl or C 1 -C 4 An alkyl group;
R 5 is a quiltOne or more R 5-1 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl, by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 5-3 Substituted "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", substituted with one or more R 5-4 Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more R 5-5 Substituted C 6 -C 10 Aryl or C 6 -C 10 An aryl group;
R 5-1 independently by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 5 -3 Substituted "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", substituted with one or more R 5-4 Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more R 5-5 Substituted C 6 -C 10 Aryl or C 6 -C 10 An aryl group;
R 5-2 、R 5-3 、R 5-4 and R 5-5 Independently halogen, cyano, hydroxy, NR 5-2-1 R 5-2-2 、C 1 -C 6 Alkyl or-C (═ O) R 5 -2-3 ；R 5-2-1 And R 5-2-2 Independently is H or C 1 -C 6 An alkyl group; r is 5-2-3 Is C 1 -C 6 An alkyl group;
L 1 is a covalent bond, O, S or NR 10 ；R 10 Is H or C 1 -C 6 An alkyl group;
L 2 being a covalent bond, by one or more R 1-3 Substituted C 1 -C 6 Alkylene or C 1 -C 6 An alkylene group;
L 3 is a covalent bond, C 3 -C 8 Cycloalkylene or "3-12 membered heterocycloalkylene with 1-4 hetero atoms selected from one or more of N, O and S";
L 4 being a covalent bond, by one or more R 1-3 Substituted C 1 -C 6 Alkylene or C 1 -C 6 An alkylene group;
L 5 is represented by one or more R 1-4 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radical, by one or more R 1-5 Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more R 1-6 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 1-7 Substituted "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S" or "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S";
R 1-3 independently of one another is halogen, hydroxy, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group;
R 1-4 、R 1-5 、R 1-6 and R 1-7 Independently halogen, hydroxy, cyano, NR 2-11 R 2-12 By one or more R 2-13 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl, by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 An alkoxy group;
R 11 is represented by one or more R 11-1 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radicals, substituted by one or more R 11-2 Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more R 11-3 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 11-4 Substituted "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", substituted with one or more R 11-5 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 An alkyl group;
R 11-5 independently by one or more R 11-1 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radicals, substituted by one or more R 11-2 Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more R 11-3 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 11-4 Substituted "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S" or "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S";
R 11-1 、R 11-2 、R 11-3 and R 11-4 Independently halogen, hydroxy, cyano, NR 2-11 R 2-12 By one or more R 2-13 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl, by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 An alkoxy group.
In a preferred embodiment of the present invention, some groups of the compounds represented by formula I or II or pharmaceutically acceptable salts thereof are defined as follows, and the groups which are not mentioned are as described in any of the embodiments (abbreviated as "in one embodiment of the present invention"),
when R is 1 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 Alkyl groups, such as methyl.
In one aspect of the invention, when R 1 Is C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl.
In one aspect of the invention, when R 8 And R 9 Independently is C 1 -C 4 When alkyl, said C 1 -C 4 Alkyl is CH 3 、C 2 H 5 iPr or n-Pr; such as CH 3 。
In one aspect of the invention, when R 8 And R 9 Independently is C 1 -C 4 At alkoxy, the C 1 -C 4 Alkoxy being OCH 3 Or OC 2 H 5 (ii) a For example OCH 3 。
In one embodiment of the present invention, when R 8 And R 9 Independently C substituted by one or more OH 1 -C 4 When alkyl, said C substituted by one or more OH 1 -C 4 Alkyl is CH 2 CH 2 OH。
In one embodiment of the present invention, when R 8 、R 9 Together with the carbon atom to which they are attached form C 3 -C 8 When a cycloalkyl group is said C 3 -C 8 Cycloalkyl being C 3 -C 6 Cycloalkyl groups, such as cyclopropyl.
In one aspect of the invention, when R 2 Is represented by one or more R 2-3 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group; such as cyclohexane.
In one aspect of the invention, when R 2 Is represented by one or more R 2-4 When the "substituted hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1 to 4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1 to 4 hetero atoms", the "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1 to 4 hetero atoms" is one or more selected from N and O, 3-6 membered heterocycloalkyl having 1 to 2 hetero atoms ", for example
Figure BDA0003481686850000041
Or
Figure BDA0003481686850000042
In one aspect of the invention, when R 2 Is represented by one or more R 2-5 Substituted C 6 -C 10 Aryl or C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl or
Figure BDA0003481686850000043
In one aspect of the invention, when R 2 Is represented by one or more R 2-6 Substituted "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" said "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" is "heteroatom is selected from one or more of N, O and S, 5-6 membered heteroaryl with 1-4 heteroatoms"; for example furan, thiophene or pyridine (e.g. furan, thiophene or pyridine)
Figure BDA0003481686850000051
)。
In one aspect of the invention, when R 2-1-1 Is represented by one or more R 2-7 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group; such as cyclohexane.
In one aspect of the invention, when R 2-1-1 Is represented by one or more R 2-8 When the substituted "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms", the "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms" is "hetero atom is one or more selected from N and O, 3-6 membered heterocycloalkyl having 1-2 hetero atoms".
In one aspect of the invention, when R 2-1-1 Is represented by one or more R 2-9 Substituted C 6 -C 10 Aryl or C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl or
Figure BDA0003481686850000052
In one aspect of the invention, when R 2-1-1 When the "hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl having 1 to 4 hetero atoms, or" hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl having 1 to 4 hetero atoms ", the" hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl having 1 to 4 hetero atoms ", the" hetero atom is one or more selected from N, O and S, and 5-6 membered heteroaryl having 1 to 4 hetero atoms "are substituted by one or more R2-10; for example furan, thiophene or pyridine (e.g. furan, thiophene or pyridine)
Figure BDA0003481686850000053
)。
In one aspect of the invention, when R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 、R 2-8 、R 2-9 And R 2-10 Independently by one or more R 2-13 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 Alkyl groups, such as methyl.
In one aspect of the invention, when R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 、R 2-8 、R 2-9 And R 2-10 Independently by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 At alkoxy, the C 1 -C 6 Alkoxy is C 1 -C 4 Alkoxy groups, such as methoxy.
In one aspect of the invention, when R 2-11 And R 2-12 Independently is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 Alkyl groups, such as methyl.
In one aspect of the invention, when R 2-2 Is represented by one or more R 2-15 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 Alkyl groups, such as methyl.
In one aspect of the invention, when R 1-1 And R 1-2 Independently C substituted by one or more halogens 1 -C 4 Alkyl or C 1 -C 4 When alkyl, said C 1 -C 4 Alkyl is methyl, ethyl or isopropyl.
In one embodiment of the invention, R 5 Is represented by one or more R 5-1 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group; such as methyl, ethyl, isopropyl or tert-butyl.
In one embodiment of the invention, R 5 Is represented by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 In the case of a cycloalkyl group,said C is 3 -C 8 Cycloalkyl being C 3 -C 6 Cycloalkyl radicals, e.g. cyclopropyl, cyclobutyl,
Figure BDA0003481686850000054
Or a cyclohexyl group.
In one embodiment of the invention, R 5 Is represented by one or more R 5-3 Substituted "heteroatom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from N, O and S", 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N and O ", 3-8 membered heterocycloalkyl with 1-2 heteroatoms; for example
Figure BDA0003481686850000061
Or
Figure BDA0003481686850000062
In one aspect of the invention, when R 5 Is represented by one or more R 5-4 When the substituted ' heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatom (S) ' or ' the heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatom (S) ', the ' heteroatom is selected from one or more of N, O and S, and the ' 5-12 membered heteroaryl with 1-4 heteroatom (S) ' is the ' the heteroatom is selected from one or more of N, O and S, and 5-6 membered heteroaryl with 1-4 heteroatom (S) '; for example furan, thiophene or pyridine (e.g. furan, thiophene or pyridine)
Figure BDA0003481686850000063
Or
Figure BDA0003481686850000064
)。
In one aspect of the invention, when R 5 Is represented by one or more R 5-5 Substituted C 6 -C 10 Aryl or C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl.
In one embodiment of the invention, R 5-1 Is represented by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl being C 3 -C 6 Cycloalkyl radicals, e.g. cyclopropyl, cyclobutyl,
Figure BDA0003481686850000065
Or a cyclohexyl group.
In one embodiment of the invention, R 5-1 Is represented by one or more R 5-3 Substituted "heteroatom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from N, O and S", 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N and O ", 3-8 membered heterocycloalkyl with 1-2 heteroatoms; for example, in
Figure BDA0003481686850000066
Or
Figure BDA0003481686850000067
In one embodiment of the present invention, when R 5-1 Is represented by one or more R 5-4 Substituted "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" said "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" is "heteroatom is selected from one or more of N, O and S, 5-6 membered heteroaryl with 1-4 heteroatoms"; such as furan, thiophene or pyridine (e.g. as
Figure BDA0003481686850000068
Or
Figure BDA0003481686850000069
)。
In one aspect of the invention, when R 5-1 Is represented by one or more R 5-5 Substituted C 6 -C 10 Aryl or C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl.
In one aspect of the invention, when R 5-2 、R 5-3 、R 5-4 And R 5-5 Independently is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group; such as methyl.
In one aspect of the invention, when R 5-2-1 And R 5-2-2 Independently is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group; such as methyl.
In one aspect of the invention, when R 5-2-3 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group; such as methyl.
In one aspect of the invention, when R 10 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group; such as methyl.
In one aspect of the present invention, when L 2 Is represented by one or more R 1-3 Substituted C 1 -C 6 Alkylene or C 1 -C 6 When alkylene, the C 1 -C 6 Alkylene being C 1 -C 4 Alkylene, for example methylene.
In one aspect of the present invention, when L 3 Is C 3 -C 8 When being cycloalkylene, said C 3 -C 8 Cycloalkylene being C 3 -C 6 A cycloalkylene group; such as cyclopropylene (e.g. cyclopropyl)
Figure BDA0003481686850000071
)。
In one aspect of the present invention, when L 3 When the "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkylene having 1-4 hetero atoms", the "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkylene having 1-4 hetero atoms" is one or more selected from N, O and S, 3-6 membered heterocycloalkylene having 1-2 hetero atoms ", for example, pyrrolidinylene (for example, pyrrolidinylene)
Figure BDA0003481686850000072
)。
In one aspect of the present invention, when L 4 Is represented by one or more R 1-3 Substituted C 1 -C 6 Alkylene or C 1 -C 6 When alkylene, the C 1 -C 6 Alkylene being C 1 -C 4 An alkylene group; such as methylene.
In one aspect of the present invention, when L 5 Is represented by one or more R 1-4 Substituted C 6 -C 10 Aryl or C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl.
In one aspect of the present invention, when L 5 Is represented by one or more R 1-5 The substituted "hetero atom is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" or "5-12 membered heteroaryl having 1-4 hetero atoms selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms", said "hetero atom is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" is "5-6 membered heteroaryl having 1-4 hetero atoms selected from one or more of N, O and S".
In one aspect of the present invention, when L 5 Is represented by one or more R 1-6 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group.
In bookIn one aspect of the invention, when L 5 Is represented by one or more R 1-7 When the substituted "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms", the "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms" is "hetero atom is one or more selected from N and O, 3-8 membered heterocycloalkyl having 1-2 hetero atoms".
In one aspect of the invention, when R 1-3 Independently is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group; such as methyl.
In one aspect of the invention, when R 1-3 Independently is C 1 -C 6 At alkoxy, the C 1 -C 6 Alkoxy is C 1 -C 4 An alkoxy group; such as methoxy.
In one aspect of the invention, when R 1-4 、R 1-5 、R 1-6 And R 1-7 Independently by one or more R 2-13 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group; such as methyl.
In one aspect of the invention, when R 1-4 、R 1-5 、R 1-6 And R 1-7 Independently by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 At alkoxy, the C 1 -C 6 Alkoxy is C 1 -C 4 An alkoxy group; such as methoxy.
In one aspect of the invention, when R 11 Is represented by one or more R 11-1 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl.
In one aspect of the invention, when R 11 Is one orPlural R 11-2 The substituted "hetero atom is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" or "5-12 membered heteroaryl having 1-4 hetero atoms selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms", said "hetero atom is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" is "5-6 membered heteroaryl having 1-4 hetero atoms selected from one or more of N, O and S".
In one aspect of the invention, when R 11 Is represented by one or more R 11-3 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is said C 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group.
In one aspect of the invention, when R 11 Is represented by one or more R 11-4 Substituted "heteroatom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from N, O and S", 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N and O ", 3-8 membered heterocycloalkyl with 1-2 heteroatoms; for example
Figure BDA0003481686850000081
In one aspect of the invention, when R 11 Is represented by one or more R 11-5 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group; such as methyl.
In one aspect of the invention, when R 11-5 Is represented by one or more R 11-1 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl.
In one aspect of the invention, when R 11-5 Is one orPlural R 11-2 The substituted "hetero atom is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" or "5-12 membered heteroaryl having 1-4 hetero atoms selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms", said "hetero atom is selected from one or more of N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" is "5-6 membered heteroaryl having 1-4 hetero atoms selected from one or more of N, O and S".
In one aspect of the invention, when R 11-5 Is represented by one or more R 11-3 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is said C 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group.
In one aspect of the invention, when R 11-5 Is represented by one or more R 11-4 Substituted "heteroatom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from N, O and S", 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N and O ", 3-8 membered heterocycloalkyl with 1-2 heteroatoms; for example
Figure BDA0003481686850000082
In one aspect of the invention, when R 11-1 、R 11-2 、R 11-3 And R 11-4 Independently by one or more R 2-13 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group; such as methyl.
In one aspect of the invention, when R 11-1 、R 11-2 、R 11-3 And R 11-4 Independently by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 At alkoxy radical, the C 1 -C 6 Alkoxy is C 1 -C 4 An alkoxy group; such as methoxy.
In one embodiment of the invention, W is NH.
In one embodiment of the present invention, X 2 Is CH.
In one embodiment of the invention, R 1 Is H or C 1 -C 6 An alkyl group; preferably H or methyl; further preferably H.
In one embodiment of the present invention, R 4 、R 6 And R 7 Independently is H.
In one embodiment of the invention, R 8 And R 9 Independently is H or C 1 -C 4 An alkyl group; or, R 8 、R 9 Together with the carbon atom to which they are attached form C 3 -C 8 A cycloalkyl group; preferably, R 8 And R 9 Independently is H or methyl, or R 8 、R 9 Together with the carbon atom to which they are attached form a cyclopropyl group; more preferably, R 8 And R 9 Independently a methyl group.
In one embodiment of the present invention, R 2 is-CHR 2-1 R 2-2 By one or more R 2-5 Substituted C 6 -C 10 Aryl radicals, substituted by one or more R 2-3 Substituted C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 2-4 Substituted "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S" or "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S"; preferably-CHR 2-1 R 2-2 (ii) a Further preferred is
Figure BDA0003481686850000091
Figure BDA0003481686850000092
Or
Figure BDA0003481686850000093
With the carbon atom being chiral, isS configuration and/or R configuration.
In one embodiment of the invention, n is 0 or 1.
In one embodiment of the invention, R 2-1-1 Is represented by one or more R 2-9 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radicals, substituted by one or more R 2-10 Substituted "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S" or "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S"; preferably phenyl, benzyl or pyridyl.
In one embodiment of the invention, R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 、R 2-8 、R 2-9 And R 2-10 Independently halogen or hydroxy.
In one embodiment of the invention, R 2-2 Is H or substituted by one or more R 2-15 Substituted C 1 -C 6 An alkyl group.
