CN115490686A

CN115490686A - Nitrogen-containing heterocyclic compound

Info

Publication number: CN115490686A
Application number: CN202210657916.9A
Authority: CN
Inventors: 吴予川; 刘霄; 谢永华; 陈曦; 郝蕊; 胡永韩
Original assignee: Suzhou Sinoway Pharmaceutical Technology Co ltd
Current assignee: Suzhou Sinoway Pharmaceutical Technology Co ltd
Priority date: 2021-06-18
Filing date: 2022-06-10
Publication date: 2022-12-20

Abstract

The invention relates to a nitrogen-containing heterocyclic compound. In particular, the invention relates to a compound shown in formula I or a pharmaceutically acceptable form thereof, a pharmaceutical composition containing the compound and medical application of the compound and the pharmaceutical composition for preventing and/or treating HPK1 related diseases.

Description

Nitrogen-containing heterocyclic compound

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable form thereof, a pharmaceutical composition containing the nitrogen-containing heterocyclic compound and a medical application of the nitrogen-containing heterocyclic compound or the pharmaceutically acceptable form thereof in preventing and/or treating HPK 1-related diseases.

Background

Hematopoietic progenitor kinase 1 (HPK 1, also known as MAP4K 1) 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 (HPK 1) compared to wild type ^-/- ) And HPK1 kinase inactivated (HPK 1 KD) T cells exhibit greater proliferative capacity and higher cytokine expression levels. Systemic lupus erythematosus patients in CD4+ T cells in HPK1 mRNA and protein expression level is also significantly reduced.

HPK1 controls the anti-tumor immune mechanism in a T cell-dependent manner, as in HPK1 ^-/- In tumor-bearing mice with HPK1 KD, T cells have stronger tumor cell killing ability, and tumor cells expressing immunosuppressive molecule PGE2 are in HPK1 ^-/- Grow slower than wild type in HPK1 KD mice. Analysis on the tumor microenvironment of HPK1 KD mice shows that the main immune cell biomarkers participating in the anti-tumor immunity effect 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 improved, and the expression of genes related to Th2 and Treg is reduced.

In 25 human cancers, the expression of HPK1 was significantly positively correlated with the T cell depletion marker PD-1, and positively correlated with other T cell depletion markers TIGIT, CTLA-4, LAG3, etc. in various tumors. Reduced HPK1 expression in low-grade gliomas (LGGs) and renal clear cell carcinomas (KIRCs) correlates with increased survival in patients, while HPK1 expansion in pancreatic cancer (PAAD) and invasive breast cancer (BRAC) correlates 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 various anti-tumor immunity promoting effects and is a potential therapeutic target for tumor immunotherapy and autoimmune diseases.

Disclosure of Invention

Through a large number of researches, the invention discovers a class of nitrogen-containing heterocyclic compounds which have potential values of preventing and/or treating HPK1 related diseases.

In a first aspect, the present invention provides a compound having the structure of formula I:

wherein

A is N, N-O or CR ⁴ ，R ⁴ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl or C _3-6 A cycloalkyl group; said C is _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl or C _3-6 Cycloalkyl is optionally substituted with one or more halo;

w is selected from N or CR ⁵ ，R ⁵ Selected from H, halogen or C _1-6 An alkyl group;

q is selected from N or CR ¹⁵ ，R ¹⁵ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl or C _3-6 A cycloalkyl group; said C is _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl or C _3-6 Cycloalkyl is optionally substituted with one or more halo;

z is selected from N or CR ¹ ，R ¹ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-6 Alkyl radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, C _2-6 Alkenyl radical, C _2-6 Alkynyl or C _1-6 Alkoxy radical, said C _1-6 Alkyl radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, C _2-6 Alkenyl radical, C _2-6 Alkynyl or C _1-6 Alkoxy radicalOptionally substituted with one or more halogens;

or, R ¹⁵ And R ¹ And the atoms to which they are attached together form C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, or 5-8 membered heteroaryl;

R ³ selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-6 Alkyl radical, C _3-8 Cycloalkyl or C _1-6 Alkoxy radical, said C _1-6 Alkyl radical, C _3-8 Cycloalkyl or C _1-6 Alkoxy is optionally substituted with one or more halo;

L ¹ selected from single bond, NH, -N (CH) ₃ )-、O、S、S(＝O)、S(＝O) ₂ 、C(＝O)、

-CH ₂ -, -C ≡ C-, -CH = CH-, or-NH-C (= O) -;

R ² is selected from C _6-10 Aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, C _6-10 Aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from halogen, oxo, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, CN, NO ₂ 、C _1-6 Alkoxy, -S (= O) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-C(＝O)R ^a 、-C(＝O)OR ^a 、-C(＝O)NR ^a R ^b 、-C(＝NR ^a )NR ^b R ^c 、-NR ^a R ^b 、-NR ^a C(＝O)R ^b 、-NR ^a C(＝O)NR ^b R ^c 、-NR ^a C(＝O)OR ^b 、-NR ^a S(＝O)NR ^b R ^c 、-NR ^a S(＝O) ₂ NR ^b R ^c or-NR ^a S(＝O) ₂ R ^b Said C is _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl or C _1-6 Alkoxy is optionally substituted by one or more groups independently selected from halogen, oxo, CN, NO ₂ Or C _1-6 Alkyl substituent substitution;

or two adjacent R ⁶ Together with the atom to which they are attached form C _5-8 Cycloalkyl, or a 5-8 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S, said C _5-8 Cycloalkyl or 5-8 membered heterocyclyl is optionally substituted with one or more R ¹⁶ Substituted, each R ¹⁶ Independently selected from halogen, oxo, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, CN, NO ₂ 、C _1-6 Alkoxy, -S (= O) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-C(＝O)R ^a 、-C(＝O)OR ^a 、-C(＝O)NR ^a R ^b 、-NR ^a R ^b 、-NR ^a C(＝O)R ^b 、-NR ^a C(＝O)NR ^b R ^c 、-NR ^a C(＝O)OR ^b 、-NR ^a S(＝O)NR ^b R ^c 、-NR ^a S(＝O) ₂ NR ^b R ^c or-NR ^a S(＝O) ₂ R ^b ，

R ^a 、R ^b And R ^c Each independently selected from H, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, -C _1-6 alkylene-C _1-6 Alkoxy, -C _1-6 alkylene-C _3-8 Cycloalkyl, -C _1-6 Alkylene- (3-to 8-membered heterocyclic group), C _6-10 Aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl radical, C _1-6 Alkylene radical, C _1-6 Alkoxy radical, C _6-10 Aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, NO ₂ 、-NR ^a R ^b Or C _1-6 Substituent of alkylGeneration; said C is _1-6 Two adjacent substituents in an alkylene group optionally form C together with the atom to which they are attached _3-8 A cycloalkyl group;

or, R ^a And R ^b 、R ^b And R ^c Or R ^a And R ^c Together with the atoms to which they are attached form a 3-12 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S, said 3-12 membered heterocyclyl being optionally substituted with one or more substituents independently selected from halogen, oxo, CN, NO ₂ 、-NR ^a R ^b 、C _1-6 Alkyl or C _1-6 Substituent substitution of alkoxy;

R ^x selected from CN, halogen, -C (= O) NR ^8a R ^8b 、-CH ₂ NR ^8c R ^8d 、Het ^a 、Het ^b 、-CH ₂ -Het ^a 、-CH ₂ -Het ^b 、C _1-6 Alkyl or C _3-6 Cycloalkyl radical, said C _1-6 Alkyl or C _3-6 Cycloalkyl is optionally substituted by 1 or 2 substituents independently selected from halogen, OH, CN or-O-C _1-4 Alkyl substituent substitution;

R ^8a 、R ^8c and R ^8d Each independently selected from H, C _1-4 Alkyl or C _3-6 Cycloalkyl radical, said C _1-4 Alkyl or C _3-6 Cycloalkyl optionally substituted by halogen, OH or-O-C _1-4 Alkyl substitution;

R ^8b is selected from C _1-4 Alkyl or C _3-6 Cycloalkyl radical, said C _1-4 Alkyl or C _3-6 Cycloalkyl optionally substituted by halogen, OH or-O-C _1-4 Alkyl substitution;

or, R ^8a And R ^8b Or R ^8c And R ^8d Together with the N atom to which they are attached form a 4-12 membered heterocyclyl comprising 1N atom and optionally 1 or 2 additional heteroatoms independently selected from N, O or S; wherein said heterocyclyl is optionally substituted on one or more C atoms by 1,2 or 3 substituents independently selected from OH, CN, halogen, R ⁹ 、-OR ⁹ 、-S(＝O) ₂ R ⁹ 、-C(＝O)R ⁹ 、-NR ^6c R ^6d or-C (= O) NR ^6a R ^6b Substituted with the substituent(s); wherein said heterocyclyl is optionally substituted on the N atom by 1 or 2 substituents independently selected from R ⁹ 、-S(＝O) ₂ R ⁹ 、-C(＝O)R ⁹ or-C (= O) NR ^6a R ^6b Substituted with the substituent(s);

Het ^a is composed of

X is selected from N or CH, R ¹¹ And R ¹² Each independently selected from H, C _1-8 Alkyl or C _3-8 A cycloalkyl group;

Het ^b is a 4-12 membered heterocyclyl, said heterocyclyl comprising 1,2 or 3 heteroatoms independently selected from N, O or S; wherein said heterocyclyl is optionally substituted on one or more C atoms by 1,2 or 3 substituents independently selected from oxo, OH, CN, halogen, R ⁹ 、-OR ⁹ 、-S(＝O) ₂ R ⁹ 、-C(＝O)R ⁹ 、-NR ^6c R ^6d or-C (= O) NR ^6a R ^6b Substituted with the substituent(s); wherein said heterocyclyl is optionally substituted on the N atom by 1 or 2 substituents independently selected from R ⁹ 、-S(＝O) ₂ R ⁹ 、-C(＝O)R ⁹ or-C (= O) NR ^6a R ^6b Substituted with the substituent(s);

each R ⁹ Independently selected from C _1-4 Alkyl or C _3-6 Cycloalkyl radical, said C _1-4 Alkyl or C _3-6 Cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, OH, -O-C _1-4 Alkyl or CN;

R ^13a is H;

R ^13b selected from H, oxo or C _1-4 An alkyl group;

R ^14a selected from H, C _1-4 Alkyl or C _3-6 A cycloalkyl group;

R ^14b selected from H, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, or a 4-12 membered heterocyclyl containing 1,2, or 3 heteroatoms independently selected from N, O or S;

or, R ^13b And R ^14b Together with the atoms to which they are attached form a 5-12 membered heteroaryl or 4-12 membered heterocyclyl group, each comprising 1N atom and optionally 1 or 2 additional heteroatoms independently selected from N, O or S; wherein said heteroaryl or heterocyclyl is optionally substituted on one or more C atoms by 1,2 or 3 substituents independently selected from OH, CN, halogen, R ⁷ 、-OR ⁷ 、-S(＝O) ₂ R ⁷ 、-C(＝O)R ⁷ 、-NR ^6c R ^6d 、-C(＝O)NR ^6a R ^6b Or Het ^c Substituted with the substituent(s); wherein said heteroaryl or heterocyclyl is optionally substituted on an optional additional N atom by 1 or 2 independently selected from R ⁷ 、-S(＝O) ₂ R ⁷ 、-C(＝O)R ⁷ 、-C(＝O)NR ^6a R ^6b Or Het ^d Substituted with the substituent(s);

towards R ^13b Is when R is a dotted bond ^13b And R ^14b Together form a ring optionally present as a bond;

at R ^13b And R ^14b When they form a ring together, R ^14a Is H; and when facing R ^13b When the dotted bond of (A) is a bond, R ^13a Is absent; or

R ^14a And R ^14b Together with the N atom to which they are attached form a 5-12 membered heteroaryl or 4-12 membered heterocyclyl, each of which comprises 1N atom and optionally 1 or 2 additional heteroatoms independently selected from N, O or S; wherein said heteroaryl or heterocyclyl is optionally substituted on one or more C atoms by 1,2 or 3 substituents independently selected from OH, CN, halogen, R ⁷ 、-OR ⁷ 、-S(＝O) ₂ R ⁷ 、-C(＝O)R ⁷ 、-NR ^6c R ^6d 、-C(＝O)NR ^6a R ^6b Or Het ^c Substituted with the substituent(s); wherein said heteroaryl or heterocyclyl is optionally substituted on the N atom by 1 or 2 substituents independently selected from R ⁷ 、-S(＝O) ₂ R ⁷ 、-C(＝O)R ⁷ 、-C(＝O)NR ^6a R ^6b Or Het ^d Substituted with the substituent(s);

at R ^14a And R ^14b Forming a ring togetherIn the case of R ^13a Is H, and R ^14b Is H;

R ^6a 、R ^6b 、R ^6c and R ^6d Each independently selected from H, C _3-6 Cycloalkyl or C _1-4 Alkyl radical, said C _3-6 Cycloalkyl or C _1-4 Alkyl is optionally substituted by-OR ¹⁰ Substituted, said C _1-4 Two substituents on the same carbon atom of an alkyl group optionally together form C _3-6 A cycloalkyl group;

each R ¹⁰ Independently selected from H or C _1-4 An alkyl group;

each Het ^c Independently is a 4-12 membered heterocyclyl containing 1,2 or 3 heteroatoms independently selected from N, O or S;

each Het ^d Independently is a 4-12 membered heterocyclyl containing 1,2 or 3 heteroatoms independently selected from N, O or S;

each R ⁷ Independently selected from C _1-4 Alkyl or C _3-6 Cycloalkyl radical, said C _1-4 Alkyl or C _3-6 Cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, OH, -O-C _1-4 Alkyl or CN;

the pharmaceutically acceptable form is selected from the group consisting of pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, nitrogen oxides, isotopic labels, metabolites and prodrugs.

In some embodiments, in the above-described compound of formula I or a pharmaceutically acceptable form thereof,

z is selected from N or CR ¹ ，R ¹ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-6 Alkyl radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, C _2-6 Alkenyl radical, C _2-6 Alkynyl or C _1-6 Alkoxy radical, said C _1-6 Alkyl radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, C _2-6 Alkenyl radical, C _2-6 Alkynyl or C _1-6 Alkoxy is optionally substituted with one or more halo;

-CH ₂ -, -C ≡ C-, -CH = CH-, or-NH-C (= O) -;

R ² is selected from C _6-10 Aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, said C _6-10 Aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from halogen, oxo, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, CN, NO ₂ 、C _1-6 Alkoxy, -S (= O) ₂ R ^a 、-S(＝O) ₂ NR ^a R ^b 、-C(＝O)R ^a 、-C(＝O)OR ^a 、-C(＝O)NR ^a R ^b 、-C(＝NR ^a )NR ^b R ^c 、-NR ^a R ^b 、-NR ^a C(＝O)R ^b 、-NR ^a C(＝O)NR ^b R ^c 、-NR ^a C(＝O)OR ^b 、-NR ^a S(＝O)NR ^b R ^c 、-NR ^a S(＝O) ₂ NR ^b R ^c or-NR ^a S(＝O) ₂ R ^b Said C is _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl or C _1-6 Alkoxy is optionally substituted by one or more groups independently selected from halogen, oxo, CN, NO ₂ Or C _1-6 Alkyl substituent substitution;

R ^a 、R ^b And R ^c Each independently selected from H, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, -C _1-6 alkylene-C _1-6 Alkoxy, -C _1-6 alkylene-C _3-8 Cycloalkyl radical, C _6-10 Aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl radical, C _1-6 Alkylene radical, C _1-6 Alkoxy radical, C _6-10 Aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, CN, NO ₂ Or C _1-6 Alkyl substituent substitution;

or, R ^a And R ^b 、R ^b And R ^c Or R ^a And R ^c Together with the atoms to which they are attached form a 3-12 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S;

or, R ^8a And R ^8b Or R ^8c And R ^8d To which they are connectedTogether form a 4-12 membered heterocyclyl, said heterocyclyl comprising 1N atom and optionally 1 or 2 additional heteroatoms independently selected from N, O or S; wherein said heterocyclyl is optionally substituted on one or more C atoms by 1,2 or 3 substituents independently selected from OH, CN, halogen, R ⁹ 、-OR ⁹ 、-S(＝O) ₂ R ⁹ 、-C(＝O)R ⁹ 、-NR ^6c R ^6d or-C (= O) NR ^6a R ^6b Substituted with the substituent(s); wherein said heterocyclyl is optionally substituted on the N atom by 1 or 2 substituents independently selected from R ⁹ 、-S(＝O) ₂ R ⁹ 、-C(＝O)R ⁹ or-C (= O) NR ^6a R ^6b Substituted with the substituent(s);

Het ^a is composed of

Het ^b is a 4-12 membered heterocyclyl, said heterocyclyl comprising 1,2 or 3 heteroatoms independently selected from N, O or S; wherein said heterocyclyl is optionally substituted on one or more C atoms by 1,2 or 3 substituents independently selected from oxo, OH, CN, halogen, R ⁹ 、-OR ⁹ 、-S(＝O) ₂ R ⁹ 、-C(＝O)R ⁹ 、-NR ^6c R ^6d or-C (= O) NR ^6a R ^6b Substituted with a substituent of (1); wherein said heterocyclyl is optionally substituted on the N atom by 1 or 2 substituents independently selected from R ⁹ 、-S(＝O) ₂ R ⁹ 、-C(＝O)R ⁹ or-C (= O) NR ^6a R ^6b Substituted with the substituent(s);

R ^13a is H;

R ^13b selected from H, oxo or C _1-4 An alkyl group;

R ^14a selected from H, C _1-4 Alkyl or C _3-6 A cycloalkyl group;

or, R ^13b And R ^14b Together with the atoms to which they are attached form a 5-12 membered heteroaryl or 4-12 membered heterocyclyl, each of which comprises 1N atom and optionally 1 or 2 additional heteroatoms independently selected from N, O or S; wherein said heteroaryl or heterocyclyl is optionally substituted on one or more C atoms by 1,2 or 3 substituents independently selected from OH, CN, halogen, R ⁷ 、-OR ⁷ 、-S(＝O) ₂ R ⁷ 、-C(＝O)R ⁷ 、-NR ^6c R ^6d 、-C(＝O)NR ^6a R ^6b Or Het ^c Substituted with the substituent(s); wherein said heteroaryl or heterocyclyl is optionally substituted on an optional additional N atom by 1 or 2 independently selected from R ⁷ 、-S(＝O) ₂ R ⁷ 、-C(＝O)R ⁷ 、-C(＝O)NR ^6a R ^6b Or Het ^d Substituted with the substituent(s);

towards R ^13b When the dotted bond is R ^13b And R ^14b Together form a ring optionally present as a bond;

at R ^14a And R ^14b When they form a ring together, R ^13a Is H, and R ^14b Is H;

each R ¹⁰ Independently selected from H or C _1-4 An alkyl group;

each R ⁷ Independently selected from C _1-4 Alkyl or C _3-6 Cycloalkyl radical, said C _1-4 Alkyl or C _3-6 Cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, OH, -O-C _1-4 Alkyl or CN.

a is selected from N or CR ⁴ ，R ⁴ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) F, cl, br, methyl, methoxy or propenyl;

w is selected from N or CR ⁵ ，R ⁵ Selected from H, F, cl or methyl;

q is selected from N or CR ¹⁵ ，R ¹⁵ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) F, cl, methyl, methoxy, ethoxyA or propenyl group;

z is selected from N or CR ¹ ，R ¹ Selected from H, F, cl, br, methyl, ethyl, isopropyl, cyclopropyl, ethenyl, ethynyl, methoxy, or ethoxy, said methyl, ethyl, isopropyl, cyclopropyl, ethenyl, ethynyl, methoxy, or ethoxy optionally substituted with one or more F, cl or Br;

R ³ selected from H, OH, F, cl, br, methyl, ethyl, cyclopropyl, methoxy or ethoxy, said methyl, ethyl, cyclopropyl, methoxy or ethoxy being optionally substituted by one or more F, cl or Br;

L ¹ selected from single bond, NH or O;

R ² selected from phenyl, pyridyl, imidazopyridinyl, pyrrolopyridyl, oxazolyl, triazolyl, pyridotriazolyl, benzimidazolyl, benzothiazolyl, pyrrolopyrimidinyl, thienopyridinyl, thienopyrimidinyl or pyrazinotriazolyl, optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from F, cl, br, oxo, methyl, CN, NO ₂ Methoxy, isopropyl, cyclopropyl, -CF ₃ 、-C(＝O)NR ^a R ^b 、-NR ^a R ^b 、

Oxazolyl or pyrazolyl optionally substituted with one or more substituents independently selected from F, cl, br, oxo, CN, NO ₂ Or a substituent of a methyl group, or a substituted methyl group,

R ^a and R ^b Each independently selected from H, methyl, ethyl, n-butyl, -ethylene-methoxy, -propylene-cyclopropyl,

The methyl, ethyl, n-butyl, -ethylene-methoxy-propylene-methoxy-propylene-cyclopropyl,

Optionally substituted with one or more groups independently selected from F, cl, br, oxo, CN, NO ₂ Or a substituent of a methyl group, or a substituted methyl group,

or, R ^a And R ^b Together with the atoms to which they are attached form a piperidinyl group, morpholinyl group,

Or two adjacent R ⁶ Together with the atoms to which they are attached form a morpholinyl, pyrrolidinyl or piperidinyl group, optionally substituted with one or more R ¹⁶ Substituted, each R ¹⁶ Independently selected from F, cl, br, oxo, methyl, CN, NO ₂ Or a methoxy group;

R ^x is selected from

Is selected from

In some embodiments, the compound of formula I, or a pharmaceutically acceptable form thereof, described above is a compound having the structure of formula I-a1, or a pharmaceutically acceptable form thereof:

wherein A, Q, Z, W, R ² 、R ³ And L ¹ As defined in formula I.

In some embodiments, in the compound of formula I or formula I-a1 described above, or a pharmaceutically acceptable form thereof, A is selected from N or CR ⁴ ，R ⁴ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl or C _3-6 A cycloalkyl group; said C is _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl or C _3-6 Cycloalkyl is optionally substituted with one or more halogens.

In some preferred embodiments, in a compound of formula I or formula I-a1 as described above or a pharmaceutically acceptable form thereof, R ⁴ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-4 Alkyl radical, C _2-4 Alkenyl or C _1-4 An alkoxy group; said C is _1-4 Alkyl radical, C _2-4 Alkenyl or C _1-4 The alkoxy groups are optionally substituted with one or more F, cl or Br.

In some more preferred embodiments, in the above compound of formula I or formula I-a1 or a pharmaceutically acceptable form thereof, R ⁴ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) F, cl, br, methyl, propenyl or methoxy.

In some embodiments, in the compound of formula I or formula I-a1 described above or a pharmaceutically acceptable form thereof, W is selected from N or CR ⁵ ，R ⁵ Selected from H, halogen or C _1-4 An alkyl group.

In some preferredIn an embodiment, in the above compound of formula I or formula I-a1 or a pharmaceutically acceptable form thereof, R ⁵ Selected from H, F, cl or methyl.

In some embodiments, in a compound of formula I or formula I-a1 as described above, or a pharmaceutically acceptable form thereof, Q is selected from N or CR ¹⁵ ，R ¹⁵ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl or C _3-6 A cycloalkyl group; said C is _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl or C _3-6 Cycloalkyl is optionally substituted with one or more halogens.

In some preferred embodiments, in a compound of formula I or formula I-a1 as described above or a pharmaceutically acceptable form thereof, R ¹⁵ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-4 Alkyl radical, C _2-4 Alkenyl or C _1-4 An alkoxy group; said C is _1-4 Alkyl radical, C _2-4 Alkenyl or C _1-4 The alkoxy groups are optionally substituted with one or more F, cl or Br.

In some more preferred embodiments, in the above compound of formula I or formula I-a1 or a pharmaceutically acceptable form thereof, R ¹⁵ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) F, cl, methyl, methoxy, propenyl, or ethoxy.

In some embodiments, in the compound of formula I or formula I-a1 above, or a pharmaceutically acceptable form thereof, Z is selected from N or CR ¹ ，R ¹ Selected from H, halogen, OH, NH ₂ 、-NH(CH ₃ )、C _1-4 Alkyl radical, C _3-6 Cycloalkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl or C _1-4 Alkoxy radical, said C _1-4 Alkyl radical, C _3-6 Cycloalkyl, C _2-4 Alkenyl radical, C _2-4 Alkynyl or C _1-4 Alkoxy is optionally substituted with one or more halogens.

In some preferred embodiments, in a compound of formula I or formula I-a1 as described above or a pharmaceutically acceptable form thereof, R ¹ Selected from H, F, cl, br, methyl, ethyl, isopropylCyclopropyl, ethenyl, ethynyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, cyclopropyl, ethenyl, ethynyl, methoxy or ethoxy being optionally substituted by one or more F, cl or Br.

In some embodiments, in the above compound of formula I or formula I-a1 or a pharmaceutically acceptable form thereof, R ³ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-4 Alkyl radical, C _3-6 Cycloalkyl or C _1-4 Alkoxy radical, said C _1-4 Alkyl radical, C _3-6 Cycloalkyl or C _1-4 Alkoxy is optionally substituted with one or more halogens.

In some preferred embodiments, in a compound of formula I or formula I-a1 as described above or a pharmaceutically acceptable form thereof, R ³ Selected from H, OH, F, cl, br, methyl, ethyl, cyclopropyl, methoxy or ethoxy, said methyl, ethyl, cyclopropyl, methoxy or ethoxy being optionally substituted by one or more F, cl or Br.

In some embodiments, in a compound of formula I or formula I-a1 described above, or a pharmaceutically acceptable form thereof, L ¹ Selected from the group consisting of a single bond, NH, O, C (= O) or

In some preferred embodiments, in a compound of formula I or formula I-a1 as described above, or a pharmaceutically acceptable form thereof, L ¹ Selected from a single bond, NH or O.