In one embodiment of the invention, R 2-15 Independently a hydroxyl group or an amino group.
In one embodiment of the invention, R 1-1 And R 1-2 Independently methyl, ethyl, isopropyl or chloro.
In one aspect of the invention, Z 1 Is O.
In one aspect of the invention, Z 2 Is N.
In one aspect of the invention, Z 3 Is O.
In one embodiment of the invention, R 5 Is represented by one or more R 5-1 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl, by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 5-3 The substituted heteroatom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms, and one or more of N, O and S, 3-12 membered heterocycle with 1-4 heteroatomsAlkyl or 5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S; preferably methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl,
Figure BDA0003481686850000101
Figure BDA0003481686850000102
Figure BDA0003481686850000103
Or
Figure BDA0003481686850000104
In one embodiment of the invention, R 5-1 Independently by one or more R 5-3 The substituted 'hetero atom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms', 'hetero atom is selected from one or more of N, O and S, and 3-12 membered heterocycloalkyl having 1-4 hetero atoms'.
In one embodiment of the invention, R 5-2 、R 5-3 、R 5-4 And R 5-5 Independently of one another halogen, hydroxy, NR 5-2-1 R 5-2-2 、C 1 -C 6 Alkyl or-C (═ O) R 5-2-3 。
In one aspect of the invention, L 1 Is NH.
In one aspect of the invention, L 2 Is a covalent bond or C 1 -C 6 Alkylene, preferably covalent or methylene.
In one aspect of the invention, L 3 Is C 3 -C 8 Cycloalkylene or "3-12 membered heterocycloalkylene with 1-4 heteroatoms selected from one or more of N, O and S"; preference is given to
Figure BDA0003481686850000105
Or
Figure BDA0003481686850000106
In one aspect of the invention, L 4 Is C 1 -C 6 An alkylene group; methylene is preferred.
In one aspect of the invention, L 5 Is C 6 -C 10 Aryl, or "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S"; preferably phenyl or
Figure BDA0003481686850000107
In one embodiment of the present invention, -C (═ O) -L 1 -L 2 -L 3 -L 4 -L 5 Is composed of
Figure BDA0003481686850000108
Or
Figure BDA0003481686850000109
In one embodiment of the invention, R 3 Is composed of
Figure BDA0003481686850000111
In one aspect of the present invention, the first and second electrodes are,
Figure BDA0003481686850000112
is composed of
Figure BDA0003481686850000113
Figure BDA0003481686850000114
Figure BDA0003481686850000115
Or
Figure BDA0003481686850000116
In one embodiment of the invention, R 11 Is "heteroatom is selected from one or more of N, O and S3-12 membered heterocycloalkyl having 1-4 hetero atoms 1 -C 6 An alkyl group; preferably methyl or
Figure BDA0003481686850000117
In the present invention, the compound represented by formula I may be any of the following compounds:
Figure BDA0003481686850000121
Figure BDA0003481686850000131
Figure BDA0003481686850000141
in the present invention, the compound represented by formula II may be any of the following compounds:
Figure BDA0003481686850000142
the invention also provides a pharmaceutical composition which comprises the compound shown as the formula I or pharmaceutically acceptable salt thereof and pharmaceutic adjuvants.
The invention also provides the application of the compound shown as the formula I or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicaments. Preferably, the medicament is used for preventing and/or treating related diseases mediated by HPK1, including but not limited to non-small cell lung cancer, squamous cell carcinoma, head and neck cancer, oral cancer, pharyngeal cancer, thyroid cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, liver cancer, colon cancer, rectal cancer, villous adenoma in large intestine, breast cancer, ductal carcinoma of breast, ovarian cancer, peritoneal cancer, endometrial cancer, uterine corpus cancer, cervical cancer, kidney cancer, renal pelvis cancer, prostate cancer, bladder cancer, neurofibromatosis, bone cancer, brain cancer, testicular cancer, glioma, skin cancer, melanoma, cytoma and sarcoma, multiple myeloma, leukemia, non-Hodgkin's lymphoma, myelodysplastic syndrome.
Unless otherwise defined, the terms used in the present invention have the following meanings:
it will be appreciated by those skilled in the art that, in accordance with common practice used in the art, the present invention describes the structural formulae used in the structural formulae of the radicals
Figure BDA0003481686850000151
Means that the corresponding group is linked to other fragments, groups in the compound through this site.
As used herein, the terms preceded and/or followed by a single dash "-", or double dash "═ indicates the bond sequence of the bond between the named substituent and the parent moiety; single dashes represent single bonds and double dashes represent double bonds. In the absence of a single dash or double dash, it is believed that a single bond is formed between the substituent and its parent moiety; further, substituents are read "left to right" unless otherwise indicated. For example,
Figure BDA0003481686850000152
indicates the left side and L 2 Connected with the right side and L 4 Are connected.
The term "plurality" means 2,3, 4 or 5, preferably 2 or 3.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Further, when the group is substituted with 1 or more of the substituents described above, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for use by the patient. The "patient" is preferably a mammal, more preferably a human.
The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19(1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camile G.Wermuth, ed., Wiley-VCH, 2002).
The terms "compound" and "pharmaceutically acceptable salt" if present as tautomers, may be present as single tautomers or mixtures thereof, preferably as more stable tautomers.
The atoms in the terms "compound" and "pharmaceutically acceptable salt" may be present in their natural or unnatural abundance. In the case of hydrogen atoms, in its natural abundance, it is understood that about 99.985% is protium and about 0.015% is deuterium; in its unnatural abundance, it is meant that about 95% thereof is deuterium. That is, one or more atoms in the terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt" can be an atom that is present in a non-natural abundance.
The term "halogen" is chosen from F, Cl, Br or I, especially F or Cl.
The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
The term "alkylene" denotes a saturated straight or branched chain alkane as a subunit consisting of two monovalent or one divalent atoms or groups which are formally eliminated. The two valencies may be on the same carbon atom or on different carbon atoms (e.g., the two valencies are on the carbon atoms at each end). For example, the methylene group may be (-CH) 2 -, the ethylene radical may be-CH 2 CH 2 -or-CH (CH) 3 )-。
The term "alkoxy" refers to the group-O-R X Wherein R is X Is an alkyl group as defined above.
The term "cycloalkyl" means a saturated mono-or polycyclic substituent consisting only of carbon and hydrogen atoms, and which may be attached to the rest of the molecule by a single bond via any suitable carbon atom; when polycyclic, they may be joined together orBridged ring systems or spiro ring systems in which the spiro ring is attached (i.e. the two geminal hydrogens on the carbon atom are replaced by an alkylene group). The cycloalkyl substituents may be attached to the central molecule via any suitable carbon atom. In some embodiments, a ring having 3 to 8 carbon atoms may be represented as C 3 -C 8 A cycloalkyl group. In some embodiments, C 3 ～C 6 Cycloalkyl groups of (C) include cyclopropyl (C) 3 ) Cyclobutyl (C) 4 ) Cyclopentyl (C) 5 ) Bicyclo [1.1.1]Pentane (C) 5 ) And cyclohexyl (C) 6 )。
The term "cycloalkylene" denotes a subunit of a saturated monocyclic or polycyclic cycloalkane consisting of carbon and hydrogen atoms formally eliminating two monovalent or one divalent atoms or groups; when polycyclic, it may be a bridged ring system or a spiro ring system, which is a bicyclic or spiro ring linkage (i.e., two geminal hydrogens on a carbon atom are replaced with an alkylene group). The two valencies may be on the same carbon atom or on different carbon atoms. For example, the cyclopropylene group may be
Figure BDA0003481686850000161
Or
Figure BDA0003481686850000162
The term "heterocycloalkyl" means a stable 3-to 12-membered saturated monocyclic or polycyclic cyclic group consisting of 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur; when polycyclic, it may be a bridged or spiro ring system, whether annulated or spiro connected. Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, and thietanyl, or stereoisomers thereof; exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, or isomers and stereoisomers thereof; exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiafuranyl, dithiofuranyl, or isomers and stereoisomers thereof. Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, sulfocyclopentanyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or isomers and stereoisomers thereof; exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepinyl, thiepanyl, and diazepanyl, or isomers and stereoisomers thereof.
The term "heterocycloalkylene" denotes an subunit of a stable 3-to 12-membered saturated monocyclic or polycyclic heterocycle consisting of 1-4 heteroatoms selected from nitrogen, oxygen and sulfur formally eliminating two monovalent or one divalent atoms or group; when polycyclic, it may be a bridged or spiro ring system, whether annulated or spiro connected. The two valencies may be on the same atom or on different atoms. For example, the pyrrolidine may be
Figure BDA0003481686850000163
Or
Figure BDA0003481686850000164
The term "aryl" refers to an aromatic monocyclic or polycyclic ring having 6 to 10 ring atoms and having zero heteroatoms, and when bicyclic, at least one ring having aromatic character, e.g., phenyl, naphthyl, or
Figure BDA0003481686850000171
The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably an aromatic 5-6 membered monocyclic or 9-10 membered bicyclic ring containing 1, 2 or 3 members independently selected from nitrogen, oxygen and sulfur, when bicyclic, at least one ring is aromatic, e.g., furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl and the like.
The term "pharmaceutical excipient" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and is intended to include all substances in a pharmaceutical formulation, except for the active ingredient. See the pharmacopoeia of the people's republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition).
The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: (1) relieving one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade that causes or contributes to a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of a disorder or disorder.
The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.
The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as desired by one of skill in the art.
The term "patient" refers to any animal, preferably a mammal, most preferably a human, who is about to, or has received administration of the compound or composition according to the embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the invention provides a HPK1 inhibitor which has better activity and novel structure.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 Synthesis of Compound I-1
Figure BDA0003481686850000181
Compound SM1(100.00mg,0.21mmol,1.00equiv), SM2(200mg,1.18mmol,5.6equiv) and 400mg of 4A molecular sieve were placed in a reaction flask and absolute ethanol (5mL) was added. The reaction flask was purged with nitrogen, stirred at room temperature for 30 minutes, and then sodium ethoxide (57mg,0.84mmol,4equiv) was added. The reaction was stirred at 90 ℃ overnight. The reaction was cooled to room temperature, concentrated and the crude product was purified on a thin layer chromatography plate using dichloromethane/methanol as eluent. The resulting product was purified by Prep-HPLC (Column: Xbridge Prep Phenyl OBD Column, 19X 250mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is MeOH Preparative; the flow rate is 25 mL/min; gradient from 70% B to 95% B in8min, 95% B; the wavelength is 254/220 nm; RT1(min):7.32) to give compound I-1(10.4mg) as a white solid ms (esi) m/z 580; 1 H NMR(400MHz,CD 3 OD-d4):δ8.71(s,1H),7.73(t,J＝1.8Hz,1H),7.55(dt,J＝8.4,0.7Hz,1H),7.48–7.36(m,3H),7.36–7.28(m,1H),7.19(dt,J＝8.3,1.7Hz,1H),5.99(d,J＝2.3Hz,1H),4.77–4.60(m,1H),3.99(ddd,J＝11.0,4.2,2.4Hz,1H),3.81(dt,J＝11.1,6.9Hz,1H),3.53–3.43(m,2H),3.40–3.35(m,1H),3.09(d,J＝11.8Hz,1H),3.06–2.94(m,5H),2.95–2.86(m,1H),2.35–2.23(m,1H),1.87(tdd,J＝17.9,8.7,3.9Hz,3H),1.60(d,J＝12.2Hz,1H),1.49(d,J＝7.7Hz,6H),1.31(t,J＝5.9Hz,1H).
EXAMPLE 2 Synthesis of Compound I-2
Figure BDA0003481686850000182
Compounds SM1(100mg,0.33mmol,1.00equiv), SM2(60mg,0.33mmol,1.00equiv), XantPhos (20mg,0.033mmol,0.1equiv), Pd 2 (dba) 3 (31mg,0.033mmol,0.1equiv) and potassium phosphate (208mg,0.98mmol,3.0equiv) were placed in a reaction flask and 1, 4-dioxane (5mL) was added and the reaction mixture was stirred under nitrogen at 100 ℃ for 16 hours. After the reaction was completed, the reaction system was cooled to room temperature, filtered through celite, and the crude product after concentration of the filtrate was purified by a silica gel column to give compound 1(40mg, yield 29.2%). ms (esi): m/z ═ 462 as a yellow solid.
Mixing compound 1(40mg,0.09mmol,1.0equiv), SM3(48mg,0.45mmol,5.0equiv), 100mg
Figure BDA0003481686850000183
The molecular sieve was placed in a reaction flask and absolute ethanol (2mL) was added, nitrogen was exchanged in the reaction flask, and stirring was carried out at room temperature for 30 minutes, then sodium ethoxide (24.5mg,0.36mmol,4.0equiv) was added, and the reaction system was stirred at 90 ℃ overnight. After the reaction was complete, the reaction was cooled to room temperature, filtered through celite, and the filtrate was concentrated to give a crude product which was prepared under high pressure (Column: Xbridge Shield RP18 OBD Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 47% B to 62% B in8min, 62% B; 254, wavelength; 220nm) to yield compound I-2 as a white solid (5.9mg, 12.5% yield). ms (esi) m/z 526.
1 H NMR(400MHz,DMSO-d 6 )δ10.32(s,1H),8.86(d,J＝7.2Hz,1H),8.66(s,1H),7.86(d,J＝8.5Hz,1H),7.52–7.43(m,2H),7.38-7.33(m,4H),7.28-7.25(m,1H),5.20(t,J＝4.9Hz,1H),4.73(q,J＝4.7Hz,1H),3.93(dt,J＝9.5,4.4Hz,1H),3.75(dt,J＝10.5,5.1Hz,1H),2.92(s,3H),1.51(s,3H),1.45(s,3H),1.35(dd,J＝9.3,3.4Hz,1H),1.27(d,J＝3.1Hz,1H),1.24(s,3H),0.98(d,J＝3.2Hz,2H).
EXAMPLE 3 Synthesis of Compound I-3
Figure BDA0003481686850000191
Dissolving compound 1(100mg,0.223mmol,1.00eq) and compound SM1(76.81mg,0.436mmol,1.95equiv), DIEA (112.64mg,0.872mmol,3.90equiv) in anhydrous DMF (2mL), adding HATU (123.20mg,0.324mmol,1.45equiv) to the reaction solution under ice bath, moving the reaction solution to room temperature, stirring overnight at room temperature under nitrogen protection, filtering the reaction solution, and purifying by high pressure preparation (Column: YMC-Actus Triart C18, 30: 150mm,5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient from 50% B to 65% B in8min, 65% B; the wavelength is 254/220 nm; RT1(min): 6.85; ) Compound I-3(51.4mg) was obtained as a white solid. Ms (esi) m/z 606; 1 H NMR(400MHz,CD 3 OD-d 4 ):δ8.48(s,1H),7.79(s,1H),7.68–7.55(m,2H),7.53–7.30(m,8H),7.31–7.23(m,2H),5.40–5.34(m,1H),4.51-4.44(m,1H),3.97–3.89(m,1H),3.87(ddd,J＝11.1,6.4,1.3Hz,1H),3.77–3.62(m,2H),3.04(s,3H),2.96–2.89(m,1H),2.83(d,J＝8.8Hz,1H),2.68–2.55(m,2H),2.46-2.37(m,1H),1.85-1.80(m,1H),1.37(s,3H),1.35(s,3H).
EXAMPLE 4 Synthesis of Compound I-4
Figure BDA0003481686850000192
Compound SM1(59.34mg,0.349mmol,1.95equiv), Compound 1(80mg,0.179mmol,1.00equiv), N, N-diisopropylethylamine (69.27mg,0.537mmol,3.90equiv) and HATU (98.6mg,0.26mmol,1.45equiv) were dissolved in DMF (2 mL). The reaction was stirred at room temperature for 16 hours under nitrogen. After the reaction, the reaction mixture was concentrated and purified by high pressure preparative purification (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 31% B to 51% B in8min, 51% B; a wavelength of 254; 220nm) to give Compound I-4(6.7mg) as a white solid MS (ES)I):m/z＝600. 1 H NMR(400MHz,CD 3 OD-d 4 ):δ8.37(s,1H),7.69(s,1H),7.48-7.53(m,2H),7.25-7.32(m,4H),7.15-7.18(m,1H),5.28(dd,J＝6.0Hz,1.2Hz,1H),3.82-3.86(m,1H),3.74-3.78(m,2H),3.62(t,J＝4.8Hz,4H),3.32(d,J＝4.8Jz,2H),2.92(s,3H),2.45-2.49(m,3H),2.30(s,2H),1.38(s,3H),1.36(s,3H),0.53(t,J＝4.8Hz,2H),0.32(t,J＝4.8Hz,2H).
EXAMPLE 5 Synthesis of Compounds I-5
Figure BDA0003481686850000201
Dissolving compound 1(100mg,0.210mmol,1.00eq) and compound SM1(77.95mg,1.050mmol,5.00equiv), sodium ethoxide (100.00mg) in absolute ethyl alcohol (2mL), stirring the reaction system at room temperature for 20 minutes under the protection of nitrogen, adding an absolute ethyl alcohol solution of sodium ethoxide into the reaction solution, stirring the reaction solution at 70 ℃ overnight, filtering the reaction solution, preparing and purifying the reaction solution under high pressure, and freeze-drying the purified reaction solution to obtain a white solid compound I-5(13.4 mg). Ms (esi) m/z 486; 1 H NMR(400MHz,CD3OD-d 4 ):δ8.78(s,1H),7.80(s,1H),7.69–7.61(m,2H),7.47–7.38(m,4H),7.30(t,J＝7.1Hz,1H),5.76–5.29(m,1H),4.04(dd,J＝11.3,4.4Hz,1H),3.95(dd,J＝11.3,6.1Hz,1H),3.05(s,3H),2.49(d,J＝0.7Hz,3H),1.49(d,J＝9.3Hz,6H).
EXAMPLE 6 Synthesis of Compound I-6
Figure BDA0003481686850000202
Compound 1(100.00mg,0.210mmol), compound SM1(167.37mg,1.050mmol), and 4A molecular sieve (300.00mg) were mixed and stirred in 3mL of absolute ethanol, stirred at room temperature for 20 minutes under nitrogen protection, sodium ethoxide (57.24mg,0.841mmol) was added, and the reaction was left to stand at 90 ℃ and stirred overnight. After the reaction was completed, the reaction solution was concentrated and purified by a silica gel column to obtain a crude product, which was then purified by high pressure preparation and freeze-dried to obtain compound I-6(18.2mg) as a white solid. Ms (esi) m/z 571; 1 H NMR(400MHz,CD 3 OD-d 4 ):δ8.68(s,1H),7.71(s,1H),7.50-7.56(m,2H),7.27-7.36(m,4H),7.16-7.20(m,1H),5.39(t,J＝5.2Hz,1H),3.83-3.95(m,2H),3.74(s,2H),3.63(t,J＝4.8Hz,4H),2.93(s,3H),2.61(t,J＝4.8Hz,4H),1.38(s,3H),1.36(s,3H).
EXAMPLE 7 Synthesis of Compounds I-7
Figure BDA0003481686850000211
Mixing compound 1(100mg,0.36mmol,1.00equiv), SM1(60mg,0.36mmol,1.0equiv), XantPhos (21mg,0.036mmol,0.1equiv), Pd 2 (dba) 3 (33mg,0.036mmol,0.1equiv) and potassium phosphate (230mg,1.08mmol,3.0equiv) were dissolved in 1, 4-dioxane (5mL) and the reaction mixture was stirred at 100 ℃ for 16 h. After the reaction was completed, the reaction system was cooled to room temperature, filtered through celite, and the crude product obtained by concentrating the filtrate was purified by a silica gel column to obtain compound 2(44mg, yield 29.3%). ms (esi): m/z ═ 433 as a yellow solid.
Compound 2(44mg,0.102mmol,1.0equiv), SM2(86.3mg,0.51mmol,5.0equiv), 100mg of 4A molecular sieves were placed in a sealed tube, absolute ethanol (2mL) was added, nitrogen gas was replaced, stirring was performed at normal temperature for 30 minutes, then sodium ethoxide (27.77mg,0.408mmol,4.00equiv) was added to the sealed tube, nitrogen gas was replaced, and the reaction flask was left to stand at 90 ℃ and stirred overnight. After the reaction was completed, the reaction system was cooled to room temperature, filtered through celite, and the filtrate was concentrated to give a crude product which was prepared under high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 22% B to 52% B in8min, 52% B; 254, wavelength; 220nm) to yield compound I-7 as a white solid (2.4mg, 4.3%). ms (esi) m/z 552. 1 H NMR(400MHz,DMSO-d 6 )δ10.45(s,1H),8.79–8.57(m,2H),8.54–8.35(m,2H),7.89(d,J＝8.5Hz,1H),7.76(d,J＝6.2Hz,2H),7.52–7.31(m,2H),4.75(d,J＝5.8Hz,2H),2.91(d,J＝10.3Hz,9H),1.84(t,J＝7.8Hz,6H),1.23(d,J＝6.5Hz,6H).
EXAMPLE 8 Synthesis of Compounds I-8
Figure BDA0003481686850000212
5-bromo-2, 3-isoindoline-1-one SM1(6g,28.3mmol,1.00equiv) was dissolved in a mixed solvent of tetrahydrofuran (100mL)/N, N-dimethylformamide (40mL) under nitrogen, and a solution of sodium hydride (1.36g,56.59mmol,2.00equiv) and tetrabutylammonium iodide (1.05g,28.3mmol,1.00equiv) in tetrahydrofuran (200mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and 4-methoxybenzyl chloride (4.43g,28.3mmol,1.00equiv) was added thereto, and stirring was continued at room temperature for 12 hours. After the reaction was completed, the reaction solution was quenched with 100mL of ice water, extracted with ethyl acetate (2 × 300mL), the combined organic phases were dried over anhydrous sodium sulfate, and the crude product after concentration was purified by column chromatography to obtain 14.5 g (yield 47.87%) of a brown solid compound ms (esi): m/z 333.
Sodium hydride (541.80mg,0.024mmol,3.00equiv) was added in portions to a tetrahydrofuran/N, N-dimethylformamide (20/60mL) mixed solvent of compound 1(2.50g,7.526mmol,1.00equiv) under nitrogen, the reaction system was stirred at room temperature for 2 hours, iodomethane (1.07g,75.3mmol,10.00equiv) was added, the reaction system was warmed to 70 ℃ and stirred for 16 hours, the temperature was reduced, the reaction liquid was quenched with 100mL of ice water, ethyl acetate (3 × 200mL) was extracted, the combined organic phases were dried over anhydrous sodium sulfate, and the concentrated crude product was purified by column chromatography to give compound 21.4 g, ms esi: (m/z 361).
Compound 2(1.4g,3.886mmol,1.00equiv), tert-butyl carbamate (2.28g,19.43mmol,5equiv), cesium carbonate (3.8g,11.7mmol,3equiv), palladium acetate (90mg,0.38mmol,0.1equiv), XantPhos (220mg,0.76mmol,0.2equiv) were dissolved in 1, 4-dioxane (20.00mL) in a 40mL sealed tube, the reaction mixture was stirred under nitrogen at 100 ℃ for 18 hours, filtered, the filtrate was concentrated and purified to give compound 3(1.1g), ms (esi): m/z ═ 397.
In a 20mL reaction flask, a solution of cerium ammonium nitrate (2.00g,3.635mmol,2.88equiv) in water (5mL), compound 3(0.50g,1.261mmol,1.00equiv) and acetonitrile (10mL) were added, the reaction was stirred at room temperature for 2 hours, the reaction was concentrated, extracted with ethyl acetate (2 × 20mL), and the combined organic phases were dried by spin column chromatography to give 4100 mg (yield 28.70%) of a yellow solid compound, ms (esi): m/z 277.
In a 100mL reaction flask, compound 4(260mg, 0.94mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (20.00mL), and the reaction mixture was stirred at room temperature for 12 hours under nitrogen atmosphere and spin-dried to give 5200 mg, ms (esi): m/z ═ 177 as a yellow solid.
In a 20mL stopcock, Compound SM2(150.00mg,0.489mmol,1.00equiv), Compound 5(200mg), Pd 2 (dba) 3 (44.78mg,0.05mmol,0.10equiv), xanthphos (28.29mg,0.05mmol,0.10equiv), potassium phosphate (311.39mg,1.47mmol,3.00equiv) were dissolved in 1, 4-dioxane (5mL), the reaction mixture was stirred at 100 ℃ for 16 hours under nitrogen protection, the reaction was concentrated and purified by column chromatography to give 6150 mg as a brown solid, ms (esi): m/z: 447.
In a 20mL reaction flask, compound 6(150mg,0.336mmol), SM3(300mg), 4A molecular sieve (500mg) and absolute ethanol (3mL) were stirred for 1 hour, sodium ethoxide (160mg) was added, the reaction was stirred at 85 ℃ for 16 hours, the reaction was concentrated, and the crude product was prepared by high pressure reverse phase (Column: XSelect CSH Prep C18 OBD Column, 19: 250mm,5 um; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 25 mL/min; gradient 40B to 62B in 10min,62B to B in min, B to B in min, B to B in min, B to B in min; 254/220nm) to give compound I-8(5.3mg) as a white solid, ms (esi) 566 m/z. 1 H NMR(300MHz,CD 3 OD-d 4 ):δ(ppm)8.69(s,1H),7.67(d,J＝1.8Hz,1H),7.53(d,J＝8.4Hz,1H),7.27–7.48(m,5H),7.04–7.23(m,1H),5.98(d,J＝1.7Hz,1H),4.69(d,J＝6.1Hz,1H),3.91–4.04(m,1H),3.80(dt,J＝11.3,6.0Hz,1H),3.46(d,J＝5.5Hz,1H),3.09(s,1H),2.96(q,J＝15.3,11.6Hz,3H),2.27(s,1H),1.85(d,J＝18.2Hz,3H),1.52(d,J＝5.6Hz,7H),1.30(d,J＝3.1Hz,2H).
EXAMPLE 9 Synthesis of Compounds I-9
Figure BDA0003481686850000231
Lithium hydroxide (28.02mg,1.170mmol,2.00equiv) was added to a mixed solution of compound 1(270.00mg,0.585mmol,1.00equiv) in tetrahydrofuran (6mL) and water (3mL), and stirred at room temperature for two hours. After the reaction was completed, the reaction system was adjusted to pH 6 with 2mol/L hydrochloric acid solution, followed by extraction with ethyl acetate, and the extract was concentrated under reduced pressure to give crude compound 2(80mg) as a white solid. MS (ESI): m/z 434.
Compound 2(80.00mg,0.185mmol,1.00equiv), compound SM1(63.43mg,0.360mmol,1.95equiv), N-diisopropylethylamine (93.03mg,0.720mmol,3.90equiv) and HATU (101.75mg,0.268mmol,1.45equiv) were dissolved in DMF (2mL) and the reaction mixture was stirred at rt for 16 h. The reaction was filtered and purified by high pressure preparative purification (Column: Xbridge Shield RP18 OBD Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 35% B to 47% B in8min, 47% B; 254, wavelength; 220nm) to give compound I-9(3.4mg) as a white solid. Ms (esi) 592/z; 1 H NMR(400MHz,DMSO-d 6 ):δ9.84(s,1H),9.70-9.74(m,1H),8.64(s,1H),8.50–8.15(m,1H),7.89(s,1H),7.63–7.48(m,1H),7.47–7.22(m,10H),5.29(p,J＝4.9Hz,1H),5.11(q,J＝3.3,2.1Hz,1H),4.38(s,1H),3.87–3.69(m,3H),3.60(s,3H),2.82(t,J＝8.4Hz,1H),2.70–2.58(m,2H),2.28(d,J＝7.3Hz,1H),2.21–2.07(m,1H),1.86–1.72(m,1H),1.40(s,3H),1.36(s,3H).
EXAMPLE 10 Synthesis of Compounds I-10
Figure BDA0003481686850000232
Compound 1(40.0mg,0.092mmol,1.00equiv), compound SM1(43.6mg,0.256mmol,1.95equiv), N, N-diisopropylethylamine (46.3mg,0.359mmol,3.90equiv) and HATU (51.5mg,0.136mmol,1.45equiv) were dissolved in DMF (2mL), and the reaction was stirred at ambient temperature under nitrogen for 16 hours. After the reaction was complete, the reaction was purified by high pressure preparative purification (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 28% B to 48% B in8min, 48% B; 254, wavelength; 220 nm; ) Compound I-10(4.6mg) was obtained as a white solid. Ms (esi) m/z 586; 1 H NMR(400MHz,DMSO-d 6 ):δ9.92(s,1H),9.68(s,1H),8.58(s,1H),8.39(s 1H),7.85(d,J＝8.0Hz,1H),7.58(d,J＝8.0Hz,1H),7.39-7.42(m,5H),7.26(s，1H)，5.28(s，1H)，5.11(s，1H)，3.90-3.95(m，1H)，3.56-3.59(m，5H)，3.51-3.55(m，5H)，3.05-3.11(m，1H)，2.31-2.33(m,2H),1.52-1.55(m,1H),1.38(s,3H),1.35(s,3H),0.83-0.85(m,3H).
EXAMPLE 11 Synthesis of Compounds I-11
Figure BDA0003481686850000241
Compound 1(100.00mg,0.217mmol,1.00equiv), SM1(65mg,0.878mmol,4.0equiv) was added to a 20mL sealed tube, dissolved in 6mL absolute ethanol, and 400mg of 4A molecular sieves was added, replaced with nitrogen and resealed. After stirring at room temperature for half an hour, sodium ethoxide (74mg,1.083mmol,5.00equiv) was added and allowed to react at 90 ℃ for two hours. After the reaction was completed, a layer of diatomaceous earth was spread on a sand core funnel, filtered, the filtrate was collected, spun-dried, and the crude product was prepared under high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 26% B to 46% B in8min, 46% B; 254, wavelength; 220nm) to yield 12.7mg (98.5%) of a white solid. MS (ESI): m/z 472. 1 H NMR(400MHz,DMSO-d 6 ):δ10.17(s,1H),9.00(d,J＝7.6Hz,1H),8.79(s,1H),8.45(s,1H),7.85(s,1H),7.62(d,J＝8.0Hz,1H),7.46-7.31(m,5H),7.28–7.25(m,1H),5.42(s,1H),5.23(s,1H),3.92–3.78(m,2H),2.45(s,3H),1.40(s,3H),1.36(s,3H).