In some embodiments, in the above compound of formula I or formula I-a1 or a pharmaceutically acceptable form thereof, R ² Is selected from C _6-10 Aryl, 5-8 membered heterocyclyl or 5-12 membered heteroaryl, said C _6-10 Aryl, 5-8 membered heterocyclyl or 5-12 membered heteroaryl optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from halogen, oxo, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 5-8 membered heterocyclyl, C _6-10 Aryl, 5-12 membered heteroaryl, CN, NO ₂ 、C _1-4 Alkoxy, -C (= O) R ^a 、-C(＝O)OR ^a 、-C(＝O)NR ^a R ^b 、-NR ^a R ^b 、-NR ^a C(＝O)R ^b 、-NR ^a C(＝O)NR ^b R ^c or-NR ^a C(＝O)OR ^b Said C is _1-4 Alkyl radical, C _3-6 Cycloalkyl, 5-8 membered heterocyclyl, C _6-10 Aryl, 5-12 membered heteroaryl or C _1-4 Alkoxy is optionally substituted by one or more groups independently selected from halogen, oxo, CN, NO ₂ Or C _1-4 Alkyl substituent substitution;

or two adjacent R ⁶ Together with the atoms to which they are attached form a 5-8 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S, said 5-8 membered heterocyclyl optionally substituted with one or more R ¹⁶ Substituted, each R ¹⁶ Independently selected from halogen, oxo, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 5-8 membered heterocyclyl, C _6-10 Aryl, 5-12 membered heteroaryl, CN, NO ₂ 、C _1-4 Alkoxy, -C (= O) R ^a 、-C(＝O)OR ^a 、-C(＝O)NR ^a R ^b 、-NR ^a R ^b 、-NR ^a C(＝O)R ^b 、-NR ^a C(＝O)NR ^b R ^c or-NR ^a C(＝O)OR ^b ，

R ^a 、R ^b And R ^c Each independently selected from H, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, -C _1-4 alkylene-C _1-4 Alkoxy, -C _1-4 alkylene-C _3-6 Cycloalkyl, -C _1-4 Alkylene- (5-to 8-membered heterocyclic group), C _6-10 Aryl, 5-8 membered heterocyclyl or 5-12 membered heteroaryl, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, -C _1-4 alkylene-C _1-4 Alkoxy, -C _1-4 alkylene-C _3-6 Cycloalkyl, -C _1-4 Alkylene- (5-to 8-membered heterocyclic group), C _6-10 Aryl, 5-8 membered heterocyclyl or 5-12 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, NO ₂ 、-NR ^a R ^b Or C _1-6 Alkyl substituent substitution; said C is _1-4 Two adjacent substituents in the alkylene radicalOptionally together with the atom to which they are attached form C _3-6 A cycloalkyl group;

or, R ^a And R ^b 、R ^b And R ^c Or R ^a And R ^c Together with the atoms to which they are attached form a 4-12 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S, said 4-12 membered heterocyclyl being optionally substituted with one or more substituents independently selected from halogen, oxo, CN, NO ₂ 、-NR ^a R ^b 、C _1-4 Alkyl or C _1-4 Substituent of alkoxy.

R ^a 、R ^b And R ^c Each independently selected from H, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, -C _1-4 alkylene-C _1-4 Alkoxy, -C _1-4 alkylene-C _3-6 Cycloalkyl radical, C _6-10 Aryl, 5-8 membered heterocyclyl or 5-12 membered heteroaryl, said C _1-4 Alkyl radical, C _3-6 Cycloalkyl, -C _1-4 alkylene-C _1-4 Alkoxy, -C _1-4 alkylene-C _3-6 Cycloalkyl radical, C _6-10 Aryl, 5-8 membered heterocyclyl or 5-12 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, CN, NO ₂ Or C _1-6 Alkyl substituent substitution;

or, R ^a And R ^b 、R ^b And R ^c Or R ^a And R ^c Together with the atoms to which they are attached form a 5-12 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S.

In some preferred embodiments, in a compound of formula I or formula I-a1 as described above or a pharmaceutically acceptable form thereof, R ² Is selected from C _6-10 Aryl or 5-12 membered heteroaryl, said C _6-10 Aryl or 5-12 membered heteroaryl optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from halogen, oxo, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 5-8 membered heterocyclyl, 5-12 membered heteroaryl, CN, NO ₂ 、C _1-4 Alkoxy, -C (= O) NR ^a R ^b or-NR ^a R ^b Said C is _1-4 Alkyl radical, C _3-6 Cycloalkyl, 5-8 membered heterocyclyl, 5-12 membered heteroaryl or C _1-4 Alkoxy is optionally substituted by one or more groups independently selected from halogen, oxo, CN, NO ₂ Or C _1-4 Alkyl substituent;

or, twoAdjacent R ⁶ Together with the atoms to which they are attached form a 5-8 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S, said 5-8 membered heterocyclyl optionally substituted with one or more R ¹⁶ Substituted, each R ¹⁶ Independently selected from halogen, oxo, C _1-4 Alkyl, 5-8 membered heterocyclic group, CN, NO ₂ 、C _1-4 Alkoxy, -C (= O) NR ^a R ^b or-NR ^a R ^b ，

R ^a And R ^b Each independently selected from H, C _1-4 Alkyl, -C _1-4 alkylene-C _1-4 Alkoxy, -C _1-4 alkylene-C _3-6 Cycloalkyl, -C _1-4 Alkylene- (5-to 8-membered heterocyclic group) or 5-to 8-membered heterocyclic group, said C _1-4 Alkyl, -C _1-4 alkylene-C _1-4 Alkoxy, -C _1-4 alkylene-C _3-6 Cycloalkyl, -C _1-4 Alkylene- (5-8 membered heterocyclyl) or 5-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, NO ₂ 、-NR ^a R ^b Or C _1-6 Alkyl substituent substitution; said C is _1-4 Two adjacent substituents in an alkylene group optionally form C together with the atom to which they are attached _3-6 A cycloalkyl group;

or, R ^a And R ^b Together with the atoms to which they are attached form a 4-8 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S, said 4-8 membered heterocyclyl being optionally substituted with one or more substituents independently selected from halogen, oxo, CN, NO ₂ 、-NR ^a R ^b 、C _1-4 Alkyl or C _1-4 Substituent of alkoxy.

In some preferred embodiments, in a compound of formula I or formula I-a1 as described above or a pharmaceutically acceptable form thereof, R ² Is selected from C _6-10 Aryl or 5-12 membered heteroaryl, said C _6-10 Aryl or 5-12 membered heteroaryl optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from halogen, oxo, C _1-4 Alkyl, 5-8 membered heterocyclyl, 5-12 membered heteroaryl, CN, NO ₂ 、C _1-4 Alkoxy radical、-C(＝O)NR ^a R ^b or-NR ^a R ^b Said C is _1-4 Alkyl, 5-8 membered heterocyclyl, 5-12 membered heteroaryl or C _1-4 Alkoxy is optionally substituted by one or more groups independently selected from halogen, oxo, CN, NO ₂ Or C _1-4 Alkyl substituent substitution;

or two adjacent R ⁶ Together with the atoms to which they are attached form a 5-8 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S, said 5-8 membered heterocyclyl optionally substituted with one or more R ¹⁶ Substituted, each R ¹⁶ Independently selected from halogen, oxo, C _1-4 Alkyl, 5-8 membered heterocyclic group, CN, NO ₂ 、C _1-4 Alkoxy, -C (= O) NR ^a R ^b or-NR ^a R ^b ，

R ^a And R ^b Each independently selected from H, C _1-4 Alkyl, -C _1-4 alkylene-C _1-4 Alkoxy, -C _1-4 alkylene-C _3-6 Cycloalkyl or 5-8 membered heterocyclyl, said C _1-4 Alkyl, -C _1-4 alkylene-C _1-4 Alkoxy, -C _1-4 alkylene-C _3-6 Cycloalkyl or 5-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, oxo, CN, NO ₂ Or C _1-6 Alkyl substituent substitution;

or, R ^a And R ^b Together with the atoms to which they are attached form a 5-8 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S.

In some more preferred embodiments, in the above compound of formula I or formula I-a1 or a pharmaceutically acceptable form thereof, R ² Selected from phenyl, pyridyl, imidazopyridinyl, pyrrolopyridyl, oxazolyl, triazolyl, pyridotriazolyl, benzimidazolyl, benzothiazolyl, pyrrolopyrimidinyl, thienopyridyl, thienopyrimidinyl or pyrazinotriazolyl, said phenyl, pyridyl, imidazopyridinyl, pyrrolopyridyl, oxazolyl, triazolyl, pyridotriazolyl, benzimidazolyl, benzothiazolyl, pyrrolopyrimidinyl, thienopyridyl, thiathiadiazolylPhenopyrimidyl or pyrazinotriazolyl optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from F, cl, br, oxo, methyl, CN, NO ₂ Methoxy, isopropyl, cyclopropyl, -CF ₃ 、NH ₂ 、

Or two adjacent R ⁶ Together with the atoms to which they are attached form a morpholinyl, pyrrolidinyl or piperidinyl group, optionally substituted with one or more R ¹⁶ Substituted, each R ¹⁶ Independently selected from F, cl, br, oxo, methyl, CN, NO ₂ Or a methoxy group.

In some more preferred embodiments, in the above compound of formula I or formula I-a1 or a pharmaceutically acceptable form thereof, R ² Selected from phenyl, pyridyl, imidazopyridyl, pyrrolopyridyl, oxazolyl or triazolyl, optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from F, cl, br, oxo, methyl, CN, NO ₂ A methoxy group,

In some particularly preferred embodiments, inIn a compound of formula I or formula I-a1 as described above or a pharmaceutically acceptable form thereof, substituted R ² Is selected from

Each R ⁶ Independently selected from F, cl, oxo, methyl, CN, methoxy, isopropyl, cyclopropyl, -CF ₃ 、NH ₂ 、

In some particularly preferred embodiments, in the compound of formula I or formula I-a1 described above or a pharmaceutically acceptable form thereof, substituted R ² Is selected from

Each R ⁶ Independently selected from F, oxo, methyl, CN, methoxy,

In some embodiments, the compound of formula I or formula I-a1, or a pharmaceutically acceptable form thereof, described above is a compound having the structure of formula I-a2, formula I-a3, or formula I-a4, or a pharmaceutically acceptable form thereof:

wherein A, Q, Z, W, R ² And R ³ As defined in formula I or formula I-a 1.

In some preferred embodiments, the compound of formula I or formula I-a1 described above, or a pharmaceutically acceptable form thereof, is a compound having the structure of formula I-a2-1, formula I-a3-1, or formula I-a4-1, or a pharmaceutically acceptable form thereof:

wherein A, Q, Z, W, R ² And R ³ As defined in formula I or formula I-a 1.

In some preferred embodiments, the compound of formula I or formula I-a1 described above, or a pharmaceutically acceptable form thereof, is a compound having the structure of formula I-a2-2, formula I-a3-2, or formula I-a4-2, or a pharmaceutically acceptable form thereof:

wherein A, Q, Z, W, R ² And R ³ As defined in formula I or formula I-a 1.

In some embodiments, the compound of formula I or formula I-a1, or a pharmaceutically acceptable form thereof, described above is a compound having the structure of formula I-a5, formula I-a6, or formula I-a7, or a pharmaceutically acceptable form thereof:

wherein R is ² As defined in formula I or formula I-a 1.

In some preferred embodiments, the compound of formula I or formula I-a1 described above, or a pharmaceutically acceptable form thereof, is a compound having the structure of formula I-a5-1, formula I-a6-1, or formula I-a7-1, or a pharmaceutically acceptable form thereof:

wherein R is ² As defined in formula I or formula I-a 1.

In some preferred embodiments, the compound of formula I or formula I-a1 described above, or a pharmaceutically acceptable form thereof, is a compound having the structure of formula I-a5-2, formula I-a6-2, or formula I-a7-2, or a pharmaceutically acceptable form thereof:

wherein R is ² As defined in formula I or formula I-a 1.

It will be understood by those skilled in the art that the present invention encompasses compounds resulting from any combination of the various embodiments. Embodiments resulting from the combination of features from one embodiment or preferred features with features from another embodiment or preferred features are also included within the scope of the present invention.

In a second aspect, the present invention also provides the following compounds, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof:

in a third aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I, formula I-a1 to formula I-a7, formula I-a2-1 to formula I-a7-1, formula I-a2-2 to formula I-a7-2, or a pharmaceutically acceptable form thereof, as described above, and one or more pharmaceutically acceptable carriers.

In a fourth aspect, the present invention provides a compound of formula I, formula I-a1 to formula I-a7, formula I-a2-1 to formula I-a7-1, formula I-a2-2 to formula I-a7-2, or a pharmaceutically acceptable form thereof, as described above, or a pharmaceutical composition as described above, for use in the prevention and/or treatment of a disease or condition mediated at least in part by HPK 1.

In a fifth aspect, the present invention provides the use of a compound of formula I, formula I-a1 to formula I-a7, formula I-a2-1 to formula I-a7-1, formula I-a2-2 to formula I-a7-2, or a pharmaceutically acceptable form thereof, as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by HPK 1.

In a sixth aspect, the present invention provides a method for the prevention and/or treatment of a disease or condition mediated at least in part by HPK1, comprising the steps of: administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of formula I as described above, formula I-a1 to formula I-a7, formula I-a2-1 to formula I-a7-1, formula I-a2-2 to formula I-a7-2, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above.

The present invention is not limited to the specific embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

Definition of terms

The following terms have the following meanings in the present invention unless otherwise specified.

The terms "comprises," "comprising," "includes," "including," "has," "having" or "containing," or any other variation thereof, are intended to cover a non-exclusive or open-ended inclusion. For example, a composition, method, or apparatus that comprises a list of elements is not necessarily limited to only those elements explicitly listed, but may include other elements not explicitly listed or inherent to such composition, method, or apparatus.

When the lower and upper limits of a range of values are disclosed, any value or any sub-range falling within the range is specifically disclosed. In particular, each numerical range of parameters disclosed herein (e.g., in the form of "about a to b," or equivalently "about a-b") is to be understood to encompass each number and subrange therein. For example, "C _1-4 "is to be understood to cover any subrange therein as well as each point value, e.g. C _2-4 、C _3-4 、C _1-2 、C _1-3 、C _1-4 Etc. and C ₁ 、C ₂ 、C ₃ 、C ₄ And so on.

The term "pharmaceutical composition" refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to an excipient that is administered with a therapeutic agent, and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable carriers that may be used in the present invention include, but are not limited to: a) A diluent; b) A lubricant; c) A binder; d) A disintegrant; e) Absorbents, coloring, flavoring and/or sweetening agents; f) An emulsifier or dispersant; and/or g) substances that enhance the absorption of the compounds, and the like.

The pharmaceutical compositions described above may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes or as an inhalant.

The above administration route can be achieved by a suitable dosage form. Dosage forms that may be used in the present invention include, but are not limited to: tablets, capsules, troches, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.

When administered orally, the above pharmaceutical compositions may be formulated into any orally acceptable dosage form, including, but not limited to, tablets, capsules, aqueous solutions, aqueous suspensions, and the like.

The pharmaceutical compositions described above may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions, or sterile injectable aqueous or oleaginous solutions. Among the carriers that can be used are, but not limited to: water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.

The pharmaceutical composition may comprise from 0.01mg to 1000mg of at least one compound of formula I, formula I-a1 to formula I-a7, formula I-a2-1 to formula I-a7-1, formula I-a2-2 to formula I-a7-2, or a pharmaceutically acceptable form thereof, as described above.

The term "a disease or disorder mediated at least in part by HPK 1" refers to a disease that involves at least a portion of the pathogenesis of HPK1, such as 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 corpus 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 lymphoma, or myelodysplastic syndromes.

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

The dosage regimen may be adjusted to provide the best desired response. For example, it can be administered in a single dose, in divided doses over time, or in proportionally smaller or larger doses depending on the circumstances. It will be appreciated that for any particular individual, the specific dosage regimen will be adjusted as needed and as the professional judgment of the person administering the composition or supervising it.

The term "in need thereof" refers to a judgment by a physician or other caregiver that an individual needs or will benefit from a prophylactic and/or therapeutic procedure, the judgment being made based on various factors within the physician's or other caregiver's expertise.

The term "individual" (or subject) refers to a human or non-human animal. The subject of the present invention includes both subjects (patients) suffering from a disease and/or disorder and normal subjects. Non-human animals of the invention include all vertebrates, e.g., non-mammals, such as birds, amphibians, reptiles, and the like, and mammals, e.g., non-human primates, livestock, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, and the like).

The term "treating" refers to alleviating or eliminating the disease or disorder in question. A subject is successfully "treated" if the subject receives a therapeutic amount of a compound of the invention or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention, and the subject exhibits an observable and/or detectable remission and/or improvement of at least one of the indications and symptoms. It is understood that treatment includes not only complete treatment, but also less than complete treatment, but achieves some biologically or medically relevant result. In particular, "treatment" means that the compound of the invention or a pharmaceutically acceptable form thereof or the pharmaceutical composition of the invention can achieve at least one of the following effects, for example: (1) Preventing disease from occurring in an animal that may be predisposed to the disease but has not yet experienced or exhibited disease pathology or symptomology; (2) Inhibiting disease in an animal experiencing or exhibiting disease pathology or symptomatology (i.e., arresting further development of pathology and/or symptomatology); (3) Ameliorating the disease (i.e., reversing pathology and/or symptomatology) in an animal experiencing or exhibiting disease pathology or symptomatology.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic/organic acid or inorganic/organic base, such salts also being referred to as acid addition salts or base addition salts. For a review of suitable Salts see, for example, jusiak, soczewinski, et al, remington's Pharmaceutical Sciences [ M ], mack Publishing Company,2005 and Stahl, wermuth, handbook of Pharmaceutical Salts: properties, selection, and Use [ M ], wiley-VCH,2002. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to an organism and that hydrolyzes in vivo to a compound of the invention or a salt thereof. Pharmaceutically acceptable esters generally include, but are not limited to, esters of the compounds of the invention with pharmaceutically acceptable carboxylic or sulfonic acids, such esters also being referred to as carboxylic or sulfonic acid esters.

The term "isomers" refers to compounds having the same molecular weight, but differing in the spatial arrangement or configuration of the atoms, due to the same number and type of atoms.

The term "stereoisomer" (or "optical isomer") refers to a stable isomer having a perpendicular plane of asymmetry due to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.) that enables rotation of plane polarized light. Since the compounds of the present invention contain asymmetric centers as well as other chemical structures that may lead to stereoisomers, the present invention also includes such stereoisomers and mixtures thereof. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "solvate" refers to a substance formed by the binding of a compound of the present invention (or a pharmaceutically acceptable salt thereof) to at least one solvent molecule by non-covalent intermolecular forces. For example, solvates include, but are not limited to, hydrates (including hemihydrate, monohydrate, dihydrate, trihydrate, and the like), ethanolates, acetonates, and the like.

The term "nitroxide" refers to a compound formed by oxidation of a nitrogen atom in the structure of a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound. For example, the nitrogen atom in the parent nucleus of a compound of formula I may form the corresponding nitroxide.

The term "isotopic label" refers to a derivatized compound formed by replacing a particular atom in a compound of the invention with its isotopic atom. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, cl, such as, but not limited to ² H(D)、 ³ H(T)、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁵ S、 ³⁶ S and ³⁷ Cl。

the term "metabolite" refers to a derivative compound formed after the compounds of the present invention are metabolized. Further information on metabolism can be found in Goodman and Gilman's: the pharmaceutical Basis of Therapeutics (9) ^th ed.)[M]McGraw-Hill International proportions, 1996. The present invention encompasses all possible metabolite forms of the compounds of the invention, i.e. substances formed in the body of the individual to whom the compounds of the invention are administered. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized by assays.

The term "prodrug" refers to a derivative compound that is capable of providing, directly or indirectly, a compound of the invention upon administration to a subject. Particularly preferred derivative compounds or prodrugs are those that, when administered to a subject, increase the bioavailability of the compounds of the invention (e.g., more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art, see, e.g., T.Higuchi, V.Stella, pro-drugs as Novel Drug Delivery Systems [ J ], american Chemical Society, vol.14,1975. Furthermore, the present invention also encompasses compounds of the present invention containing protecting groups. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting Groups, such as those described in t.w.greene, p.g.m.wuts, protective Groups in Organic Synthesis [ M ], john Wiley & Sons, 2006. These protecting groups may be removed at a suitable subsequent stage using methods known in the art.

The term "independently of each other" means that at least two groups (or ring systems) present in the structure in the same or similar range of values may have the same or different meaning in a particular case. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, and when substituent X is hydrogen, substituent Y may be either hydrogen, halogen, hydroxy, cyano, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X may be hydrogen, or may be halogen, hydroxy, cyano, alkyl or aryl.

The term "substituted" means that one or more (e.g., 1,2, 3, or 4) atoms (e.g., hydrogen atoms) or groups of atoms (e.g., triflate groups) on the specified group are replaced with other atoms or groups of atoms, provided that the specified group in the present case satisfies the valence requirements and forms a stable compound after substitution. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. If a substituent is described as "optionally substituted with …," that substituent may be unsubstituted or substituted. If a first substituent is described as being optionally substituted with one or more of the list of second substituents, one or more hydrogen atoms in the first substituent may be replaced, either individually or each independently, with one or more of the list of second substituents, or not.

The term "halogen", when used herein alone or in combination with other groups, refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

The term "alkyl", when used herein alone or in combination with other groups, refers to a straight or branched chain aliphatic hydrocarbon group. For example, the term "C" as used in the present invention _1-4 Alkyl "refers to an alkyl group having 1 to 4 carbon atoms. For example, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. Alkyl groups may be optionally substituted or unsubstituted.

The term "alkylene" as used herein, alone or in combination with other groups, refers to a straight or branched chain divalent aliphatic hydrocarbon group, wherein the two groups (or segments) to which it is attached may be attached to either the same carbon atom or to different carbon atoms. For example, the term "C" as used herein _1-4 Alkylene "means an alkylene having 1 to 4 carbon atoms (e.g., methylene, 1,1-ethylene, 1,2-ethylene, 1,2-propylene, 1,3-butylene, and the like). The alkylene group may be optionally substituted or unsubstituted.

The term "alkoxy" as used herein alone or in combination with other groups, refers to an alkyl group attached to the remainder of the molecule through an oxygen atom. For example, the term "C" as used herein _1-6 Alkoxy "means an alkoxy group having 1 to 6 carbon atoms. For example, alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like. Alkoxy groups may be optionally substituted or unsubstituted.

The term "cycloalkyl" as used herein alone or in combination with other groups means saturated or partially saturated, monoCyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon groups. For example, the term "C" as used in the present invention _3-8 Cycloalkyl "refers to cycloalkyl groups having 3 to 8 carbon atoms. Common cycloalkyl groups include, but are not limited to, monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like; or bicyclic cycloalkyl radicals, including fused, bridged or spiro rings, e.g. bicyclo [1.1.1]Pentyl, bicyclo [2.2.1 ] s]Heptyl, bicyclo [3.2.1]Octyl, bicyclo [5.2.0]Nonyl, decalinyl, and the like. Cycloalkyl groups in the present invention are optionally substituted with one or more substituents described herein.

The term "heterocyclyl", alone or in combination with other groups, as used herein, refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, e.g., fused, bridged or spiro) non-aromatic group whose ring atoms are composed of carbon atoms and at least one heteroatom selected from N, O and S, wherein the S atom is optionally substituted to form S (= O), S (= O) ₂ Or S (= O) (= NR) ^x )，R ^x Independently selected from H or C _1-4 An alkyl group. If the valence requirement is met, the heterocyclyl group may be attached to the remainder of the molecule through any one of the ring atoms. For example, the term "3-8 membered heterocyclic group" as used in the present invention means a heterocyclic group having 3 to 8 ring atoms. Common heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, or trithianyl. The heterocyclic group in the present invention is optionally substituted with one or more substituents described herein.

The term "aryl" as used herein alone or in combination with other groups refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated pi-electron system. For example, the term "C" as used in the present invention _6-10 Aryl "refers to an aryl group having 6 to 10 carbon atoms. Common aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthenyl, azulenyl, fluorenylIndenyl, pyrenyl, and the like. Aryl groups in the present invention are optionally substituted with one or more substituents described herein.

The term "heteroaryl" as used herein alone or in combination with other groups refers to a monocyclic or fused polycyclic aromatic group having a conjugated pi-electron system, the ring atoms of which are composed of carbon atoms and at least one heteroatom selected from N, O and S. Heteroaryl groups, if the valence requirement is met, may be attached to the rest of the molecule through any one of the ring atoms. For example, the term "5-8 membered heteroaryl" as used herein refers to heteroaryl having 5 to 8 ring atoms. Common heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and its benzo derivatives, pyrrolopyridyl, pyrrolopyrazinyl, pyrazolopyridyl, imidazopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, pyridotriazolyl, thienopyridinyl, thienopyrimidinyl, pyrazinotriazolyl, purinyl, and the like. Heteroaryl groups in the present invention are optionally substituted with one or more substituents described herein (e.g., halogen, C) _1-6 Alkyl, etc.).

The term "alkenyl", when used herein alone or in combination with other groups, refers to a straight or branched chain aliphatic hydrocarbon group having at least one C = C double bond. For example, the term "C" as used in the present invention _2-6 Alkenyl "means alkenyl having 2 to 6 carbon atoms. Common alkenyl groups include, but are not limited to, ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-octenyl, n-decenyl, and the like. Alkenyl groups in the present invention are optionally substituted with one or more substituents described herein.

The term "alkynyl", when used herein alone or in combination with other groups, refers to a straight or branched chain aliphatic hydrocarbon group having at least one C ≡ C triple bond. For example, the term "C" as used in the present invention _2-6 Alkynyl "refers to alkynyl groups having 2 to 6 carbon atoms. Common alkynyl groups includeBut are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butynyl, and the like. Alkynyl groups in the present invention are optionally substituted with one or more substituents described herein.

The term "oxo" when used herein alone or in combination with other groups means = O.

Detailed Description

In order to make the objects and technical solutions of the present invention clearer, embodiments of the present invention will be described in detail below with reference to examples. It will be understood by those skilled in the art that the following examples are illustrative of the present invention only and should not be taken as limiting the scope of the invention.

The reagents or instruments used in the examples are all conventional products which are commercially available. Those who do not have specific conditions noted are conducted under conventional conditions or conditions recommended by the manufacturer. The term "room temperature" used in the present invention means 20 ℃. + -. 5 ℃. As used herein, the term "about" when used in reference to a value or range of values is intended to encompass the value or range of values and tolerances acceptable to those skilled in the art for that value or range of values, e.g., within ± 10%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, etc.

The structures of the compounds described in the following examples were determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS).