EXAMPLE 12 Synthesis of Compounds I-12
Figure BDA0003481686850000242
Compound 1(150mg,0.325mmol,1.00equiv), SM1(206.95mg,1.3mmol,4.00equiv) was added to a 20mL sealed tube and dissolved in 6mL of absolute ethanol, 400mg of 4A molecular sieve was added, the nitrogen gas was replaced, and the tube was sealed. After stirring at room temperature for half an hour, sodium ethoxide (110.6mg,1.625mmol,5.00equiv) was added and allowed to react at 90 ℃ for two hours. After the reaction was complete, a layer of diatomaceous earth was placed in a sand core funnel, filtered, the filtrate collected, spun dry, and the crude product prepared under high pressure (Column: X Bridge Shield RP18 OBD Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 30% B to 40% B in8min, 40% B; 254, wavelength; 220nm) to yield 10mg (98.9%) of a white solid. MS (ESI): m/z 557. 1 H NMR(400MHz,DMSO-d 6 ):δ10.21(s,1H),9.05(d,J＝7.9Hz,1H),8.81(s,1H),8.47(s,1H),7.91(s,1H),7.63(d,J＝8.0Hz,1H),7.49-7.35(m,4H),7.30-7.26(m,2H),5.43(dt,J＝8.8,4.8Hz,1H),5.20(d,J＝4.8Hz,1H),3.91(dt,J＝9.4,4.4Hz,1H),3.87–3.72(m,3H),3.59(t,J＝4.5Hz,4H),2.61(t,J＝4.6Hz,4H),1.42(s,3H),1.39(s,3H).
EXAMPLE 13 Synthesis of Compounds I-13
Figure BDA0003481686850000251
Compound 1(100mg,0.239mmol), compound SM1(202.2mg,1.195mmol), 400mg of 4A molecular sieve were placed in a reaction flask and absolute ethanol (5mL) was added. After stirring at room temperature for 30 minutes under nitrogen, sodium ethoxide (65.05mg,0.956mmol) was added to the reaction flask, the nitrogen was replaced, and the reaction was left to stir at 90 ℃ overnight. Cooling the reaction system to room temperature, and then carrying out column chromatography purification by using dichloromethane/methanol eluent to obtain a crude product. The crude product was further purified by reverse phase preparative liquid phase (Column: Xbridge Prep OBD C18 Column,30 x 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 15% B to 40% B in8min, 40% B) gave compound I-13 as a white solid (1 mg). Ms (esi) m/z 538; 1 H NMR(400MHz,DMSO-d6):δ10.41(s,1H),8.70(s,1H),8.63(s,1H),8.51-8.52(m,1H),8.46-8.48(m,2H),7.84(d,J＝8.0Hz,1H),7.75-7.77(m,2H),7.47-7.48(m,1H),7.40-7.41(m,1H),4.73(d,J＝5.2Hz,2H),2.86(t,J＝8.0Hz,6H),1.80-1.82(m 6H),1.25(s,6H).
EXAMPLE 14 Synthesis of Compounds I-14
Figure BDA0003481686850000252
Compound 1(73.00mg,0.163mmol), compound SM1(93.1mg,0.815mmol), 300mg of 4A molecular sieve were placed in a reaction flask and absolute ethanol (5mL) was added. The reaction mixture was stirred at room temperature under nitrogen for 30 minutes, then sodium ethoxide (44.4mg,0.652mmol) was added. The reaction was stirred at 90 ℃ overnight. After cooling the reaction system to room temperature, the crude product is obtained by column chromatography purification with dichloromethane/methanol. The crude product was then subjected to reverse phase to prepare a liquid phase (Column: Xbridge Prep OBD C18 Column,30 x 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 ) The mobile phase B is ACN; the flow rate is 60 mL/min; gradient 35% B to 60% B in8min, 60% B) to give compound I-14 as a white solid (4.1 mg). Ms (esi) m/z 512; 1 H NMR(400MHz,DMSO-d 6 ):δ10.28(s,1H),8.83-8.84(d,J＝7.2Hz,1H),8.66(s,1H),8.48(s,1H),7.82(d,J＝8.4Hz,1H),7.48-7.50(m,1H),7.37(s,1H),7.34-7.35(m,4H),7.26-7.28(m,1H),5.18(t,J＝4.8Hz,1H),4.71(d,J＝6.8Hz,1H),3.90-3.94(m,1H),3.72-3.77(m,1H),1.52(s,3H),1.45(s,3H),1.33-1.35(m,1H),1.24-1.26(m,4H),0.97-1.00(m,2H).
EXAMPLE 15 Synthesis of Compounds I-15
Figure BDA0003481686850000261
Compound 1(100.00mg,0.217mmol,1.00equiv) and SM1(146.67mg,0.867mmol,4.0equiv) were added to a 20mL sealed tube and dissolved in 6mL of absolute ethanol, 400mg of 4A molecular sieve was added, the nitrogen was replaced and resealed. After stirring at room temperature for half an hour, sodium ethoxide (73.72mg,1.083mmol,5.00 equi) was addedv), reacting at 90 ℃ for two hours. After the reaction was completed, a layer of diatomaceous earth was spread on a sand core funnel, filtered, the filtrate was collected, spun-dried, and the crude product was prepared under high pressure (Column: X Bridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient from 30% B to 50% B in8min, 50% B; 254, wavelength; 220nm) to yield 25.7mg (92.3%) of a white solid. MS (ESI) m/z 567. 1 H NMR(400MHz,DMSO-d 6 ):δ10.19(s,1H),9.29(d,J＝7.7Hz,1H),8.76(s,1H),8.45(s,1H),7.92(s,1H),7.62(d,J＝8.4Hz,1H),7.54–7.32(m,5H),7.28(t,J＝7.0Hz,1H),5.37(dt,J＝8.4,4.7Hz,1H),5.23(s,1H),4.01–3.77(m,2H),2.91(t,J＝7.6Hz,6H),1.85(dd,J＝10.3,5.8Hz,6H),1.40(s,3H),1.36(s,3H).
EXAMPLE 16 Synthesis of Compounds I-16
Figure BDA0003481686850000262
Compound 1(300mg,0.651mmol,1.00equiv), SM1(792.0mg,3.25mmol,5.00equiv) was added to a 20mL sealed tube and dissolved in 10mL of absolute ethanol, 1.5g of 4A molecular sieves was added, the nitrogen was replaced, and the tube was sealed. After stirring at room temperature for half an hour, sodium ethoxide (178.5mg,2.604mmol,4.00equiv) was added and allowed to react at 90 ℃ for two hours. After completion of the reaction, the reaction system was cooled to room temperature, filtered through celite, and the filtrate was taken out to be dried by spin drying to obtain compound 2(212mg, 51.0%) as a white solid using thin layer chromatography (dichloromethane: methanol ═ 3: 1). MS (ESI): m/z 640.
Compound 2(200mg,0.313mmol.1.00equiv) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (2mL) was added to the reaction under nitrogen at room temperature. After stirring for 30 min, the reaction mixture was concentrated at low temperature under reduced pressure and the crude product was prepared under high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 ) The mobile phase B is ACN; the flow rate is 60 mL/min; gradient from 10% B to 40% B in 7min, 40% B; wavelength: 220nm) to give Compound I-16(110.4mg, yield 65.3%))MS(ESI):m/z＝540. 1 H NMR(400MHz,DMSO-d 6 ):δ9.52(s,1H),8.83(d,J＝5.7Hz,1H),8.66(s,1H),8.39(s,1H),7.68(d,J＝1.8Hz,1H),7.46(dd,J＝8.3,1.8Hz,1H),7.41(d,J＝8.3Hz,1H),7.36(d,J＝4.6Hz,5H),7.28(q,J＝5.1,4.5Hz,1H),5.92(s,1H),4.62(d,J＝5.6Hz,1H),3.89(d,J＝8.0Hz,1H),3.71(d,J＝7.9Hz,2H),3.34-3.31(m,1H),3.24-2.95(m,3H),2.36-2.34(m,1H),2.17-2.15(m,2H),2.06-2.04(m,2H),1.40(s,3H),1.39(s,3H).
EXAMPLE 17 Synthesis of Compounds I-17
Figure BDA0003481686850000271
Compound 1(300mg,0.65 mmol,1equiv), SM1(170mg, 1.08mmol,1.6equiv) was added to a 20mL sealed tube and dissolved in 8mL of absolute ethanol, 1.5g of 4A molecular sieves was added, the nitrogen was replaced and the tube was resealed. After stirring at room temperature for half an hour, sodium ethoxide (200mg, 5equiv) was further added to the reaction system. The reaction mixture was left at 90 ℃ for 12 hours. After the reaction was completed, a layer of diatomaceous earth was spread on a sand core funnel, filtered, the filtrate was collected, spun-dried, and the crude product was prepared under high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 ) The mobile phase B is ACN; the flow rate is 60 mL/min; gradient 25% B to 40% B in8min, 40% B; wavelength: 220nm) to give the product as a white solid (21.2mg, 92.2%).
MS(ESI):m/z＝554. 1 H NMR(400MHz,CD 3 OD-d 4 ):δ10.26(s,1H),9.54(d,J＝6.4Hz,1H),9.46(s,1H),9.16(s,1H),8.51(s,1H),8.26-8.10(m,6H),6.77(s,1H),6.02(s,1H),5.44-5.43(m,1H),4.67-4.64(m,1H),4.51-4.43(m,1H),3.66-3.61(m,3H),3.01(s,3H),2.89-2.82(m,4H),2.67-2.64(m,2H),2.21(d,J＝5.1Hz,6H).
EXAMPLE 18 Synthesis of Compounds I-18
Figure BDA0003481686850000272
Mixing compound 1(240mg,0.519mmol,1.00equiv), 2(631mg, 2.595)mmol,5.00equiv), 300mg
Figure BDA0003481686850000273
Putting a molecular sieve into a reaction bottle, adding ethanol (3mL), replacing nitrogen in the reaction bottle, stirring at normal temperature for 30 minutes, then adding sodium ethoxide (178.5mg,2.604mmol,4.00equiv) into the reaction bottle, replacing nitrogen, putting the reaction bottle at 90 ℃ for reacting for 16 hours, after the reaction is finished, cooling the reaction system to room temperature, filtering with diatomite, taking filtrate for spin drying, and using thin layer chromatography (dichloromethane: methanol ═ 3:1) to obtain a white solid compound 3(210mg, 63.1%). (ESI), [ M + H] + ＝641.
Compound 3(200.00mg,0.312mmol,1.00equiv) was dissolved in methylene chloride (4mL), and trifluoroacetic acid (2mL) was added thereto to react for 30 minutes at room temperature with replacement of nitrogen. The reaction mixture was then concentrated to give a crude product (110.4mg) prepared under high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 ) The mobile phase B is ACN; the flow rate is 60 mL/min; gradient 10% B to 35% B in 9min, 35% B; wavelength: 220nm) to give a yellow solid (28.5mg, 16.9%). (ESI), [ M + H] + ＝541； 1 H NMR(400MHz,DMSO-d 6 )δ10.21(s,1H),9.12(d,J＝7.6Hz,1H),8.81(s,1H),8.46(s,1H),7.86(s,1H),7.63(d,J＝8.6Hz,1H),7.46(d,J＝8.3Hz,1H),7.45–7.34(m,4H),7.28(t,J＝7.0Hz,1H),5.40(d,J＝7.2Hz,1H),5.24(s,1H),3.93(dd,J＝10.7,4.3Hz,1H),3.83(dd,J＝10.9,5.2Hz,1H),3.11(t,J＝12.0Hz,2H),2.24(d,J＝13.6Hz,2H),1.97(s,3H),1.40(s,3H),1.36(s,3H).
EXAMPLE 19 Synthesis of Compounds I-19
Figure BDA0003481686850000281
Compound 1(400mg,8.05mmol), an aqueous hydroxylamine solution (2.66g,80.520mmol) were placed in a reaction flask, absolute ethanol (10.0mL) was added, nitrogen gas was purged from the reaction flask, and the reaction flask was placed at 90 ℃ for reaction overnight. After completion of the reaction, the reaction system was cooled to room temperature, washed once with water, extracted (5 × 10mL) with isopropanol/chloroform (1:1), and the crude product obtained was dried at low temperature to give compound 2(1.1g, 79.16%) as a white solid, and ms (esi): m/z 158.
Anhydrous ethanol (10mL) was added to a reaction flask containing compound 2(408mg,2.600mmol), substrate SM2(400mg,0.867mmol) and 800mg of molecular sieve, and the reaction flask was purged with nitrogen. After stirring at room temperature for 30 minutes, sodium ethoxide (235.92mg,3.467mmol) was added to the reaction flask, the nitrogen was replaced, and the reaction flask was allowed to react at 90 ℃ overnight. After cooling the reaction to room temperature, the reaction mixture was quenched with CH 2 Cl 2 The crude product was obtained by climbing on a MeOH 10:1 plate. The crude product obtained was purified using Prep-HPLC (Column: Xbridge Shield RP18 OBD Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 38% B to 52% B in 7min, 52% B) gave compound as a white solid (16.8mg, 3.48%). Ms (esi) m/z 555; 1 H NMR(400MHz,DMSO-d 6 ):δ9.32–9.30(d,1H),8.78(s,1H),7.71–7.66(m,1H),7.65–7.64(m,1H),7.60–7.58(m,1H),7.47–7.38(m,4H),7.31–7.28(m,1H),5.47(s,1H),4.08–4.04(m,1H),3.99–3.95(m,1H),3.24(s,1H),3.10(s,1H),2.78(s,1H),2.56–2.53(m,3H),2.28–2.26(m,2H),2.16–2.13(m,2H),1.53(s,3H),1.50(s,3H).
EXAMPLE 20 Synthesis of Compounds I-20
Figure BDA0003481686850000282
Compound 1(1g, 1equiv) was dissolved in absolute ethanol (10mL), and 50% aqueous hydroxylamine solution (4.34g, 10equiv) was added to the reaction system under nitrogen protection, followed by stirring at 90 ℃ for 12 hours. The organic solvent was removed by rotary evaporation at low temperature to give a white solid (800mg, 93%). (ESI), [ M + H] + ＝186。
A mixture of Compound 2(480mg, 3equiv) and Compound 3(300mg, 1equiv), 4A molecular sieves (1g) was dissolved in absolute ethanol (30mL) and stirred at room temperature for 30 minutes under nitrogen. Then, sodium ethoxide (200.00mg,4.00equiv) was further added to the reaction system. Stirring is carried out for 12 hours under the condition of 90 ℃ of nitrogen. Spin-drying the solvent under high pressurePreparation (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 ) The mobile phase B is ACN; the flow rate is 60 mL/min; gradient 20% B to 45% B in 7min, 45% B; wavelength: 220nm) to obtain a white solid compound (16mg), (ESI), [ M + H [)] + ＝583. 1 H NMR(400MHz,Methanol-d 4 )δ9.34(s,1H),8.78(s,1H),7.79(s,1H),7.72–7.56(m,2H),7.43(dt,J＝15.0,7.6Hz,4H),7.31(t,J＝7.2Hz,1H),5.46(s,1H),4.48(d,J＝13.5Hz,1H),4.07–3.95(m,3H),3.42–3.34(m,1H),3.32–3.27(m,1H),3.02(t,J＝11.5Hz,1H),2.16(d,J＝2.1Hz,5H),1.98–1.80(m,2H),1.53(s,3H),1.51(s,3H).