Nuclear Magnetic Resonance (NMR) measuring apparatus Bruker 400MHz NMR was used, and deuterated methanol (CD) was used as a measuring solvent ₃ OD), deuterated chloroform (CDCl) ₃ ) Hexadeuterio dimethyl sulfoxide (DMSO-d) ₆ ) The internal standard substance is Tetramethylsilane (TMS).

Abbreviations in the Nuclear Magnetic Resonance (NMR) data in the following examples represent the following meanings:

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

All chemical shift (δ) values are given in parts per million (ppm).

Mass Spectrometry (MS) was performed using an Agilent 6120B mass spectrometer with an electrospray ion source (ESI).

Synthesis of Compounds

EXAMPLE 1 Synthesis of intermediate A

Synthesis of Compound 2:

NBS (58.4g, 328mmol, 1.00equiv) was added portionwise to a solution of Compound 1 (50g, 328mmol, 1.00equiv) in acetonitrile (600 mL) at 0 ℃ and the reaction was allowed to react for 16 hours at 15 ℃ under a nitrogen atmosphere. After completion of the reaction, compound 2 was obtained as a pale yellow solid by filtration (45 g, yield 59.48%). M/z (ES +), [ M + H +] ⁺ ＝232。 ¹ H NMR(400MHz,CDCl ₃ ):δppm 7.36(d,J＝8.7Hz,1H),6.97(d,J＝8.7Hz,1H),5.86(s,2H),3.97(s,3H)。

Synthesis of Compound 3:

sodium nitrite (15.46g, 225mmol,1.3 equiv) was added portionwise to a hydrochloric acid (3 mol/L,400 mL) solution of Compound 2 (40g, 173mmol, 1.00equiv) at 0 deg.C, the reaction was stirred at room temperature under nitrogen for 2 hours, the reaction mixture was added dropwise to a 60 deg.C solution of potassium iodide (34.52g, 207mmol,1.2 equiv) in water (100 mL), and the reaction was stirred at 60 deg.C for 30 minutes. After the reaction was complete, the reaction mixture was extracted with ethyl acetate, the organic phase was dried, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1)) to give off-white solid compound 3 (28.6 g, yield 55.3%). M/z (ES +), [ M ] M] ⁺ ＝297。

Synthesis of Compound 4:

compound 3 (18.6g, 54.4mmol, 1.00equiv), pd (dppf) Cl ₂ CH ₂ Cl ₂ (2.23g, 2.72mmol, 0.05equiv), cuprous iodide (1.05g, 5.44mmol, 0.1equiv) were dissolved in N, N-dimethylacetamide (60 mL), the compound SM1 (81.6 mL,1mol/L in DMA, 81.6mmol, 1.5equiv) was added under nitrogen, the reaction system was reacted at 80 ℃ for 2 hours, after completion of the reaction, the reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was dried, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate = 8:1) to give compound 4 as an off-white solid (15 g, 93% yield). M/z (ES +), [ M + H +] ⁺ ＝256。

Synthesis of Compound 5:

compound 4 (15g, 58.8mmol, 1.00equiv) was dissolved in tetrahydrofuran (100 mL), lithium aluminum hydride (2.23g, 58.8mmol, 1equiv) was slowly added thereto at 0 ℃ and the reaction system was reacted at 0 ℃ for 1 hour in a nitrogen atmosphere. After completion of the reaction, quenched with ice water, extracted with ethyl acetate, the organic phase was dried and the crude product was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to yield compound 5 as an off-white solid (3 g, 22% yield). M/z (ES +), [ M ]] ⁺ ＝227。

Synthesis of Compound 6:

compound 5 (3 g,13.2mmol, 1.00equiv) and manganese dioxide (9.2 g,105.7mmol, 8equiv) were dissolved in dichloromethane (30 mL), and the reaction system was stirred overnight at 30 ℃ under a nitrogen atmosphere. After completion of the reaction, the system was filtered, the solvent was spin-dried, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give off-white solid compound 6 (1.7 g, yield)56.6％)。m/z(ES+),[M+H] ⁺ ＝226。

Synthesis of intermediate a:

in a 40mL sealed tube, compound 6 (1.7g, 6.29mmol, 1.00equiv), 4A molecular sieve (2 g), and SM2 (2.29g, 6.29mmol, 1equiv) were dissolved in dichloromethane (30 mL), and the reaction was allowed to react at 30 ℃ for 6 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered, the filtrate was dried by spinning, the mixture was dissolved in hexafluoroisopropanol (20 mL), and then added dropwise to hexafluoroisopropanol (20 mL) of copper trifluoromethanesulfonate (454mg, 1.258mmol, 0.2equiv) and compound SM3 (420mg, 1.258mmol, 0.2equiv), and the reaction mixture was reacted overnight under a nitrogen atmosphere at room temperature. After completion of the reaction, the reaction system was concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 8:1) to give intermediate a (2.0 g, 93% yield) as a brown solid. M/z (ES +), [ M + H +] ⁺ ＝283。

EXAMPLE 2 Synthesis of Compound I-1

Synthesis of Compound 2:

lithium bistrimethylsilylamide (13.95mL, 13.950mmol, 3equiv) was added to a solution of compound 1 (1g, 4.650mmol, 1equiv) in tetrahydrofuran (20 mL) at 0 ℃ and di-tert-butyl dicarbonate (2.037g, 9.300mmol, 2equiv) was added under a nitrogen atmosphere, and the reaction was warmed to room temperature and stirred for 2 hours. After the reaction was complete, quench with water, extract with ethyl acetate, spin dry the organic phase and purify the crude by thin layer chromatography (petroleum ether/ethyl acetate = 5:1) to give compound 2 as an off-white solid (1.4 g, 95.4% yield). M/z (ES +), [ M + H +] ⁺ ＝316。

Synthesis of Compound 3:

compound 2 (1.4g, 4.442mmol, 1equiv), compound SM2 (1.35g, 5.330mmol, 1.2equiv), pd (dppf) Cl ₂ (0.65g, 0.888mmol, 0.2equiv) and potassium acetate (1.31g, 13.326mmol, 3equiv) were dissolved in 1,4-dioxane (10 mL) and reacted at 100 ℃ for 2 hours under a nitrogen atmosphere. After completion of the reaction, the solvent was dried off and the crude product was purified by thin layer chromatography (petroleum ether/ethyl acetate = 5:1) to give compound 3 as a brown solid (1.12 g, 67.66% yield). M/z (ES +), [ M + H +] ⁺ ＝281。

Synthesis of Compound 4:

in a 40mL stopcock, compound 3 (775mg, 2.761mmol, 1equiv), compound SM1 (1.32g, 2.761mmol, 1equiv) were dissolved in 1,4-dioxane/water (16 mL/4 mL), and Pd (dppf) Cl was added ₂ (0.40g, 0.552mmol, 0.2equiv) and potassium carbonate (1.14g, 8.283mmol, 3equiv) were added to the reaction system. The reaction was carried out under nitrogen at 100 ℃ for 2 hours. After TLC monitored completion of the reaction, purification by thin layer chromatography (petroleum ether/ethyl acetate = 1:1) gave compound 4 as a brown solid (1 g, 52.78% yield). M/z (ES +), [ M + H +] ⁺ ＝586。

Synthesis of Compound 5:

compound 4 (900mg, 1.537mmol, 1equiv), compound SM2 (468.44mg, 1.844mmol, 1.2equiv), pd (dppf) Cl in a 40mL vial ₂ (0.65g, 0.888mmol, 0.2equiv) and potassium acetate (1.31g, 13.326mmol, 3equiv) were dissolved in 1,4-dioxane (10 mL) and reacted at 100 ℃ for 2 hours under a nitrogen atmosphere. After the reaction was completed, the reaction system was concentrated, and the crude product was purified by thin layer chromatography (petroleum ether/ethyl acetate = 1:1) to give compound 5 (520 mg, yield 48.67) as a brown solid％)。m/z(ES+),[M+H] ⁺ ＝633。

Synthesis of Compound 6:

compound 5 (60mg, 0.095mmol, 1equiv), intermediate A (34.14mg, 0.105mmol, 1.1equiv), pd (dppf) Cl, in a 40mL lock tube ₂ (13.88mg, 0.019mmol, 0.2equiv) and potassium carbonate (39.33mg, 0.285mmol, 3equiv) were dissolved in 1,4-dioxane/water (5 mL/1 mL) and reacted at 80 ℃ for 2 hours under a nitrogen atmosphere. After completion of the reaction, the filtrate was filtered, the filtrate was dried by rotary drying, and the crude product was purified by thin layer chromatography (dichloromethane: methanol = 10). M/z (ES +), [ M ]] ⁺ ＝753。

Synthesis of compound 7:

in an 8mL sealed tube, compound 6 (49mg, 0.065mmol, 1equiv) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2 mL) was added to the reaction system, and the mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the reaction solution was spin-dried to obtain Compound 7 (30 mg, yield 41.73%) as a brown solid. M/z (ES +), [ M ]] ⁺ ＝653。

Synthesis of Compound I-1:

compound 7 (30mg, 0.046mmol, 1.00equiv) was dissolved in methanol (5 mL) in a 20mL lock tube, and 2mol/L aqueous sodium hydroxide solution (2 mL) was added to the solution, and the reaction was allowed to react at 65 ℃ for 1 hour in a nitrogen atmosphere. After the reaction was completed, the reaction solution was dried, and the mixture was purified by preparative liquid phase under high pressure (Xbridge Shield RP18OBD column, 30X 150mm,5 μm; flow rate: 60mL/min; gradient: 15% B to 40% B within 8 min; 40% B; wavelength: 254nm RT1 (min): 7.67) to obtain white solid compound I-1 (3.1 mg, 10.19% yield). M/z (ES +), [ M + H +] ⁺ ＝498。 ¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.02(s,1H),9.06(s,1H),8.71(s,1H),7.95(d,J＝8.3Hz,1H),7.72-7.88(m,3H),7.30(s,1H),6.09(s,1H),4.29-4.32(m,3H),3.89-3.97(m,2H),3.88(dd,J＝11.1,3.2Hz,1H),3.77(dd,J＝10.6,2.7Hz,1H),3.41-3.60(m,4H),3.33-3.35(m,1H),3.15-3.20(m,1H),2.89-2.97(m,2H),1.57-1.78(m,4H)。

EXAMPLE 3 Synthesis of Compound I-2

Synthesis of compound 1 reference was made to the synthesis of compound 7 in example 2.

Compound 1 (40mg, 0.067mmol, 1.00equiv) was dissolved in methanol (5 mL) in an 8mL lock tube, an aqueous solution of sodium hydroxide (2M, 1mL) was added dropwise, and the reaction mixture was stirred at 65 ℃ for 45 minutes. After the reaction was complete, the reaction solution was spun dry and the crude product was purified by preparative high pressure liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient from 25% to 50% B within 8min, 50% B; the wavelength is 254nm; RT1 (min): 7.93) gave compound I-2 as a white solid (6.4 mg, 21.53% yield). M/z (ES +), [ M + H +] ⁺ ＝441； ¹ H NMR(400MHz,CD ₃ OD-d ₄ ):δppm 9.05(s,1H),8.91(s,1H),7.83-7.93(m,2H),7.73-7.80(m,2H),7.71(s,1H),7.49(t,J＝7.8Hz,2H),7.28-7.36(m,1H),4.45-4.48(m,1H),4.00-4.12(m,2H),3.89-3.99(m,2H),3.58-3.72(m,4H),3.13–3.32(m,3H),1.79-2.04(m,3H),1.67-1.76(m,1H)。

EXAMPLE 4 Synthesis of Compound I-3

In an 8mL lock tube, compound 1 (60mg, 0.101mmol, 1.00equiv) was dissolved in methanol (5 mL), and hydrogen hydroxide was added dropwiseAqueous sodium (2M, 1mL) and the reaction mixture was stirred at 65 ℃ for 45 min. After the reaction was complete, the reaction solution was spun down and the crude product was purified by preparative high pressure liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 15% to 45% within 8min, 45% by weight B; the wavelength is 254nm; RT1 (min): 6.52) gave compound I-3 as a white solid (1.0 mg, 2.89% yield). M/z (ES +), [ M + H +] ⁺ ＝442； ¹ H NMR(400MHz,CD ₃ OD-d ₄ ):δppm 9.10(s,1H),9.09(s,1H),8.98(s,1H),8.93(s,1H),8.50(dd,J＝4.9,1.5Hz,1H),8.28(dt,J＝8.0,1.9Hz,1H),7.82-7.97(m,3H),4.47(dd,J＝10.3,3.3Hz,1H),4.07-4.16(m,2H),3.99(dd,J＝11.6,3.3Hz,1H),3.88-3.95(m,1H),3.57-3.75(m,4H),3.10-3.20(m,3H),1.81-1.96(m,3H),1.71-1.73(m,1H)。

EXAMPLE 5 Synthesis of Compound I-4

Compound 1 (99mg, 0.148mmol, 1equiv) was dissolved in methanol (5 mL) in a 20mL lock tube, an aqueous solution of sodium hydroxide (2M, 2mL) was added dropwise, and the reaction mixture was stirred at 65 ℃ for 45 minutes. After completion of the reaction, the reaction solution was spun down and the crude product was purified by preparative high pressure liquid phase (Xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₃ ·H ₂ O), mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 15% to 40% B within 8min, 40% B; the wavelength is 220nm; RT1 (min): 7.63) gave compound I-4 as a white solid (11.5 mg, 15.1% yield). M/z (ES +), [ M + H +] ⁺ ＝513。 ¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.02(s,1H),9.07(s,1H),8.32(s,1H),7.67-8.00(m,2H),7.47-7.55(m,2H),5.62(s,1H),4.29-4.43(m,3H),3.76-3.97(m,5H),3.23-3.53(m,5H),3.07-3.11(m,4H),2.06(s,3H),1.71-1.96(m,4H)。

EXAMPLE 6 Synthesis of Compound I-5

Compound 1 (40mg, 0.065mmol, 1equiv) was dissolved in methanol (5 mL) in a 20mL sealed tube, an aqueous solution of sodium hydroxide (2M, 1mL) was added dropwise, and the reaction mixture was stirred at 65 ℃ for 45 minutes. After the reaction was complete, the reaction solution was spun down and the crude product was purified by preparative high pressure liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B of water (10 mmol/L NH) ₄ HCO ₃ ) (ii) a The flow rate is 60mL/min; gradient from 25% to 50% B within 8min, 50% B; the wavelength is 254nm; RT1 (min): 7.98) gave compound I-5 as a white solid (3.1 mg, 10.19% yield). M/z (ES +), [ M + H +] ⁺ ＝459； ¹ H NMR(400MHz,DMSO-d6):δppm12.21(s,1H),9.09(s,1H),8.68(s,1H),7.94(d,J＝8.3Hz,1H),7.70-7.91(m,3H),7.33-7.39(m,3H),4.30(dd,J＝10.0,3.2Hz,1H),3.99(dd,J＝11.8,3.2Hz,2H),3.88(dd,J＝11.0,3.2Hz,1H),3.77(dd,J＝10.8,2.8Hz,1H),3.49-3.66(m,3H),3.44-3.45(m,1H),3.21-3.23(m,1H),2.88-2.97(m,2H),1.64-1.79(m,4H)。

¹⁹ F NMR(376MHz,DMSO-d ₆ ):δppm-115.20。

EXAMPLE 7 Synthesis of Compound I-6

Compound 1 (50mg, 0.077mmol, 1.00equiv) was dissolved in methanol (3 mL) in a 20mL lock tube, an aqueous solution of sodium hydroxide (2M, 1mL) was added dropwise, and the reaction mixture was stirred at 65 ℃ for 45 minutes. After the reaction was completed, the reaction solution was spin-dried, and the crude product was purified by preparative high-pressure liquid phase (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient from 22% to 30% within 8min, 30% by weight B; wavelength 254-220nm; RT1 (min): 10.4) gave compound I-6 as a white solid (5 mg, 13.1% yield). M/z (ES +), [ M + H +] ⁺ ＝496。 ¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.15(s,1H),9.07(s,1H),8.90(s,1H),8.61(s,1H),7.94-8.11(m,3H),7.98(d,J＝8.3Hz,1H),7.83(d,J＝8.3Hz,1H),7.70(dd,J＝14.5,8.2Hz,1H),4.43(s,2H),4.31(d,J＝9.8Hz,1H),3.71-4.03(m,4H),3.44-3.64(m,4H),3.10-3.30(s,1H),2.99(d,J＝6.6Hz,2H),1.88–1.55(m,4H)。

EXAMPLE 8 Synthesis of Compound I-7

Compound 1 (20mg, 0.032mmol, 1equiv) was dissolved in methanol (5 mL) in a 20mL sealed tube, and a 2mol/L aqueous solution of sodium hydroxide (2 mL) was added thereto, and the mixture was reacted at 65 ℃ for 1 hour with nitrogen gas purged. After completion of the reaction, the reaction solution was dried and purified by high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 20% to 50% within 7min, 50% by weight B; wavelength is 220nm; RT1 (min): 6.0) gave compound I-7 as a white solid (2.9 mg, 19.2% yield). M/z (ES +), [ M + H +] ⁺ ＝466.3。 ¹ H NMR(400MHz,DMSO-d ₆ )δ12.37(s,1H),9.12(d,J＝2.0Hz,1H),8.89(d,J＝2.0Hz,1H),8.20(s,1H),8.07–8.02(m,3H),7.91–7.85(m,3H),4.31(dd,J＝10.0,3.2Hz,1H),3.99(d,J＝11.2Hz,2H),3.89(dd,J＝11.2,3.2Hz,1H),3.78(d,J＝11.2Hz,1H),3.60–3.43(m,4H),3.36–3.21(m,2H),2.98(s,2H),1.85–1.63(m,4H)。

EXAMPLE 9 Synthesis of Compound I-8

In a 20mL lock tubeCompound 1 (40mg, 0.064mmol, 1equiv) was dissolved in methanol (5 mL), and 2mol/L aqueous sodium hydroxide solution (1.5 mL) was added thereto, and the mixture was reacted at 65 ℃ for 1 hour with nitrogen purged. After the reaction was complete, the reaction solution was spun dry and purified by high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 25% to 55% by weight B within 7min, 55% by weight B; the wavelength is 220nm; RT1 (min): 7.08) gave compound I-8 as a white solid (6.9 mg, 22.8% yield). M/z (ES +), [ M + H +] ⁺ ＝471.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ11.98(s,1H),9.07(s,1H),8.78(s,1H),8.06–7.74(m,5H),7.07(s,2H),4.31(s,1H),3.99–3.55(m,12H),2.98(s,3H),1.88–1.62(m,4H)。

EXAMPLE 10 Synthesis of Compound I-9

Compound 1 (50mg, 0.075mmol, 1equiv) was dissolved in methanol (5 mL) in a 20mL sealed tube, and a 2mol/L aqueous solution of sodium hydroxide (1.5 mL) was added, and the mixture was reacted at 65 ℃ for 1 hour with nitrogen gas purged. After completion of the reaction, the reaction solution was dried and purified by high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 15% to 45% B within 7min, 45% B; the wavelength is 220nm; RT1 (min): 7.03) gave compound I-9 as a white solid (6.7 mg, 17.3% yield). M/z (ES +), [ M + H +] ⁺ ＝512.3。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.18(s,1H),9.10(s,1H),8.88(s,1H),8.02–7.84(m,5H),7.52(s,2H),4.30(s,1H),3.98–3.77(m,4H),3.58–3.25(m,5H),3.02(s,9H),1.80–1.65(m,4H)。

EXAMPLE 11 Synthesis of Compound I-10

Compound 1 (20mg, 0.030mmol, 1equiv) was dissolved in methanol (5 mL) in a 20mL sealed tube, and a 2mol/L aqueous solution of sodium hydroxide (2 mL) was added thereto, and the mixture was reacted at 65 ℃ for 1 hour with nitrogen purged. After the reaction was complete, the reaction solution was spun dry and purified by high pressure preparative liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₃ ·H ₂ O), mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 18% to 43% in 8min, 43% by weight B; the wavelength is 254nm; RT1 (min): 7.82) gave compound I-10 as a white solid (3.5 mg, 22.2% yield). MS (ESI) < M + H] ⁺ ＝512.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ12.15(s,1H),9.05(d,J＝2.0Hz,1H),8.88(d,J＝2.0Hz,1H),8.05–7.94(m,2H),7.93–7.74(m,3H),7.54(t,J＝8.0Hz,1H),7.30(dt,J＝7.6,1.6Hz,1H),4.35–4.25(m,1H),3.99(d,J＝11.2Hz,2H),3.88(dd,J＝11.2,3.2Hz,1H),3.81–3.73(m,1H),3.61–3.42(m,4H),3.25–3.13(m,1H),3.02–2.98(m,8H),1.84–1.62(m,4H)。

EXAMPLE 12 Synthesis of Compound I-11

Compound 1 (80mg, 0.134mmol, 1.00equiv) was dissolved in methanol (4 mL) in a 20mL sealed tube, and a 2mol/L aqueous solution of sodium hydroxide (1 mL) was added thereto, and the mixture was reacted at 65 ℃ for 1 hour with nitrogen gas purged. After completion of the reaction, the reaction solution was dried, and purified by preparative liquid phase under high pressure (Xbridge Prep OBD C18 column, 30X 150mm,5 μ M; flow rate: 60mL/min; gradient: 10% B to 37% B in 8 min; 37% B; wavelength: 220nm RT1 (min): 7.82) to obtain white solid compound I-11 (19.8 mg, yield 33.3%. MS (ESI): M + H: [ M + H ]] ⁺ ＝442.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ12.38(s,1H),9.13(s,1H),8.94(s,1H),8.59(d,J＝5.0Hz,2H),8.26(s,1H),8.05(d,J＝8.0Hz,1H),7.97–7.71(m,3H),4.35–4.26(m,1H),3.96–3.76(m,4H),3.58–3.42(m,5H),2.98(s,3H),1.78–1.62(m,4H)。

EXAMPLE 13 Synthesis of Compound I-12

Compound 1 (50mg, 0.070mmol, 1equiv) was dissolved in methanol (4 mL) in a 20mL sealed tube, and 2mol/L aqueous sodium hydroxide solution (1.5 mL) was added, and the mixture was reacted at 65 ℃ for 1 hour with nitrogen purged. After completion of the reaction, the reaction solution was dried and purified by preparative liquid phase under high pressure (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₃ ·H ₂ O), mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 19% to 44% B within 8min, 44% B; the wavelength is 254nm; RT1 (min): 7.63) gave compound I-12 as a white solid (5.4 mg, 13.7% yield). MS (ESI) < M + H] ⁺ ＝556.4。 ¹ H NMR(400MHz,DMSO-d ₆ )δ12.17(s,1H),9.09(d,J＝2.0Hz,1H),8.88(d,J＝2.0Hz,1H),8.09–7.98(m,2H),7.89–7.82(m,3H),7.53–7.45(m,2H),4.30–4.28(m,1H),3.99(d,J＝10.8Hz,2H),3.89(dd,J＝10.8,2.8Hz,1H),3.78(dd,J＝10.8,2.8Hz,1H),3.70–3.41(m,8H),3.27–3.11(m,4H),3.02–2.97(m,5H),1.88–1.60(m,4H)。

EXAMPLE 14 Synthesis of Compound I-13

Synthesis of compound 1 reference example 2 synthesis of compound 7:

compound 1 (95mg, 0.132mmol, 1equiv) was dissolved in methanol (5 mL) in a 20mL sealed tube, and 2mol/L aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at 65 ℃ for 1 hour with nitrogen purged. After completion of the reaction, the reaction solution was spun dry and purified by preparative high-pressure liquid phase (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water(10mmol/L NH ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 14 to 38% B within 8min, 38%; the wavelength is 220nm; RT1 (min): 7.77) gave compound I-13 as a white solid (2.7 mg, 3.6% yield). MS (ESI): [ M + H] ⁺ ＝566.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ12.23(s,1H),9.10(d,J＝2.0Hz,1H),8.88(d,J＝2.0Hz,1H),8.07–8.00(m,2H),7.91(d,J＝8.0Hz,2H),7.83(d,J＝8.0Hz,1H),7.72(d,J＝8.0Hz,2H),4.71(s,4H),4.56(s,2H),4.30–4.24(m,3H),4.00–3.77(m,5H),3.61–3.40(m,4H),3.23–3.18(m,1H),2.98(s,2H),1.85–1.67(m,4H)。

EXAMPLE 15 Synthesis of Compound I-14

Compound 1 (20mg, 0.031mmol, 1equiv) was dissolved in methanol (5 mL) in a 20mL sealed tube, and 2mol/L aqueous sodium hydroxide solution (2 mL) was added thereto, and the mixture was reacted at 65 ℃ for 1 hour with nitrogen gas purged. After completion of the reaction, the reaction solution was dried and purified by preparative high pressure liquid phase (Xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₃ ·H ₂ O), mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 14 to 39% B within 8min, 39%; the wavelength is 254nm; RT1 (min): 7.85) gave compound I-14 as a white solid (1.8 mg, 11.8% yield). MS (ESI) < M + H] ⁺ ＝496.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ12.22(s,1H),9.10(d,J＝2.0Hz,1H),8.94(d,J＝2.0Hz,1H),8.49(s,1H),8.08–8.00(m,3H),7.93(d,J＝8.0Hz,1H),7.83(d,J＝8.0Hz,1H),7.74(d,J＝8.0Hz,1H),4.46(s,2H),4.30(d,J＝10.0Hz,1H),3.99(d,J＝10.8Hz,2H),3.89(dd,J＝10.8,3.2Hz,1H),3.78(d,J＝10.8Hz,1H),3.62–3.47(m,4H),3.30–3.21(m,2H),3.00–2.95(m,2H),1.81–1.65(m,4H)。

EXAMPLE 16 Synthesis of Compound I-15

Compound 1 (30mg, 0.045mmol, 1equiv) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified by preparative high pressure liquid phase (Xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₃ ·H ₂ O), mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 18% to 43% in 8min, 43% by weight B; the wavelength is 254nm; RT1 (min): 7.78) gave compound I-15 as a white solid (5.2 mg, 24.74% yield). M/z (ES +), [ M + H +] ⁺ ＝460； ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.53(s,1H),9.14(s,1H),8.83(s,1H),8.66(s,1H),8.49(d,J＝7.5Hz,1H),8.12(s,1H),7.95–8.02(m,2H),7.84(d,J＝8.0Hz,1H),4.29(d,J＝9.7Hz,1H),3.94-4.04(m,2H),3.89(dd,J＝11.1,3.2Hz,1H),3.78(dd,J＝10.7,2.7Hz,1H),3.41-3.63(m,4H),3.20(d,J＝11.7Hz,1H),2.97(s,2H),2.66-2.69(m,1H),1.75-1.79(m,3H),1.60-1.63(m,1H)。