EXAMPLE 21 Synthesis of Compounds I-21
Figure BDA0003481686850000291
Dissolving the compound 1(1g,0.008mol,1.00equiv) in ethanol (10mL), adding hydroxylamine aqueous solution (5.28g,0.080mol,10.0equiv) into the reaction solution, stirring overnight at 90 ℃ under nitrogen protection, extracting the reaction solution with dichloromethane to remove impurities, extracting with a mixed solution of chloroform and acetone (1:1), and concentrating the extract under reduced pressure to obtain a crude compound, namely a white solid compound 2(800 mg). M/z (ESI), [ M + H] + ＝173；
Dissolving compound 2(546mg,3.170mmol,5.00equiv), compound 3(300mg,0.650mmol,1.00equiv) and 4A molecular sieve (1.5g) in ethanol (5mL), stirring at room temperature for 30 min under nitrogen protection, adding sodium ethoxide (177mg,2.601mmol,4.00equiv) into the reaction solution, stirring at 90 deg.C under nitrogen protection for 2 hr, preparing the reaction solution under high pressure (Column: Xbridge Prep OBD C18 Column,30 x 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 ) The mobile phase B is ACN; the flow rate is 60 mL/min; gradient 20% B to 37% B in8min, 37% B; wavelength: 220nm) to give a compound (13.8mg) as a white solid. M/z (ESI), [ M + H] + ＝570； 1 H NMR(400MHz,DMSO-d 6 )δ10.21(s,1H),9.05(d,J＝7.7Hz,1H),8.81(s,1H),8.46(s,1H),7.91(s,1H),7.63(d,J＝8.5Hz,1H),7.48–7.28(m,6H),5.42(d,J＝6.8Hz,1H),5.23(s,1H),3.89(s,1H),3.81(d,J＝7.1Hz,2H),3.31(s,2H),2.64(s,3H),2.40(s,3H),2.20(s,3H),1.42(s,3H),1.39(s,3H).
EXAMPLE 22 Synthesis of Compounds I-22
Figure BDA0003481686850000301
A mixture of Compound 1(100mg, 1equiv) and 2(90.7mg, 5equiv), 4A molecular sieves (1g) was dissolved in absolute ethanol (8mL) and stirred at room temperature for 30 minutes under nitrogen. Then, sodium ethoxide (59mg, 4equiv) was added to the reaction system. Stirring was carried out for 12 hours at 90 ℃ under nitrogen. Filtered, spun dry and prepared by high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 ) The mobile phase B is ACN; the flow rate is 60 mL/min; gradient from 30% B to 60% B in8min, 60% B; wavelength: 220nm) to yield the product as a white solid (19.2, 99.2%). [ M + H ]] + ＝548. 1 H NMR(400MHz,DMSO-d 6 )δ10.21(s,1H),9.12(d,J＝7.9Hz,1H),8.81(s,1H),8.44(s,1H),7.93(d,J＝1.8Hz,1H),7.66–7.56(m,1H),7.51–7.18(m,6H),5.41(d,J＝6.0Hz,1H),5.19(s,1H),3.91(d,J＝6.6Hz,1H),3.81(d,J＝6.0Hz,1H),3.71(t,J＝8.5Hz,1H),3.31–3.05(m,2H),3.07–2.79(m,2H),1.42(s,3H),1.39(s,3H).
EXAMPLE 23 Synthesis of Compounds I-23
Figure BDA0003481686850000302
A mixture of Compound 1(100mg, 1equiv), 2(95mg, 5equiv) and 4A molecular sieves (1.5g) was dissolved in absolute ethanol (8mL) and stirred at room temperature for 30 minutes under nitrogen. Then, sodium ethoxide (59mg, 4equiv) was added to the reaction system. Stirring for 12 hours at 90 ℃ under the protection of nitrogen. Filtered, spun dry and prepared by high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 ) The mobile phase B is ACN; the flow rate is 60 mL/min; gradient from 30% B to 55% B in8min, 55% B; wavelength: 220nm) gave the product as a white solid (21.2mg, 92.2%). MS (Mass Spectrometry)(ESI):[M+H] + ＝486. 1 HNMR(400MHz,DMSO-d6)δ10.16(s,1H),9.13(d,J＝7.8Hz,1H),8.79(s,1H),8.43(s,1H),7.88(d,J＝1.8Hz,1H),7.72–7.59(m,1H),7.50–7.18(m,6H),5.43–5.39(m,1H),5.20(t,J＝4.9Hz,1H),3.94–3.80(m,2H),2.82(q,J＝7.6Hz,2H),1.41–1.31(m,9H).
EXAMPLE 24 Synthesis of Compounds I-24
Figure BDA0003481686850000311
A mixture of compound 1(100mg, 1equiv) and 2(110mg, 5equiv), 4A molecular sieve (1g) was dissolved in absolute ethanol (8mL) and stirred at room temperature for 30 minutes under nitrogen. Then, sodium ethoxide (59mg, 4equiv) was added to the reaction system. Stirring was carried out at 90 ℃ for 12 hours under nitrogen. Filtered, spun-dried and prepared by autoclaving (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 ) The mobile phase B is ACN; the flow rate is 60 mL/min; gradient from 30% B to 60% B in8min, 60% B; wavelength: 220nm) gave the product as a white solid (17.4mg, 95%). MS (ESI) [ M + H] + ＝500. 1 HNMR(400MHz,DMSO-d6)δ10.15(s,1H),9.23(d,J＝7.8Hz,1H),8.78(s,1H),8.42(s,1H),7.90(d,J＝1.8Hz,1H),7.63(dd,J＝8.3,1.8Hz,1H),7.47–7.26(m,6H),5.42–5.38(m,1H),5.18(t,J＝4.9Hz,1H),3.94–3.82(m,2H),3.19–3.13(m,1H),1.42–1.35(m,12H).
EXAMPLE 25 Synthesis of Compounds I-25
Figure BDA0003481686850000312
A mixture of compound 1(100mg, 1equiv) and 2(125mg, 5equiv), 4A molecular sieves (1g) was dissolved in absolute ethanol (8mL) and stirred at room temperature for 30 min under nitrogen. Then, sodium ethoxide (59mg, 4equiv) was added to the reaction system. Stirring for 12 hours at 90 ℃ under the protection of nitrogen. The solvent was filtered off and prepared by high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 ) Flow ofThe mobile phase B is ACN; the flow rate is 60 mL/min; gradient from 35% B to 65% B in8min, 65% B; wavelength: 220nm) gave the product as a white solid (16.9, 99.6%). MS (ESI) [ M + H ]] + ＝514. 1 H NMR(400MHz,DMSO-d 6 )δ10.16(s,1H),9.32(d,J＝7.8Hz,1H),8.77(s,1H),8.43(s,1H),7.92(d,J＝1.8Hz,1H),7.63(d,J＝8.4Hz,1H),7.48–7.35(m,5H),7.27(t,J＝7.2Hz,1H),5.40–5.38(m,1H),5.19(s,1H),3.94–3.82(m,2H),1.42–1.39(m,15H).
EXAMPLE 26 Synthesis of Compounds I-26
Figure BDA0003481686850000321
A mixture of Compound 1(150mg, 1equiv) and Compound 2(185mg, 5equiv), 4A molecular sieves (1.5g) was dissolved in anhydrous ethanol (8mL), and stirred under nitrogen at room temperature for 30 minutes. Then, sodium ethoxide (89mg, 4equiv) was further added to the reaction system. Stirring was carried out for 12 hours at 90 ℃ under nitrogen. The solvent was filtered off and prepared by high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 ) The mobile phase B is ACN; the flow rate is 60 mL/min; gradient from 30% B to 55% B in8min, 55% B; wavelength: 220nm) to obtain a white solid product (16 mg). (ESI), [ M + H] + ＝498. 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.12(d,J＝7.8Hz,1H),8.75(s,1H),8.43(s,1H),7.88(d,J＝1.8Hz,1H),7.63–7.61(m,1H),7.46–7.26(m,6H)，5.37–5.35(m,1H),5.19(t,J＝4.9Hz,1H),3.92–3.80(m,2H),2.24–2.20(m,1H),1.41(s,3H),1.37(s,3H),1.14–1.11(m,3H),1.02–0.99(m,1H).
EXAMPLE 27 Synthesis of Compounds I-27
Figure BDA0003481686850000322
Compound 1(1g, 1equiv), 50% aqueous hydroxylamine solution (6.3g, 10equiv) was dissolved in absolute ethanol (20mL) and stirred overnight at 90 ℃ under nitrogen. The solvent was removed by rotary evaporation to give a white solid (1.1g, 98%). (ESI), [ M + H] + ＝138。
Compound 3(100mg, 1equiv), 2(148.00mg,5.00equiv), 1g of 4A molecular sieve was dissolved in ethanol (5mL), stirred under nitrogen at room temperature for 30 minutes, and sodium ethoxide (58.00mg,5.00equiv) was added to the reaction system and reacted at 90 ℃ overnight. Filtration of the spin-dried solvent and high pressure preparation (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 27% B to 50% B in 7min, 50% B; wavelength: 220nm) gave the product as a white solid (10.2mg, 96%). (ESI), [ M + H] + ＝535. 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.46–9.25(m,2H),8.95–8.78(m,2H),8.54–8.40(m,2H),7.85(s,1H),7.68–7.63(m,2H),7.47–7.32(m,5H),7.27(t,J＝7.2Hz,1H),5.43–5.40(m,2H),4.01–3.93(m,2H),1.41(s,3H),1.36(s,3H).
EXAMPLE 28 Synthesis of Compounds I-28
Figure BDA0003481686850000331
Compound 1(100.00mg,0.216mmol,1.00equiv), 2(147.93mg,1.079mmol,5.00equiv), 400mg of 4A molecular sieve were charged into a 20ml sealed tube, dissolved in 8ml of anhydrous ethanol, stirred under nitrogen at normal temperature for half an hour, then added with sodium ethoxide (51.38mg,0.755mmol,3.50equiv), and reacted at 90 ℃ under nitrogen for two hours. After the reaction was complete, the filter was spun dry and prepared by high pressure (Column: X Bridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 25% B to 48% B in8min, 48% B; wavelength: 220nm) gave 10mg (92.9%) of a white solid. MS (ESI) [ M + H] + ＝535. 1 H NMR(400MHz,DMSO-d 6 )δ10.23(s,1H),9.35(d,J＝7.7Hz,1H),8.90(s,1H),8.87–8.80(m,1H),8.44(s,1H),8.25(d,J＝7.8Hz,1H),8.08(td,J＝7.7,1.8Hz,1H),7.88(d,J＝1.8Hz,1H),7.69–7.60(m,2H),7.50–7.35(m,5H),7.32–7.25(m,1H),5.45–5.41(m,1H),5.34(t,J＝5.2Hz,1H),4.07–3.89(m,2H),1.42(s,3H),1.37(s,3H).
EXAMPLE 29 Synthesis of Compounds I-29
Figure BDA0003481686850000332
Compound 1(260mg), Compound 2(150mg), Pd were added to a 20ml sealed tube 2 (dba) 3 (78mg), Xantphos (50mg), potassium phosphate (543mg) and 10mL of 1, 4-dioxane were reacted under nitrogen at 100 ℃ for 2 h. After the reaction was complete, the crude product was purified by spin-drying on a silica gel column to give a brown solid product 3(250mg 97.1%). MS (ESI): M + H] + ＝418.
Compound 3(100mg), compound 4(210mg) and 4A molecular sieve (400mg) were added to a 20mL sealed tube, 6mL of ethanol was added, and after stirring under nitrogen at room temperature for 0.5h, sodium ethoxide (200mg) was added, and the reaction was allowed to proceed overnight at 90 ℃. After the reaction was complete, filtration and spin-drying were carried out to purify the product (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/LNH4HCO3+ 0.1% NH) 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 20% B to 40% B in 7min, 40% B; wavelength: 220nm) gave a white solid (13.2mg, 99.4%). MS (ESI) [ M + H] + ＝537. 1 H NMR(400MHz,DMSO-d 6 )δ9.64(s,2H),8.70(d,J＝3.4Hz,2H),8.62(d,J＝4.9Hz,1H),8.41(s,1H),8.34(d,J＝6.2Hz,1H),7.96(d,J＝7.7Hz,1H),7.76(s,1H),7.59(t,J＝6.5Hz,1H),7.53(d,J＝8.4Hz,1H),7.47(d,J＝8.3Hz,1H),6.10(s,1H),4.71(d,J＝5.8Hz,2H),3.43(t,J＝8.0Hz,6H),2.23(t,J＝8.0Hz,6H),1.40(s,6H).
EXAMPLE 30 Synthesis of Compounds I-30
Figure BDA0003481686850000341
Anhydrous ethanol (5mL) was added to a reaction flask containing compound 1(100.00mg,0.231mmol), compound 2(195.65mg,1.156mmol) and 500mg of molecular sieves, and the inside of the reaction flask was purged with nitrogen. After stirring for 30 minutes at room temperature, sodium ethoxide (62.94mg,0.925mmol) was added to the flask, the nitrogen was replaced, and the flask was placed at 90 deg.CThe reaction was allowed to proceed overnight. After cooling the reaction to room temperature, the reaction mixture was quenched with CH 2 Cl 2 The crude product was obtained by climbing on a plate with MeOH 5: 1. The resulting crude product was purified using Prep-HPLC (Column: Sunfire Prep C18 Column, 30X 150mm,5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate:60 mL/min; gradient: 6% B to 23% B in8min, 23% B) to give the compound as a white solid (5.3mg). MS (ESI) [ M + H] + ＝538； 1 H NMR(400MHz,DMSO-d6):δ8.78(s,1H),8.69(s,1H),8.56–8.55(m,1H),8.15–8.13(m,1H),7.85–7.80(m,1H),7.69–7.67(m,1H),7.57–7.55(m,1H),7.49–7.47(m,1H),4.96(s,2H),3.37(t,J＝8.0Hz,6H),2.22(t,J＝8.0Hz,6H),1.26(s,6H).
EXAMPLE 31 Synthesis of Compounds I-31
Figure BDA0003481686850000342
Compound 1(500.00mg,2.26mmol,1.00equiv), SM1(1.56g,11.31mmol,5.00equiv), N-diisopropylethylamine (1.46g,5.0eq) were dissolved in acetonitrile (20mL) and stirred at room temperature under nitrogen for 4 hours. After the reaction was completed, the reaction mixture was concentrated by rotary evaporation, and the crude product was purified by column chromatography (dichloromethane/methanol-15/1) to give compound 2(270mg) as a brown solid. MS (ESI): m/z 323.
Mixing compound 2(100mg,0.31mmol,1.00equiv), compound SM2(109.99mg,0.62mmol,2equiv), Xantphos (27mg,0.1equiv), Pd 2 (dba) 3 (44.86mg,0.1equiv) and potassium phosphate (450mg, 3.0eq) were dissolved in dioxane (5mL) and stirred at 90 ℃ overnight under nitrogen. After completion of the reaction, the reaction mixture was concentrated by rotary evaporation, and the crude product was purified by column chromatography (dichloromethane/methanol-10/1) to give compound 3(130mg) as a brown solid. MS (ESI) m/z 463.
Compound 3(100mg,0.216mmol,1.00equiv), SM3(109.77mg,0.649mmol,3.00equiv) was dissolved in ethanol (5mL), and 500mg of 4A molecular sieve was added to the reaction system, followed by stirring at room temperature under a nitrogen atmosphere for 30 minutes. Sodium ethoxide (59mg,0.865mmol,4.00eq) was added and stirred at 90 ℃ under nitrogen overnight. After the reaction is finished, the reaction mixture is concentrated by rotary evaporation, and the crude product is prepared by high pressure(Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/LNH4HCO3), mobile phase B: ACN; flow rate:60 mL/min; gradient: 5% B to 35% B in8min, 35% B; wavelength: 220 nm; RT1(min):7.77) to give compound I-31(2.2mg) as a white solid, MS (ESI): m/z 568 1 H NMR(400MHz,DMSO-d 6 ):δ10.11(s,1H),9.31(s,1H),8.67-8.80(m,1H),8.55-8.60(m,1H),8.48–8.41(m,1H),7.88–7.70(m,1H),7.66–7.54(m,1H),7.30–7.47(m,1H),5.46–5.19(m,2H),4.01–3.81(m,1H),3.70-4.02(m,2H),3.01(s,6H),1.93(s,3H),1.91(s,3H),1.38(d,J＝13.3Hz,4H),1.26–1.10(m,2H).