¹⁹ F NMR(376MHz,DMSO-d ₆ ):δ(ppm)-130.10。

EXAMPLE 17 Synthesis of Compound I-16

Compound 1 (70mg, 0.103mmol, 1equiv) and NaOH (1mL, 2M) were added to methanol (5 mL) in a 20mL lock tube and reacted under nitrogen at 65 ℃ for 1 hour. After the reaction is finished, the reaction solution is dried by spinning, and column chromatography CH is carried out ₂ Cl ₂ The crude product was obtained from MeOH (10 ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient at 8min-15-41% by B, 41-B; the wavelength is 254nm; RT1 (min): 7.68) gave compound I-16 as a white solid (10.3 mg, 18.9% yield). MS (ESI) < M + H] ⁺ ＝524.2。 ¹ H NMR(400MHz,CD ₃ OD)δ9.06(d,J＝2.0Hz,1H),8.99(d,J＝2.0Hz,1H),8.05(d,J＝8.0Hz,1H),7.94–7.83(m,3H),7.78(d,J＝8.0Hz,1H),7.71(s,1H),4.46(dd,J＝10.4,3.2Hz,1H),4.12–4.09(m,2H),4.03–3.89(m,2H),3.74–3.59(m,6H),3.20–3.10(m,8H),1.97–1.83(m,3H),1.73–1.69(m,1H)。

EXAMPLE 18 Synthesis of Compound I-17

Compound 1 (56mg, 0.074mmol, 1equiv) was dissolved in methylene chloride (1 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude was purified by preparative high pressure liquid phase (Xbridge Prep OBD C18 column, 30 x 150mm,5 μm; flow rate: 60mL/min; gradient: 21% B to 51% B within 8 min; 51% B; wavelength: 254nm RT1 (min): 7.53) to yield compound I-17 as a white solid (20.3 mg, yield 49.11%). MS (ESI): m/z =552. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.16(s,1H),9.06(s,1H),8.87(s,1H),8.02(s,1H),7.97(d,J＝8.2Hz,1H),7.89(d,J＝7.8Hz,1H),7.82(d,J＝8.3Hz,1H),7.76(s,1H),7.54(t,J＝7.7Hz,1H),7.26(d,J＝7.6Hz,1H),4.31(d,J＝8.6Hz,1H),3.98(d,J＝11.0Hz,2H),3.88(dd,J＝11.2,3.1Hz,1H),3.78(dd,J＝11.0Hz,3.2Hz,1H),3.46-3.62(m,6H),3.19-3.25(m,1H),2.99(d,J＝6.7Hz,2H),1.67-1.84(m,3H),1.37-1.66(m,7H)。

EXAMPLE 19 Synthesis of Compound I-18

Compound 1 (75mg, 0.099mmol, 1equiv) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.5 mL) was added, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified by high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30 x 150mm,5 μm; flow rate: 60mL/min; gradient: 13% B to 43% B within 8 min; 43% B within 1 min; wavelength: 254nm RT1 (min): 7.43) to yield compound I-18 as a white solid (29.3 mg, yield 52.56%). MS (ESI): m/z =554. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.11(s,1H),9.07(s,1H),8.88(s,1H),7.95-8.06(m,2H),7.91(d,J＝7.9Hz,1H),7.78-7.87(m,2H),7.55(t,J＝7.7Hz,1H),7.31(d,J＝7.6Hz,1H),4.33-4.35(m,1H),3.93-4.04(m,2H),3.91-3.92(m,1H),3.88-3.89(m,1H),3.73–3.44(m,11H),3.18-3.22(m,1H),2.91-3.07(m,2H),1.55-1.90(m,4H)。

EXAMPLE 20 Synthesis of Compounds I-19

Compound 1 (54mg, 0.07mmol, 1equiv) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified by high pressure preparative liquid phase (XSelectCSH Prep C18OBD column, 19X 250mm,5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 30mL/min; gradient: 20% B to 30% B within 8 min; 30% B; wavelength: 254 220220nm, RT1 (min): 7.77) to yield compound I-19 as a white solid (18 mg, 44.78% yield). MS (ESI) m/z =570. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.21(s,1H),9.78(s,1H),9.28(s,1H),8.98(d,J＝9.0Hz,1H),8.92(s,1H),8.17(d,J＝8.3Hz,1H),7.97-8.08(m,2H),7.93(d,J＝7.9Hz,1H),7.80(s,1H),7.53(t,J＝7.7Hz,1H),7.27(s,1H),5.10(t,J＝10.5Hz,1H),4.19-4.25(m,1H),4.01-4.16(m,1H),4.11(d,J＝12.2Hz,2H),3.93(d,J＝10.5Hz,1H),3.89(s,1H),3.56(t,J＝12.3Hz,3H),3.42(t,J＝12.1Hz,3H),3.33-3.35(m,1H),3.22(s,3H),3.00-3.11(m,2H),2.98(s,3H),1.77-1.96(m,2H),1.68-1.73(m,3H)。

EXAMPLE 21 Synthesis of Compound I-20

Compound 1 (54mg, 0.076mmol, 1equiv) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.5 mL) was added, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product obtained was purified by high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30 x 150mm,5 μm; flow rate: 60mL/min; gradient: 26% B to 51% B in 8 min; wavelength: 254nm RT1 (min): 6.87) to yield compound I-20 as a pale yellow solid (13.1 mg, yield 33.22%). (ES +), MS: m/z =508. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.19(s,1H),9.06(s,1H),8.96(s,1H),8.41(s,1H),8.25(s,1H),8.08(s,1H),7.97(d,J＝8.3,2H),7.91(d,J＝7.7Hz,1H),7.82(d,J＝8.2Hz,1H),7.65(t,J＝7.8Hz,1H),7.41(s,1H),4.30(dd,J＝10.3,3.1Hz,1H),3.99(d,J＝11.0Hz,2H),3.92(dd,J＝11.3,3.1Hz,1H),3.75(dd,J＝10.9,2.9Hz,1H),3.67(t,J＝10.6Hz,1H),3.47-3.61(m,2H),3.21(s,1H),2.85-3.05(m,2H),1.80-1.85(m,3H),1.64-1.72(m,1H)。

EXAMPLE 22 Synthesis of Compound I-21

Compound 1 (50mg, 0.070mmol, 1equiv) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product obtained was purified by high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30 x 150mm,5 μm; flow rate: 60mL/min; gradient: 14% B to 44% B within 8 min; 44% B; wavelength: 254nm RT1 (min): 7.50) to give a white solidCompound I-21 (7.9 mg, 21.65% yield). (ES +), MS (ESI): m/z =512. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.15(s,1H),9.05(s,1H),8.88(s,1H),7.94-8.03(m,2H),7.76-7.82(m,3H),7.54(t,J＝7.6Hz,1H),7.23(d,J＝7.7Hz,1H),4.30(d,J＝9.6Hz,1H),3.99(d,J＝11.0Hz,2H),3.88(d,J＝11.0Hz,1H),3.77(d,J＝11.2Hz,1H),3.56(d,J＝11.1Hz,3H),3.50-3.54(s,5H),2.97-3.05(m,2H),1.89(s,3H),1.73-1.84(m,3H),1.63(d,J＝12.6Hz,1H),1.24(s,1H)。

EXAMPLE 23 Synthesis of Compound I-22

Compound 1 (70mg, 0.093mmol, 1equiv) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.5 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product obtained was subjected to a high pressure preparation of the liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 30% to 60% within 7min, 60% B; the wavelength is 220nm; RT1 (min): 6.20) gave compound I-22 as a white solid (16.5 mg, yield 31.52%). M/z (ES +), [ M + H +] ⁺ ＝554。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.16(s,1H),9.09(s,1H),8.87(s,1H),7.89-8.02(m,2H),7.82-7.87(m,3H),7.47(d,J＝7.7Hz,2H),4.32(dd,J＝10.2,3.2Hz,1H),3.99(d,J＝10.8Hz,2H),3.89(dd,J＝11.2,3.1Hz,1H),3.78(d,J＝10.6Hz,1H),3.41-3.64(m,6H),3.15-3.25(m,2H)2.98(s,5H),1.67-1.87(m,3H),1.45-1.66(m,3H),1.35(s,1H),1.15(s,1H),0.87-0.92(m,3H)。

EXAMPLE 24 Synthesis of Compound I-23

Compound 1 (40mg, 0.052mmol, 1equiv) was dissolved in DCM (2 mL), TFA (1 mL) was added, the reaction flask was purged with nitrogen, and the reaction was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product obtained was subjected to a high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is AC N; the flow rate is 60mL/min; a gradient from 10% to 37% B within 8min, 37% B; the wavelength is 254nm; RT1 (min): 7.83) gave compound I-23 as a white solid (12.9 mg, yield 43.40%). MS (ESI) M/z [ M + H ]] ⁺ ＝566。 ¹ H NMR(400MHz,DMSO-d ₆ )：δ(ppm)12.23(s,1H),9.10(s,1H),8.88(s,1H),7.98-8.10(m,2H),7.81-7.94(m,3H),7.69-7.74(m,2H),4.71(s,4H),4.56(s,2H),4.25-4.28(m,3H),3.88-3.99(m,2H),3.76-3.91(m,2H),3.52-3.61(m,4H),3.18-3.20(m,1H),2.97(s,2H),1.61-1.82(m,4H).

EXAMPLE 25 Synthesis of Compound I-24

Compound 1 (200mg, 0.312mmol, 1.0equiv), aniline (35mg, 0.374mmol, 1.2equiv), brettphos (16.7mg, 0.0312mmol, 0.1equiv), pd were placed in a sealed tube ₂ (dba) ₃ (28.5mg, 0.0312mmol, 0.1equiv) and potassium carbonate (129mg, 0.936mmol, 3equiv) were dissolved in a solution of 1,4-dioxane (5 ml), the reaction system was stirred at 90 ℃ for 2 hours under a nitrogen atmosphere, the solvent was dried by spinning, and the resulting crude product was purified by thin layer chromatography (dichloromethane/methanol = 10/1) to give a white solid compound 2 (130 mg, yield 64%). MS (ESI): M/z [ M + H ])] ⁺ ＝655.

Compound 2 (60mg, 0.092mmol,1.0 equiv) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction, the reaction solution was spin-dried. The crude product obtained was subjected to a high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B is ACN(ii) a The flow rate is 60mL/min; a gradient from 27% to 51% B within 8min, 51% B within 1 min; the wavelength is 254nm; RT1 (min): 7.72) gave compound I-24 as a white solid (7.8 mg, yield: 15.9%). MS (ESI) M/z [ M + H ]] ⁺ ＝455. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)11.46(s,1H),10.21(s,1H),8.50(s,1H),8.01(s,1H),7.88(s,1H),7.70(s,1H),7.53(d,J＝8.0Hz,1H),7.36-7.41(m,2H),7.10-7.14(m,2H),6.82(d,J＝8.0Hz,2H),4.14-4.16(m,1H),3.96-4.00(m,3H),3.66-3.78(m,2H),3.52(t,J＝12.0Hz,4H),2.90-2.97(m,3H),1.57-1.81(m,3H).

EXAMPLE 26 Synthesis of Compound I-25

Compound 1 (100mg, 0.141mmol,1.0 equiv) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was spin-dried. The resulting crude product was subjected to high pressure preparative liquid phase (YMC-Actus Triart C18 ExRS column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 20% to 44% B within 8min, 44% B; the wavelength is 220nm; RT1 (min): 7.72) to yield compound I-25 as a white solid (2 mg, yield: 2.65%). MS (ESI) M/z [ M + H ]] ⁺ ＝509. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)11.74(s,1H),8.54(s,1H),8.38(s,1H),7.80-7.91(m,3H),7.52-7.57(m,2H),7.36(d,J＝8.1Hz,1H),7.19(s,1H),6.63(s,1H),6.18(d,J＝8.0Hz,1H),4.17(s,1H),3.92-3.96(m,2H),3.53(s,3H),3.50-3.52(m,2H),3.47-3.50(m,4H),2.94-3.15(m,3H),1.74-1.81(m,1H),1.55-1.67(m,3H).

EXAMPLE 27 Synthesis of Compound I-26

Compound 1 (100mg, 0.156mmol, 1.0equiv), phenol (17.6mg, 0.187mmol, 1.2equiv), BINAP (10mg, 0.0156mmol, 0.1equiv), BINAP Pd G2 (14.5mg, 0.0156mmol, 0.1equiv), and cesium carbonate (152mg, 0.468mmol, 3.0equiv) were dissolved in dioxane (5 mL) in a sealed tube, the reaction system was stirred at 120 ℃ for 2 hours in a nitrogen atmosphere, the solvent was dried by spinning, and the resulting crude product was purified by thin layer chromatography (dichloromethane/methanol = 10/1) to give white solid compound 2 (20 mg). MS (ESI): M/z [ M/[ M ])] ⁺ ＝655.