EXAMPLE 32 Synthesis of Compounds I-32
Figure BDA0003481686850000351
Compound 1(75mg), compound 2(125mg) and 4A molecular sieve (300mg) were added to a 20mL sealed tube, 8mL of ethanol was added, stirring was performed under nitrogen at room temperature for 0.5h, sodium ethoxide (100mg) was added, and the reaction was performed at 90 ℃ for 3 h. After the reaction was complete, filtration and spin-drying were carried out and purification was carried out under high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/LNH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 20% B to 45% B in 7min, 45% B; wavelength: 220nm) gave the product as a white solid (2.6mg, 99.4%). MS (ESI) [ M + H] + ＝556. 1 H NMR(400MHz,DMSO-d 6 )δ9.49(s,1H),8.74–8.56(m,2H),8.38(s,1H),7.69(d,J＝1.8Hz,1H),7.51–7.24(m,7H),5.97(s,1H),5.20(t,J＝5.0Hz,1H),4.64(q,J＝5.6Hz,1H),3.93–3.74(m,3H),3.68–3.47(m,5H),2.63(t,J＝4.7Hz,4H),1.41(s,3H),1.40(s,3H).
EXAMPLE 33 Synthesis of Compounds I-33
Figure BDA0003481686850000352
Dissolving Compound 1(100mg, 1equiv) and Compound 2(186mg, 5equiv) in ethanol (10mL), adding 1g of 4A molecular sieve, and introducing nitrogen gasStirring for 30 minutes at warm conditions. Then, sodium ethoxide (58.00mg,5.00equiv) was added to the reaction system, and the reaction was carried out overnight at 90 ℃ under nitrogen. The reaction solution was spun dry and prepared by high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 20% B to 40% B in 7min, 40% B; wavelength: 220nm) gave a white solid (14mg, 99%). (ES +), [ M + H] + ＝569. 1 H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.68(s,1H),8.60(d,J＝6.1Hz,1H),8.36(s,1H),7.68(d,J＝1.7Hz,1H),7.54–7.06(m,7H),5.97(s,1H),4.64(t,J＝5.7Hz,1H),3.84(d,J＝12.8Hz,3H),3.66(dd,J＝10.8,6.2Hz,1H),2.68(s,4H),2.50–2.42(m,3H),2.22(s,3H),1.41(s,3H),1.40(s,3H).
EXAMPLE 34 Synthesis of Compounds I-34
Figure BDA0003481686850000361
In a 100mL reaction flask, 1g of compound 1, 1.1g of compound 2 and 1.2g N, N-diisopropylethylamine were dissolved in 40mL of acetonitrile, and the mixture was stirred overnight at room temperature under nitrogen, after completion of the reaction, the crude product was purified by flash column chromatography to give 21.18g (94%) of a white solid compound. MS (ESI) [ M + H] + ＝386.
Compound 3(300mg,0.777mmol,1.00equiv), Compound 4(143.85mg,0.816mmol,1.05equiv), Pd were added to a 40mL sealed tube 2 (dba) 3 (71.19mg,0.078mmol,0.1equiv), XantPhos (44.98mg,0.078mmol,0.1equiv) and potassium phosphate (495.06mg,2.332mmol,3equiv) were dissolved in 16mL of 1, 4-dioxane and reacted at 100 ℃ under nitrogen for 2 hours. After completion of the reaction, it was spin dried and chromatographed with DCM: MeOH/15:1 to give 260mg (89.3%) of Compound 5 as a yellow solid. MS (ESI) [ M + H] + ＝526.
Compound 5(260.00mg,0.495mmol,1.00equiv), compound 6(418.52mg,2.473mmol,5.00equiv) and 500mg of 4A molecular sieve were added to a 20mL sealed tube, followed by 6mL of anhydrous ethanol, nitrogen gas was purged, and after stirring at room temperature for half an hour, sodium ethoxide (168.30) was addedmg,2.473mmol,5.00equiv), nitrogen at 90 ℃ for 3h after completion of the reaction, filtration was spin-dried and chromatographed with DCM: MeOH/3:1 to give 80mg (90.2%) of Compound 7 as an off-white solid. MS (ESI) [ M + H] + ＝631.
Compound 7(80.00mg,0.127mmol,1.00equiv) was added to a 20mL sealed tube, dissolved in 4mL of dichloromethane, followed by addition of 1.5mL of trifluoroacetic acid and stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was spin-dried and prepared by high pressure (Column: XSelect CSH OBD Column 30X 150mm 5um, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate:60 mL/min; gradient: 7% B to 15% B in8min, 15% B; wavelength: 254nm) to give 11.7mg of a white solid compound. MS (ESI) [ M + H] + ＝531. 1 H NMR(400MHz,Methanol-d 4 )δ8.67(s,1H),7.80–7.78(m,1H),7.69–7.67(m,1H),7.55–7.53(m,1H),6.42(s,1H),3.58(t,J＝8.0Hz,6H),3.39(s,2H),3.02(s,2H),2.39(t,J＝8.0Hz,6H),1.58(d,J＝4.1Hz,6H),1.24(s,6H).
EXAMPLE 35 Synthesis of Compounds I-35
Figure BDA0003481686850000362
Compound 1(500mg, 1.0eq), compound SM1(941.8mg, 3.0eq), and N, N-diisopropylethylamine (1.46g,5.0eq) were dissolved in acetonitrile (20mL), and the reaction was stirred overnight at 50 ℃ under a nitrogen atmosphere. After the reaction was completed, the solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (dichloromethane/methanol-10/1) to give compound 2(270mg) as a brown solid. MS (ESI): m/z 322.
Mixing compound 2(100.0mg,0.31mmol,1.0equiv), compound SM2(164.3mg,0.93mmol,3.0equiv), Xantphos (17.9mg,0.031mmol,0.1equiv), Pd 2 (dba) 3 (28.5mg,0.031mmol,0.1equiv) and potassium phosphate (251mg,3.0eq) were dissolved in dioxane (8mL), and the reaction was stirred under nitrogen at 90 ℃ overnight. After the reaction was completed, the solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (dichloromethane/methanol-10/1) to give compound 3(60mg) as a yellow solid. MS (ESI): m/z 434.
Compound 3(60mg, 1eq), SM2(117.12 m)g,0.692mmol,5equiv) and 500mg of 4A molecular sieve were dissolved in ethanol (5mL), stirred at room temperature under nitrogen for 30 minutes, and sodium ethoxide (47.10mg,0.692mmol,5equiv) was added to the reaction system and reacted at 90 ℃ overnight. Filtered, spun dry and prepared at high pressure (Xbridge Prep C18 OBD Column,30 x 50mm,5 μm 13 nm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient from 10% B to 40% B in8min, 40% B; RT1(min):7.23) gave compound I-35(2.9 mg). MS (ESI) m/z 567. 1 H NMR(400MHz,DMSO-d 6 ):δ9.50(s,1H),8.91(s,1H)，8.71–8.56(m,1H),8.51(dd,J＝4.8,1.6Hz,1H),8.38(s,1H),7.83–7.65(m,2H),7.60–7.19(m,2H),5.94(s,1H),5.32(d,J＝16.5Hz,1H),4.72(d,J＝5.5Hz,1H),4.13–3.61(m,2H),3.01(d,J＝11.5Hz,6H),1.93(s,3H),1.91(s,3H),1.36–1.31(m,6H),1.24–1.10(m,2H).
EXAMPLE 36 Synthesis of Compounds I-36
Figure BDA0003481686850000371
SM1(154.1mg,1.09mmol,5.00equiv), Compound 1(100.0mg,0.217mmol,1.0equiv), 500mg of 4A molecular sieve were placed in a reaction flask, absolute ethanol (5mL) was added, the reaction flask was purged with nitrogen and stirred at room temperature for 30 minutes, sodium ethoxide (59.0mg,0.868mmol,4.0equiv) was added, and the reaction was stirred at 90 ℃ overnight. After completion of the reaction, it was cooled to room temperature, and the resulting mixture was concentrated to obtain a crude product by column chromatography (dichloromethane/methanol: 10: 1). The crude product was prepared in reverse phase to a liquid phase (Column: XBridge Prep OBD C18 Column,30 x 150mm,
Figure BDA0003481686850000372
mobile phase A water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 45% B to 70% B in 7min, 70% B) to give compound I-36 as a white solid (10.3 mg). MS (ESI): m/z 540. 1 H NMR(400MHz,DMSO-d 6 ):δ1.27-1.43(m,9H),1.56-1.59(d,3H),1.76-1.80(m,2H),2.01-2.15(m，2H),2.87-2.90(m,1H),3.81-3.93(m,2H),5.19-5.21(m,1H),5.38-5.40(m,1H),7.26-7.29(m,1H),7.35-7.47(m,5H),7.60-7.62(m,1H),7.91(s,1H),8.44(s,1H),8.77(s,1H),9.22-9.24(m,1H),10.18(s,1H).
EXAMPLE 37 Synthesis of Compound I-37
Figure BDA0003481686850000381
Compound 1(50.0mg,0.112mmol,1.00eq), compound SM1(57.7mg,0.335mmol,3eq) and 500mg 4A molecular sieve were dissolved in ethanol (4mL), stirred at room temperature for 30 minutes under nitrogen, sodium ethoxide (30.4mg,0.447mmol,4eq) was added and the reaction mixture was stirred at 90 ℃ overnight. After the reaction was complete, the reaction was filtered and spun dry and the crude product was prepared by high pressure (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 15% B to 40% B in8min, 40% B; wavelength is 220 nm; RT1(min):7.70) gave compound I-37 as a white solid (7.8 mg). MS (ESI): m/z 570. 1 H NMR(400MHz,DMSO-d6):δ10.31(s,1H),8.78–8.69(m,2H),8.49(s,1H),7.83(d,J＝8.5Hz,1H),7.52(d,J＝8.5Hz,1H),7.45(s,1H),7.40–7.32(m,4H),7.28(td,J＝5.9,2.7Hz,1H),4.74(q,J＝5.8Hz,1H),3.92(dd,J＝10.8,4.3Hz,1H),3.81(s,2H),3.73(dd,J＝10.9,5.7Hz,1H),2.65(s,4H),2.37(s,4H),2.17(s,3H),1.46(s,3H),1.29(s,3H).
EXAMPLE 38 Synthesis of Compounds I-38
Figure BDA0003481686850000382
Compound 1(2.00g,9.09mmol,1.00equiv), SM1(1.51g,9.99mmol,1.1equiv) was placed in a reaction flask and acetonitrile (20.0mL) and N, N-diisopropylethylamine (3.52g,27.27mmol,3equiv) were added. The reaction mixture was stirred at 50 ℃ overnight under nitrogen. After completion of the reaction, the reaction system was cooled to room temperature, concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate: 5:1) to give compound 2(600mg) as a white solid, ms (esi): m/z 335.
Compound 2(200mg,0.597mmol,1.00equiv), substrate SM2(116.44mg,0.657mmol,1.1equiv), XantPhos (34.57mg,0.06mmol,0.1equiv), potassium phosphate (634mg,2.985mmol,5equiv) and Pd 2 (dba) 3 (34.35mg,0.06mmol,0.1equiv) was dissolved in anhydrous 1, 4-dioxane (20 mL). The reaction was stirred at 90 ℃ under nitrogen overnight. After the reaction is finished, the reaction system is cooled to room temperature and then concentrated, and the crude product is purified by dichloromethane/methanol to obtain a brown solid product 3. MS (ESI): m/z 476.
Anhydrous ethanol (5mL) was added to compound 3(100mg,0.21mmol,1.00equiv), SM3(72.01mg,0.63mmol,3equiv), and 1g of 4A molecular sieve in a reaction flask, and the inside of the reaction flask was purged with nitrogen. After stirring at room temperature for 30 minutes, sodium ethoxide (57.24mg,0.84mmol,4equiv) was added. The reaction was stirred at 90 ℃ overnight under nitrogen. After the reaction was completed, the reaction mixture was concentrated to give a crude product which was purified by high pressure preparative purification (Column: Xbridge Prep OBD C18 Column, 30X 150mm,5 μm; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate:60 mL/min; Gradient: 35% B to 65% B in8min, 65% B; Wave Length:220 nm; RT1(min): 7.50;) to give Compound I-38 as a white solid (24.6mg, 22% yield). MS (ESI): m/z 526. 1 H NMR(400MHz,DMSO-d 6 ):δ10.44(s,1H),8.65(s,1H),8.51(s,1H),8.10(s,1H),7.88(d,J＝8.5Hz,1H),7.68(s,1H),7.53(d,J＝8.5Hz,1H),7.27(d,J＝4.4Hz,4H),7.25–7.08(m,1H),5.09(s,1H),3.85(s,1H),3.58(dd,J＝10.6,4.5Hz,1H),3.53–3.47(m,1H),3.08(dd,J＝13.7,6.4Hz,1H),2.87(dd,J＝13.7,6.8Hz,1H),1.50(s,3H),1.45(s,6H),1.34–1.21(m,1H),1.18–1.06(m,1H),0.99(d,J＝3.4Hz,2H).
EXAMPLE a Synthesis of Compound II-1
Figure BDA0003481686850000391
Mixing compound 1(1g,3mmol), compound SM1(453mg,3mmol), XantPhos (89.7mg,9.75mol), Pd 2 (dba) 3 (173.6mg,0.3mmol) and potassium phosphate (1.9g,9mmol) were placed in a reaction flask1, 4-dioxane (10mL) was added and the reaction was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. After completion of the reaction, it was cooled to room temperature, filtered through celite, and the filtrate was spin-dried, and the crude product was purified by column chromatography to give compound 2(300mg,0.689mmol, 23%) as a yellow solid, ms (esi): m/z ═ 436.
Compound 2(300mg,0.689mmol), SM2(256.5mg,3.46mmol), 600mg
Figure BDA0003481686850000393
The molecular sieve was placed in a reaction flask and absolute ethanol (0.5mL) was added. The reaction was stirred at room temperature for 30 minutes under nitrogen, then sodium ethoxide (187.7mg,2.756mmol) was added to the reaction flask and the reaction was left to stir at 90 ℃ overnight. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated to give a crude product which was purified by reverse phase preparative purification (Column: YMC-Actus Triart C18, 30X 150mm,5 μm; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 47% B to 57% B in8min, 57% B; the wavelength is 254/220 nm; ) Compound II-1 was obtained as a white solid (47.6mg,0.107mmol, 16%). Ms (esi) m/z 446; 1 H NMR(400MHz,DMSO-d 6 )：δ10.17(s,1H),9.26(s,1H),9.06(d,J＝7.2Hz,1H),8.78(s,1H),8.52–8.40(m,1H),7.94(d,J＝8.9Hz,1H),7.59(d,J＝9.0Hz,1H),7.46–7.32(m,4H),7.30–7.21(m,1H),5.37(s,1H),5.23(t,J＝5.0Hz,1H),3.90(dt,J＝11.0,4.5Hz,1H),3.76(dt,J＝10.7,5.3Hz,1H),2.46(s,3H).
EXAMPLE b Synthesis of Compound II-2
Figure BDA0003481686850000392
Mixing compound 1(300mg,0.97mmol), compound SM1(147.7mg,0.97mmol), XantPhos (56.61mg,0.097mmol), Pd 2 (dba) 3 (89.6mg,0.097mmol) and potassium phosphate (623.1mg,2.93mmol) were placed in a reaction flask, 1, 4-dioxane (0.5mL) was added, and the reaction was stirred at 100 ℃ for 16 hours under nitrogen. After the reaction is finished, the reaction system is cooled to the roomWarm, filtration through celite, and concentration of the filtrate to give crude product which is purified by column chromatography to give compound 2 as a yellow solid (150mg, 36.5% yield.) ms (esi) m/z 421.
Compound 2(150mg,0.36mmol), SM2(303.6mg,1.79mmol), 300mg
Figure BDA0003481686850000403
The molecular sieve was placed in a reaction flask and absolute ethanol (0.5mL) was added, the reaction stirred at room temperature for 30 minutes under nitrogen, then sodium ethoxide (97.2mg,1.43mmol) was added and stirred at 90 ℃ overnight. After the reaction was completed, the reaction system was cooled to room temperature, filtered through Celite, and the filtrate was concentrated to give a crude product which was subjected to Prep-HPLC (Column: Xbridge Shield RP18 OBD Column, 30X 150mm,5 um; mobile phase A: water (10 mmol/LNH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient of 40B to 60B in8min, 60B to B in min, B to B in min, B to B in min, B to B in min; 254; 220nm) to yield compound II-2 as a white solid (85.5mg, 46% yield.) ms (esi) m/z 540; 1 H NMR(400MHz,DMSO-d 6 ):δ9.42(s,1H),9.19(s,1H),8.84(d,J＝6.1Hz,1H),8.64(s,1H),8.38(d,J＝2.2Hz,1H),7.91(d,J＝8.9Hz,1H),7.46–7.34(m,5H),7.34–7.26(m,1H),5.94(s,1H),5.25(t,J＝4.8Hz,1H),4.63(q,J＝5.6Hz,1H),3.87(dt,J＝10.6,4.3Hz,1H),3.68(dt,J＝10.7,5.5Hz,1H),2.88(dd,J＝9.4,6.1Hz,6H),1.85(dd,J＝9.4,6.2Hz,6H).
EXAMPLE c Synthesis of Compound II-3
Figure BDA0003481686850000401
Mixing compound 1(145mg,0.33mmol), SM1(283.3mg,1.67mmol), 290mg
Figure BDA0003481686850000402
The molecular sieve was placed in a reaction flask, absolute ethanol (0.5mL) was added, nitrogen was replaced and the mixture was stirred at room temperature for 30 minutes, then sodium ethoxide (90.7mg,1.33mmol) was added, and the reaction was stirred overnight at 90 ℃ under nitrogen. After the reaction is finished, the reaction system is cooledCooling to room temperature, filtering with diatomaceous earth, concentrating the filtrate to obtain crude product, and subjecting to Prep-HPLC (Column: Xbridge Prep OBD C18 Column,30 × 150mm 5 um; mobile phase A: water (10mmol/L NH) 4 HCO 3 +0.1％NH 3 .H 2 O), mobile phase B is ACN; the flow rate is 60 mL/min; gradient 25% B to 55% B in8min, 55% B; 254, wavelength; 220nm) to yield compound II-3 as a white solid (85.5mg, 46% yield.) ms (esi) m/z 541; 1 H NMR(400MHz,DMSO-d 6 ):δ10.17(s,1H),9.36(d,J＝7.0Hz,1H),9.25(s,1H),8.75(s,1H),8.50(s,1H),7.94(d,J＝8.9Hz,1H),7.60(d,J＝9.0Hz,1H),7.48–7.41(m,2H),7.38(t,J＝7.7Hz,2H),7.28–7.21(m,1H),5.42–5.16(m,2H),3.93(dt,J＝10.7,4.4Hz,1H),3.78(dt,J＝10.5,4.7Hz,1H),2.89(t,J＝7.7Hz,6H),1.97–1.73(m,6H).
effect embodiment: biological experiment method
Test compounds were dissolved in 100% DMSO and the stock concentration was 10 mM. The test was started at 10 μ M, diluted in a three-fold gradient, ten data points, and repeated twice for each point.
ADP-Glo is adopted in the experiment of inhibiting the activity of HPK1 kinase by the compound TM A platform. Reactions were performed in 384-well plates containing 0.3nM HPK1, 5. mu.M ATP, 0.05mg/ml MBP, 0-10. mu.M compound, 1% DMSO per well. The reaction buffer was 50mM HEPES, 10mM MgCl 2 1mM EGTA, 1mM DTT, 0.01% Brij 35, pH 7.5. The compound was incubated with kinase at 25 ℃ for 15min and the reaction was initiated by addition of substrate and ATP. After 1 hour of reaction at 25 ℃, ADP-Glo was added TM Reagents, reaction stopped and incubated at 25 ℃ for 1 hour. The kinase detection reagent was added and the chemiluminescent signal was detected after 1 hour incubation at 25 ℃. From this reading, percent inhibition was calculated and IC of the compound was calculated using a four parameter fit 50 . The results are shown in table 1:
TABLE 1
Compound (I) IC 50 Compound (I) IC 50 Compound (I) IC 50
I-1 A I-2 A I-3 C
I-4 C I-5 C I-6 A
I-7 A I-8 A I-9 A
I-10 C I-11 A I-12 A
I-13 A I-14 A I-15 A
I-16 A I-17 A I-18 A
I-19 A I-20 A I-21 A
I-22 A I-23 A I-24 A
I-25 A I-26 A I-27 A
I-28 A I-29 C I-30 B
I-31 A I-32 A I-33 A
I-34 A I-35 B I-36 A
I-37 A I-38 C
II-1 C II-2 A II-3 A
Wherein A represents IC 50 0.01-5 nM; b represents IC 50 Is 5-10 nM; c represents IC 50 Is 10-100 nM.

Claims (10)

1. A compound according to formula I or II:
Figure FDA0003481686840000011
w is NH or O;
X 1 and X 2 Independently is N or CH; y is N or CR 4 ；
R 1 Is H, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group;
R 4 、R 6 and R 7 Independently H, hydroxy, halogen, CH 3 Or OCH 3 ；
R 8 And R 9 Independently H, hydroxy, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy, C substituted by one or more OH 1 -C 4 An alkyl group; or, R 8 、R 9 Together with the carbon atom to which they are attached form C 3 -C 8 A cycloalkyl group;
R 2 is-CHR 2-1 R 2-2 By one or more R 2-3 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 2-4 Substituted "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", substituted with one or more R 2-5 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radicals, substituted by one or more R 2-6 Substituted "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S" or "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S";
R 2-1 is H or- (CH) 2 )n-R 2-1-1 (ii) a n is 0, 1, 2 or 3;
R 2-1-1 to be one or moreR 2-7 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 2-8 Substituted "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", substituted with one or more R 2-9 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radicals, substituted by one or more R 2-10 Substituted "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S" or "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S";
R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 、R 2-8 、R 2-9 and R 2-10 Independently halogen, hydroxy, cyano, NR 2-11 R 2-12 By one or more R 2-13 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl, by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 An alkoxy group;
R 2-11 and R 2-12 Independently is H or C 1 -C 6 An alkyl group;
R 2-13 and R 2-14 Independently cyano, hydroxy, amino, or halogen;
R 2-2 is H, substituted by one or more R 2-15 Substituted C 1 -C 6 Alkyl or C 1 -C 6 An alkyl group;
R 2-15 independently cyano, hydroxy, amino or halogen;
R 3 is composed of
Figure FDA0003481686840000021
or-C (═ Z) 3 )-L 1 -L 2 -L 3 -L 4 -L 5 ；
Z 1 Is O, S, NH or-CR 1-1 ；
Z 2 Is N or-CR 1-2 ；
Z 3 Is NH, O or S;
R 1-1 and R 1-2 Independently H, halogen, C substituted by one or more halogens 1 -C 4 Alkyl or C 1 -C 4 An alkyl group;
R 5 is represented by one or more R 5-1 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl, by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 5-3 Substituted "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", substituted with one or more R 5-4 Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more R 5-5 Substituted C 6 -C 10 Aryl or C 6 -C 10 An aryl group;
R 5-1 independently by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 5-3 Substituted "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", substituted with one or more R 5-4 Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more R 5-5 Substituted C 6 -C 10 Aryl or C 6 -C 10 An aryl group;
R 5-2 、R 5-3 、R 5-4 and R 5-5 Independently halogen, cyano, hydroxy, NR 5-2-1 R 5-2-2 、C 1 -C 6 Alkyl or-C (═ O) R 5-2-3 ；R 5-2-1 And R 5-2-2 Independently is H or C 1 -C 6 An alkyl group; r 5-2-3 Is C 1 -C 6 An alkyl group;
L 1 is a covalent bond, O, S or NR 10 ；R 10 Is H or C 1 -C 6 An alkyl group;
L 2 being a covalent bond, by one or more R 1-3 Substituted C 1 -C 6 Alkylene or C 1 -C 6 An alkylene group;
L 3 is a covalent bond, C 3 -C 8 Cycloalkylene or "3-12 membered heterocycloalkylene with 1-4 heteroatoms selected from one or more of N, O and S";
L 4 being a covalent bond, by one or more R 1-3 Substituted C 1 -C 6 Alkylene or C 1 -C 6 An alkylene group;
L 5 is represented by one or more R 1-4 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radicals, substituted by one or more R 1-5 Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more R 1-6 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 1-7 Substituted "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S" or "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S";
R 1-3 independently of one another is halogen, hydroxy, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group;
R 1-4 、R 1-5 、R 1-6 and R 1-7 Independently halogen, hydroxy, cyano, NR 2-11 R 2-12 By one or more R 2-13 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl, by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 An alkoxy group;
R 11 is represented by one or more R 11-1 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radicals, substituted by one or more R 11-2 Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more R 11-3 Substituted C 3 -C 8 Cycloalkyl, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 11-4 Substituted "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms", substituted with one or more R 11-5 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 An alkyl group;
R 11-5 independently by one or more R 11-1 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radical, by one or more R 11-2 Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more R 11-3 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 11-4 Substituted "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S" or "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S";
R 11-1 、R 11-2 、R 11-3 and R 11-4 Independently halogen, hydroxy, cyano, NR 2-11 R 2-12 By one or more R 2-13 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl, by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 An alkoxy group.
2. The compound of formula I or II, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is R 1 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 1 Is C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl;
and/or when R 8 And R 9 Independently is C 1 -C 4 When alkyl, said C 1 -C 4 Alkyl is CH 3 、C 2 H 5 iPr or n-Pr;
and/or when R 8 And R 9 Independently is C 1 -C 4 At alkoxy, the C 1 -C 4 Alkoxy being OCH 3 Or OC 2 H 5 ；
And/or when R 8 And R 9 Independently C substituted by one or more OH 1 -C 4 When alkyl, said C substituted by one or more OH 1 -C 4 Alkyl is CH 2 CH 2 OH；
And/or when R 8 、R 9 Together with the carbon atom to which they are attached form C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group;
and/or when R 2 Is represented by one or more R 2-3 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group;
and/or when R 2 Is represented by one or more R 2-4 Substituted "hetero atom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms" or "hetero atom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms", said "hetero atom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms" is "hetero atom is selected from one or more of N and O, 3-6 membered heterocycloalkyl having 1-2 hetero atoms";
and/or when R 2 Is represented by one or more R 2-5 Substituted C 6 -C 10 Aryl or C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl or
Figure FDA0003481686840000031
And/or when R 2 Is represented by one or more R 2-6 Substituted "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" said "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" is "heteroatom is selected from one or more of N, O and S, 5-6 membered heteroaryl with 1-4 heteroatoms";
and/or when R 2-1-1 Is represented by one or more R 2-7 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group;
and/or when R 2-1-1 Is represented by one or more R 2-8 The substituted heteroatom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms, or the heteroatom is selected from one or more of N, O and S, 3-1 membered heterocycloalkyl with 1-4 heteroatoms2-membered heterocycloalkyl ", the" hetero atom is selected from one or more of N, O and S, and the 3-to 12-membered heterocycloalkyl having 1 to 4 hetero atoms "is" 3-to 6-membered heterocycloalkyl having 1 to 2 hetero atoms and one or more of N and O;
and/or when R 2-1-1 Is represented by one or more R 2-9 Substituted C 6 -C 10 Aryl or C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl or
Figure FDA0003481686840000041
And/or when R 2-1-1 When the "hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms selected from N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" substituted by one or more R2-10, the "hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" is one or more selected from N, O and S, 5-6 membered heteroaryl having 1-4 hetero atoms ";
and/or when R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 、R 2-8 、R 2-9 And R 2-10 Independently by one or more R 2-13 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 、R 2-8 、R 2-9 And R 2-10 Independently by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 At alkoxy, the C 1 -C 6 Alkoxy is C 1 -C 4 An alkoxy group;
and/or when R 2-11 And R 2-12 Independently is C 1 -C 6 When alkyl is present, theC 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 2-2 Is represented by one or more R 2-15 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 1-1 And R 1-2 Independently C substituted by one or more halogens 1 -C 4 Alkyl or C 1 -C 4 When alkyl, said C 1 -C 4 Alkyl is methyl, ethyl or isopropyl;
and/or, R 5 Is represented by one or more R 5-1 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or, R 5 Is represented by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group;
and/or, R 5 Is represented by one or more R 5-3 Substituted "heteroatom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from N, O and S", 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N and O ", 3-8 membered heterocycloalkyl with 1-2 heteroatoms;
and/or when R 5 Is represented by one or more R 5-4 When the substituted "hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" or "5-12 membered heteroaryl having 1-4 hetero atoms is one or more selected from N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms", said "hetero atom is one or more selected from N, O and S, and 5-12 membered heteroaryl having 1-4 hetero atoms" is "hetero atom5-6 membered heteroaryl selected from one or more of N, O and S, with 1-4 heteroatoms;
and/or when R 5 Is represented by one or more R 5-5 Substituted C 6 -C 10 Aryl or C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl;
and/or, R 5-1 Is represented by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group;
and/or, R 5-1 Is represented by one or more R 5-3 Substituted "heteroatom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from N, O and S", 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N and O ", 3-8 membered heterocycloalkyl with 1-2 heteroatoms;
and/or when R 5-1 Is represented by one or more R 5-4 Substituted "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" said "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" is "heteroatom is selected from one or more of N, O and S, 5-6 membered heteroaryl with 1-4 heteroatoms";
and/or when R 5-1 Is represented by one or more R 5-5 Substituted C 6 -C 10 Aryl or C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl;
and/or when R 5-2 、R 5-3 、R 5-4 And R 5-5 Independently is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 5-2-1 And R 5-2-2 Independently is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 5-2-3 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 10 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when L 2 Is represented by one or more R 1-3 Substituted C 1 -C 6 Alkylene or C 1 -C 6 When alkylene, the C 1 -C 6 Alkylene being C 1 -C 4 An alkylene group;
and/or when L 3 Is C 3 -C 8 When being cycloalkylene, C is 3 -C 8 Cycloalkylene being C 3 -C 6 A cycloalkylene group;
and/or when L 3 When the compound is 'one or more of N, O and S, 3-12 membered heterocycloalkylene with 1-4 heteroatoms', the 'one or more of N, O and S is/are heteroatom (S)' and the '3-12 membered heterocycloalkylene with 1-4 heteroatoms' is 'one or more of N, O and S, and 3-6 membered heterocycloalkylene with 1-2 heteroatoms';
and/or when L 4 Is represented by one or more R 1-3 Substituted C 1 -C 6 Alkylene or C 1 -C 6 When alkylene, the C 1 -C 6 Alkylene is C 1 -C 4 An alkylene group;
and/or when L 5 Is represented by one or more R 1-4 Substituted C 6 -C 10 Aryl or C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl;
and/or when L 5 Is represented by one or more R 1-5 Substituted "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" said "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" is "heteroatom is selected from one or more of N, O and S, 5-6 membered heteroaryl with 1-4 heteroatoms";
and/or when L 5 Is represented by one or more R 1-6 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group;
and/or when L 5 Is represented by one or more R 1-7 Substituted "heteroatom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from N, O and S", 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N and O ", 3-8 membered heterocycloalkyl with 1-2 heteroatoms;
and/or when R 1-3 Independently is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 1-3 Independently is C 1 -C 6 At alkoxy, the C 1 -C 6 Alkoxy is C 1 -C 4 An alkoxy group;
and/or when R 1-4 、R 1-5 、R 1-6 And R 1-7 Independently by one or more R 2-13 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 1-4 、R 1-5 、R 1-6 And R 1-7 Independently is one ofOr a plurality of R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 At alkoxy, the C 1 -C 6 Alkoxy is C 1 -C 4 An alkoxy group;
and/or when R 11 Is represented by one or more R 11-1 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl;
and/or when R 11 Is represented by one or more R 11-2 Substituted "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" said "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" is "heteroatom is selected from one or more of N, O and S, 5-6 membered heteroaryl with 1-4 heteroatoms";
and/or when R 11 Is represented by one or more R 11-3 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is said C 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group;
and/or when R 11 Is represented by one or more R 11-4 Substituted "heteroatom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from N, O and S", 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N and O ", 3-8 membered heterocycloalkyl with 1-2 heteroatoms;
and/or when R 11 Is represented by one or more R 11-5 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 11-5 Is a quiltOne or more R 11-1 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl is said to C 6 -C 10 Aryl is phenyl;
and/or when R 11-5 Is represented by one or more R 11-2 Substituted "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" said "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" is "heteroatom is selected from one or more of N, O and S, 5-6 membered heteroaryl with 1-4 heteroatoms";
and/or when R 11-5 Is represented by one or more R 11-3 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl being C 3 -C 6 A cycloalkyl group;
and/or when R 11-5 Is represented by one or more R 11-4 Substituted "heteroatom is selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from N, O and S", 3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N and O ", 3-8 membered heterocycloalkyl with 1-2 heteroatoms;
and/or when R 11-1 、R 11-2 、R 11-3 And R 11-4 Independently by one or more R 2-13 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 11-1 、R 11-2 、R 11-3 And R 11-4 Independently by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 When alkoxy, theC is 1 -C 6 Alkoxy is C 1 -C 4 An alkoxy group.
3. The compound of formula I or II, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is R 1 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl;
and/or when R 8 And R 9 Independently is C 1 -C 4 When alkyl, said C 1 -C 4 Alkyl is CH 3 ；
And/or when R 8 And R 9 Independently is C 1 -C 4 At alkoxy, the C 1 -C 4 Alkoxy being OCH 3 ；
And/or when R 8 、R 9 Together with the carbon atom to which they are attached form C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl is cyclopropyl;
and/or when R 2 Is represented by one or more R 2-3 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 The cycloalkyl is cyclohexane;
and/or when R 2 Is represented by one or more R 2-4 When the substituted "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms", said "hetero atom is one or more selected from N, O and S, and 3-12 membered heterocycloalkyl having 1-4 hetero atoms" is
Figure FDA0003481686840000071
And/or when R 2 Is represented by one or more R 2-6 The substituted heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, or the heteroatom is selected from N, O and SAnd 5-12 membered heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S, and 5-12 membered heteroaryl having 1-4 heteroatoms selected from furan, thiophene or pyridine (e.g., furan, thiophene or pyridine)
Figure FDA0003481686840000072
)；
And/or when R 2-1-1 Is represented by one or more R 2-7 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 The cycloalkyl is cyclohexane;
and/or when R 2-1-1 Is represented by one or more R 2-10 When the substituted "hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms", said "hetero atom is one or more selected from N, O and S, and 5-12 membered heteroaryl having 1-4 hetero atoms" is furan, thiophene or pyridine (for example, furan, thiophene or pyridine)
Figure FDA0003481686840000073
)；
And/or when R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 、R 2-8 、R 2-9 And R 2-10 Independently by one or more R 2-13 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl;
and/or when R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 、R 2-8 、R 2-9 And R 2-10 Independently by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 At alkoxy radical, the C 1 -C 6 Alkoxy is methoxy;
and/or when R 2-11 And R 2-12 Independently is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl;
and/or when R 2-2 Is represented by one or more R 2-15 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl;
and/or, R 5 Is represented by one or more R 5-1 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, isopropyl or tert-butyl;
and/or, R 5 Is represented by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl is cyclopropyl, cyclobutyl,
Figure FDA0003481686840000074
Or cyclohexyl;
and/or, R 5 Is represented by one or more R 5-3 When the substituted "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms", said "hetero atom is one or more selected from N, O and S, and 3-12 membered heterocycloalkyl having 1-4 hetero atoms" is
Figure FDA0003481686840000075
And/or when R 5 Is represented by one or more R 5-4 When the substituted "hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl having 1-4 hetero atoms", said "hetero atom is one or more selected from N, O and S, and 5-12 membered heteroaryl having 1-4 hetero atoms" is furan, thiophene or pyridine (for example, furan, thiophene or pyridine)
Figure FDA0003481686840000081
)；
And/or, R 5-1 Is represented by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl or C 3 -C 8 When a cycloalkyl group is present, C is 3 -C 8 Cycloalkyl is cyclopropyl, cyclobutyl,
Figure FDA0003481686840000082
Or cyclohexyl;
and/or, R 5-1 Is represented by one or more R 5-3 When the substituted "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms", said "hetero atom is one or more selected from N, O and S, and 3-12 membered heterocycloalkyl having 1-4 hetero atoms" is
Figure FDA0003481686840000083
And/or when R 5-1 Is represented by one or more R 5-4 When the substituted "hetero atom is one or more selected from N, O and S, 5-to 12-membered heteroaryl having 1 to 4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 5-to 12-membered heteroaryl having 1 to 4 hetero atoms", said "hetero atom is one or more selected from N, O and S, and 5-to 12-membered heteroaryl having 1 to 4 hetero atoms" is furan, thiophene or pyridine (for example, furan, thiophene or pyridine)
Figure FDA0003481686840000084
)；
And/or when R 5-2 、R 5-3 、R 5-4 And R 5-5 Independently is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl;
and/or when R 5-2-1 And R 5-2-2 Independently is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl；
And/or when R 5-2-3 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl;
and/or when R 10 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl;
and/or when L 2 Is represented by one or more R 1-3 Substituted C 1 -C 6 Alkylene or C 1 -C 6 When alkylene, the C 1 -C 6 Alkylene is methylene;
and/or when L 3 Is C 3 -C 8 When being cycloalkylene, C is 3 -C 8 Cycloalkylene is cyclopropylene (for example)
Figure FDA0003481686840000085
)；
And/or when L 3 When the "3-12 membered heterocycloalkylene group having 1 to 4 hetero atoms and one or more hetero atoms selected from N, O and S" is used, the "hetero atom is one or more selected from N, O and S, and the" 3-12 membered heterocycloalkylene group having 1 to 4 hetero atoms "is pyrrolidinylene (e.g., pyrrolidinylene)
Figure FDA0003481686840000086
)；
And/or when L 4 Is represented by one or more R 1-3 Substituted C 1 -C 6 Alkylene or C 1 -C 6 When alkylene, the C 1 -C 6 Alkylene is methylene;
and/or when R 1-3 Independently is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl;
and/or when R 1-3 Independently is C 1 -C 6 At alkoxy, the C 1 -C 6 Alkoxy is methoxy;
and/or when R 1-4 、R 1-5 、R 1-6 And R 1-7 Independently is one ofOr a plurality of R 2-13 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl;
and/or when R 1-4 、R 1-5 、R 1-6 And R 1-7 Independently by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 At alkoxy, the C 1 -C 6 Alkoxy is methoxy;
and/or when R 11 Is represented by one or more R 11-4 When the substituted "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms", said "hetero atom is one or more selected from N, O and S, and 3-12 membered heterocycloalkyl having 1-4 hetero atoms" is
Figure FDA0003481686840000091
And/or when R 11 Is represented by one or more R 11-5 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl;
and/or when R 11-5 Is represented by one or more R 11-4 When the substituted "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms" or "hetero atom is one or more selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 hetero atoms", said "hetero atom is one or more selected from N, O and S, and 3-12 membered heterocycloalkyl having 1-4 hetero atoms" is
Figure FDA0003481686840000092
And/or when R 11-1 、R 11-2 、R 11-3 And R 11-4 Independently by one or more R 2-13 Substituted C 1 -C 6 Alkyl or C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl;
and/or when R 11-1 、R 11-2 、R 11-3 And R 11-4 Independently by one or more R 2-14 Substituted C 1 -C 6 Alkoxy or C 1 -C 6 At alkoxy, the C 1 -C 6 Alkoxy is methoxy.
4. The compound of formula I or II, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein W is NH;
and/or, X 2 Is CH;
and/or, R 1 Is H or C 1 -C 6 An alkyl group;
and/or, R 4 、R 6 And R 7 Independently is H;
and/or, R 8 And R 9 Independently is H or C 1 -C 4 An alkyl group; or, R 8 、R 9 Together with the carbon atom to which they are attached form C 3 -C 8 A cycloalkyl group;
and/or, R 2 is-CHR 2-1 R 2-2 By one or more R 2-5 Substituted C 6 -C 10 Aryl radicals, substituted by one or more R 2-3 Substituted C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 2-4 Substituted "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S" or "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S";
and/or n is 0 or 1;
and/or, R 2-1-1 Is represented by one or more R 2-9 Substituted C 6 -C 10 Aryl radical, C 6 -C 10 Aryl radicals, substituted by one or more R 2-10 The substituted ' hetero atom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms ' or ' hetero atom is selected from one or more of N, O and S, with 1-4 hetero atoms5-12 membered heteroaryl;
and/or, R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 、R 2-8 、R 2-9 And R 2-10 Independently halogen or hydroxy;
and/or, R 2-2 Is H or substituted by one or more R 2-15 Substituted C 1 -C 6 An alkyl group;
and/or, R 2-15 Independently is hydroxy or amino;
and/or, R 1-1 And R 1-2 Independently methyl, ethyl, isopropyl or chloro;
and/or, Z 1 Is O;
and/or, Z 2 Is N;
and/or, Z 3 Is O;
and/or, R 5 Is represented by one or more R 5-1 Substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl, by one or more R 5-2 Substituted C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Cycloalkyl radicals, substituted by one or more R 5-3 Substituted 'hetero atom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 hetero atoms', 'hetero atom selected from one or more of N, O and S, 3-12 membered heterocycloalkyl with 1-4 hetero atoms' or 'hetero atom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms';
and/or, R 5-1 Independently by one or more R 5-3 Substituted "one or more heteroatoms selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 heteroatoms", "one or more heteroatoms selected from N, O and S, 3-12 membered heterocycloalkyl having 1-4 heteroatoms";
and/or, R 5-2 、R 5-3 、R 5-4 And R 5-5 Independently of one another halogen, hydroxy, NR 5-2-1 R 5-2-2 、C 1 -C 6 Alkyl or-C (═ O) R 5-2-3 ；
And/or, L 1 Is NH；
And/or, L 2 Is a covalent bond or C 1 -C 6 An alkylene group;
and/or, L 3 Is C 3 -C 8 Cycloalkylene or "3-12 membered heterocycloalkylene with 1-4 heteroatoms selected from one or more of N, O and S";
and/or, L 4 Is C 1 -C 6 An alkylene group;
and/or, L 5 Is C 6 -C 10 Aryl, or "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S";
and/or, R 3 Is composed of
Figure FDA0003481686840000101
And/or, R 11 Is "3-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of N, O and S" or C 1 -C 6 An alkyl group.
5. The compound of formula I or II, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is 1 Is H or methyl;
and/or, R 8 And R 9 Independently is H or methyl, or R 8 、R 9 Together with the carbon atom to which they are attached form a cyclopropyl group;
and/or, R 2 is-CHR 2-1 R 2-2 ；
And/or, R 2-1-1 Is phenyl, benzyl or pyridyl;
and/or, R 5 Is methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl,
Figure FDA0003481686840000102
Figure FDA0003481686840000103
Figure FDA0003481686840000111
And/or, L 2 Is a covalent bond or a methylene group;
and/or, L 3 Is composed of
Figure FDA0003481686840000112
And/or, L 4 Is methylene;
and/or, L 5 Is phenyl or
Figure FDA0003481686840000113
And/or, R 11 Is methyl or
Figure FDA0003481686840000114
6. The compound of formula I or II, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is 1 Is H;
and/or, R 8 And R 9 Independently is methyl;
and/or, R 2 Is composed of
Figure FDA0003481686840000115
Figure FDA0003481686840000116
The carbon atom with the mark is a chiral carbon atom and is in an S configuration and/or an R configuration.
7. A compound of formula I or II, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 wherein-C (═ O) -L 1 -L 2 -L 3 -L 4 -L 5 Is composed of
Figure FDA0003481686840000117
And/or the presence of a gas in the gas,
Figure FDA0003481686840000121
is composed of
Figure FDA0003481686840000122
Figure FDA0003481686840000123
8. The compound of formula I or II, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound of formula I is any one of the following:
Figure FDA0003481686840000124
Figure FDA0003481686840000131
Figure FDA0003481686840000141
Figure FDA0003481686840000151
the compound shown in the formula II is any one of the following compounds:
Figure FDA0003481686840000152
9. a pharmaceutical composition, which comprises the compound shown in the formula I as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant.
10. The use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the prevention and/or treatment of a disease associated with HPK1 mediated disease;
preferably, the related diseases mediated by HPK1 are non-small cell lung cancer, squamous cell carcinoma, head and neck cancer, oral cancer, pharyngeal cancer, thyroid cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, liver cancer, colon cancer, rectal cancer, villous adenoma of the large intestine, breast cancer, ductal carcinoma of the breast, ovarian cancer, peritoneal cancer, endometrial cancer, uterine body cancer, cervical cancer, renal pelvis cancer, prostate cancer, bladder cancer, neurofibromatosis, bone cancer, brain cancer, testicular cancer, glioma, skin cancer, melanoma, cell tumors and sarcomas, multiple myeloma, leukemia, non-hodgkin's lymphoma, myelodysplastic syndrome.
CN202210069863.9A 2021-01-22 2022-01-21 HPK1 inhibitor, preparation method thereof, pharmaceutical composition and application thereof Pending CN114805330A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023138612A1 (en) * 2022-01-19 2023-07-27 Silexon Ai Technology Co., Ltd. Heterocyclic compounds useful as hpk1 inhibitors
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
WO2023138612A1 (en) * 2022-01-19 2023-07-27 Silexon Ai Technology Co., Ltd. Heterocyclic compounds useful as hpk1 inhibitors

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