Compound 2 (35mg, 0.053mmol, 1.0equiv) was dissolved in methylene chloride (1 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction, the reaction solution was spin-dried. The crude product was subjected to a high pressure preparative liquid phase (Xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₃ ^. H ₂ O), mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 35% to 60% within 8min, 60% by weight B; the wavelength is 254nm; RT1 (min): 7.38) gave compound I-26 as a white solid (2.1 mg, 8.53% yield). MS (ESI) M/z [ M + H ]] ⁺ ＝456. ¹ H NMR(400MHz,CD ₃ OD-d ₄ ):δ(ppm)8.34(s,1H),8.04(s,1H),7.84(s,1H),7.58(dd,J＝8.1,2.1Hz,1H),7.43–7.48(m,3H),7.27–7.29(m,3H),5.62(s,1H),4.31–4.34(m,1H),4.09–4.12(m,2H),3.81–3.90(m,2H),3.51-3.71(m,4H),3.06-3.33(m,3H),1.61-1.89(m,4H).

EXAMPLE 28 Synthesis of Compound I-27

Compound 1 (30mg, 0.043mmol, 1.0equiv) was dissolved in methylene chloride (2 mL), trifluoroacetic acid (1 mL) was added, the reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature for 1 hour. After the reaction, the reaction solution was dried by spinning, and the resulting crude product was subjected to high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 10% to 35% B within 8min, 35% B; the wavelength is 254nm; RT1 (min): 7.97) gave compound I-27 as a white solid (9.1 mg, 41.53% yield). MS (ESI) M/z [ M + H ]] ⁺ ＝503. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.54(s,1H),9.11(s,2H),8.56(s,1H),8.32(s,1H),7.93(d,J＝8.3Hz,1H),7.86(d,J＝8.2Hz,1H),4.32(d,J＝9.5Hz,1H),3.96-4.02(m,2H),3.90-3.92(m,1H),3.80-3.82(m,1H),3.45-3.71(m,7H),3.20-3.31(m,1H),2.95-3.02(m,5H),1.63-1.80(m,4H).

EXAMPLE 29 Synthesis of Compound I-28

Compound 1 (70mg, 0.090mmol,1.0 equiv) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 hour under nitrogen. After the reaction was completed, the reaction solution was spin-dried. The crude product obtained was subjected to a high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 25% to 55% by weight B within 7min, 55% by weight B; the wavelength is 220nm; RT1 (min): 7.15) gave compound I-28 as a white solid (11.3 mg, 21.5% yield). MS (ESI) M/z [ M + H ]] ⁺ ＝580。 ¹ H NMR(400MHz,CD ₃ OD-d ₄ ):δ(ppm)9.06(s,1H),8.99(s,1H),7.81-7.95(m,5H),7.59(t,J＝7.7Hz,1H),7.35(s,1H),4.46-4.62(m,4H),3.91-4.11(m,4H),3.62-3.69(m,5H),3.14(s,3H),1.70-1.95(m,5H),1.31-1.35(m,3H),0.81-1.08(m,2H),0.46-0.48(m,2H),0.14-0.20(m,2H).

EXAMPLE 30 Synthesis of Compound I-29

Compound 1 (40mg, 0.055mmol, 1equiv) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction flask was purged with nitrogen and the reaction was stirred at room temperature for 1 hour. After the reaction, the reaction solution was dried by spinning, and the resulting crude product was subjected to high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 19% to 44% B within 8min, 44% B; the wavelength is 254nm; RT1 (min): 7.73) to give compound I-29 as a white solid (2.8 mg, yield: 9.19%). MS (ESI) M/z [ M + H ]] ⁺ ＝524. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.11(s,1H),9.05(s,1H),9.00(s,1H),8.34(s,1H),7.97(d,J＝8.3Hz,2H),7.83(d,J＝8.2Hz,1H),7.54(d,J＝7.4Hz,1H),7.41-7.43(m,2H),4.33(d,J＝9.6Hz,1H),3.90-3.97(m,4H),3.77-3.80(m,2H),3.52-3.62(m,5H),2.99-3.36(m,4H),2.11-2.14(m,2H),1.62-1.84(m,5H).

EXAMPLE 31 Synthesis of Compound I-30

Compound 1 (50mg, 0.069mmol, 1equiv) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, the reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product obtained was subjected to a high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient from 20% to 50% within 8min, 50% by weight B; the wavelength is 254nm; RT1 (min): 7.40) gave compound I-30 as a white solid (4.1 mg, yield: 10.92%). MS (ESI) M/z [ M + H ]] ⁺ ＝521. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.11(s,1H),9.06(s,1H),8.91(s,1H),8.17(s,1H),7.96-7.99(m,2H),7.82(d,J＝8.4Hz,2H),7.72-7.76(m,1H),7.71-7.73(m,3H),7.50(t,J＝7.7Hz,1H),6.81(s,1H),4.29-4.31(m,1H),3.91-3.99(m,2H),3.88(s,3H),3.86-3.87(m,1H),3.73-3.75(m,1H),3.51-3.57(m,4H),3.20-3.25(m,1H),2.88-2.98(m,2H),1.67-1.82(m,4H).

EXAMPLE 32 Synthesis of Compound I-31

Compound 1 (50mg, 0.071mmol,1.0 equiv) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 hour under nitrogen. After the reaction, the reaction solution was spin-dried. The resulting crude product was subjected to a high pressure preparative liquid phase (Xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 15% to 45% B within 7min, 45% B; the wavelength is 220nm; RT1 (min): 7.38) gave compound I-31 as a white solid (7.9 mg, 22% yield). MS (ESI) M/z [ M + H ]] ⁺ ＝509。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.55(s,1H),9.76(s,1H),9.31(s,1H),9.12(s,1H),8.72(d,J＝5.2Hz,1H),8.54(s,1H),8.45(s,1H),8.34(s,1H),8.23(d,J＝8.3Hz,1H),8.03-8.06(m,2H),7.48(s,1H),6.97-7.23(m,1H),5.10(s,1H),4.19(d,J＝9.6Hz,1H),4.09(d,J＝9.6Hz,1H),3.90-3.99(m,2H),3.87(t,J＝11.2Hz,1H),3.73(t,J＝11.2Hz,1H),3.54-3.60(m,3H),3.05-3.19(m,1H),1.85-1.93(m,1H),1.65-1.77(m,3H).

EXAMPLE 33 Synthesis of Compound I-32

Compound 1 (40mg, 0.054mmol, 1.0equiv) was dissolved in methylene chloride (6 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction, the reaction solution was spin-dried. The resulting crude product was subjected to a high pressure preparative liquid phase (XSelect CSH Prep C18OBD column, 19X 250mm,5 μm; mobile phase A: water (0.05%)TFA), mobile phase B is ACN; the flow rate is 30mL/min; a gradient from 22% to 32% within 8min, 32% by weight; 254, wavelength; 220nm; RT1 (min): 7.10) gave compound I-32 as a white solid (7.1 mg, 23.97% yield). MS (ESI) M/z [ M + H ]] ⁺ ＝538。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.12(s,1H),9.73(d,J＝8.8Hz,1H),9.26(s,1H),8.93-8.98(m,2H),8.23(s,2H),8.14(d,J＝8.4Hz,1H),7.98-8.01(m,2H),7.95(s,1H),7.38(s,1H),7.32(d,J＝8.8Hz,1H),5.08(s,1H),3.94-4.19(m,5H),3.89(s,3H),3.66-3.85(m,2H),3.17(s,2H),167-1.85(m,5H).

EXAMPLE 34 Synthesis of Compound I-33

Compound 1 (50mg, 0.067mmol, 1equiv) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, nitrogen gas was purged into the reaction flask, and the reaction system was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product obtained was subjected to a high pressure preparative liquid phase (Xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₃ ^. H ₂ O), mobile phase B is ACN; the flow rate is 60mL/min; gradient from 26% to 42% within 8min, 42% B; the wavelength is 254nm; RT1 (min): 7.62) gave compound I-33 as a white solid (29.8 mg, 81.5% yield). MS (ESI) M/z [ M ]] ⁺ ＝546. ¹ H NMR(400MHz,Methanol-d4):δ(ppm)9.11(s,1H),9.01(s,1H),8.04(d,J＝8.4Hz,2H),7.95(d,J＝8.4Hz,2H),7.86(d,J＝8.4Hz,1H),7.47(d,J＝8.0Hz,1H),5.15(d,J＝6.8Hz,1H),3.95-4.30(m,5H),3.50-3.79(m,5H),3.11-3.16(m,4H),3.00(s,3H),2.01-2.05(m,1H),1.73-1.89(m,3H).

EXAMPLE 35 Synthesis of Compound I-34

Compound 1 (70mg, 0.092mmol, 1equiv) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, the reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was subjected to a high pressure preparative liquid phase (Xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₃ ^. H ₂ O), mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 30% to 50% within 8min, 50% by weight B; the wavelength is 254nm; RT1 (min): 7.63) to yield compound I-34 as a white solid (10.6 mg, yield: 20.17%). MS (ESI) M/z [ M + H ]] ⁺ ＝564. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.21(s,1H),9.10(s,1H),8.88(s,1H),8.06(s,1H),8.01(d,J＝8.3Hz,1H),7.84-7.88(m,3H),7.72(d,J＝8.1Hz,2H),4.30-4.35(m,3H),3.94-4.13(m,4H),3.89(d,J＝11.2,1H),3.78(d,J＝10.7Hz,1H),3.45-3.66(m,5H),3.17-3.23(m,1H),2.95-2.98(m,2H),2.18(t,J＝7.6Hz,4H),1.56-1.91(m,6H).

EXAMPLE 36 Synthesis of Compound I-35

Compound 1 (45mg, 0.06mmol,1.0 equiv) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product was subjected to a high pressure preparative liquid phase (Xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 19% to 44% B within 8min, 44% B; the wavelength is 254nm; RT1 (min): 7.30) to yield compound I-35 as a white solid (10.9 mg, 32.5% yield) MS (ESI): M/z [ M + H ]] ⁺ ＝554. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.22(s,1H),9.12(s,1H),8.89(s,1H),7.99-8.09(m,2H),7.92(d,J＝8.2Hz,2H),7.85(d,J＝8.4Hz,1H),7.74(d,J＝8.2Hz,2H),4.50-4.53(m,1H),4.37-4.39(m,1H),4.21-4.27(m,3H),3.95-3.99(m,2H),3.82-3.89(m,2H),3.75-3.79(m,2H),3.37-3.61(m,5H),3.02(s,3H),2.92-3.01(m,2H),1.61-1.82(m,4H).

EXAMPLE 37 Synthesis of Compounds I-36

Compound 1 (45mg, 0.059mmol, 1.0equiv) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, the reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was subjected to a high pressure preparative liquid phase (Xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 16% to 41% B within 8min, 41% B within 1 min; the wavelength is 254nm; RT1 (min): 7.47) gave compound I-36 as a white solid (11.3 mg, 33.8% yield). MS (ESI) M/z [ M + H ]] ⁺ ＝567. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.22(s,1H),9.11(s,1H),8.89(s,1H),8.06(s,1H),8.01(d,J＝8.3Hz,1H),7.91(d,J＝8.1Hz,2H),7.83(d,J＝8.3Hz,1H),7.74(d,J＝8.1Hz,2H),4.30-4.38(m,2H),4.06-4.15(m,2H),3.99(d,J＝10.9Hz,2H),3.85-3.93(m,2H),3.78(d,J＝11.0Hz,1H),3.52-3.60(m,4H),3.20-3.36(m,1H),3.10-3.17(m,1H),2.90-3.09(m,2H),2.10(s,6H),1.72-1.81(m,3H),1.59-1.63(m,1H).

EXAMPLE 38 Synthesis of Compound I-37

Compound 1 (35mg, 0.046mmol,1.0 equiv) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, the reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature for 1 hour. After the reaction is finished, spin-drying the reactionAnd (4) liquid. The crude product obtained was subjected to a high pressure preparative liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 10% to 40% B within 7min, 40% B; wavelength is 220nm; RT1 (min): 7.73) gave compound I-37 as a white solid (4.9 mg, 18.8% yield). MS (ESI) M/z [ M + H ]] ⁺ ＝569. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.18(s,1H),9.13(s,1H),8.89(s,1H),8.04(d,J＝8.0,2H),7.85-7.90(m,3H),7.48(d,J＝8.0Hz,2H),4.42-4.43(m,1H),3.99(d,J＝11.0Hz,2H),3.91-3.98(m,1H),3.81-3.90(m,1H),3.50-3.61(m,8H),3.05-3.36(m,3H),3.04(s,3H),2.30(s,1H),2.25(s,3H),2.03(s,3H),1.69-1.83(m,3H),1.64-1.74(m,1H).

EXAMPLE 39 Synthesis of Compound I-38

Compound 1 (25mg, 0.032mmol,1.0 equiv) was dissolved in dichloromethane DCM (3 mL), trifluoroacetic acid (1 mL) was added, the reaction flask was purged with nitrogen, and the reaction was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified by high pressure preparative liquid phase (Xbridge Shield RP18OBD column, 30X 150mm,5 μm; flow rate: 60mL/min; gradient: 15% B to 45% B within 8 min; 45% B; wavelength: 254nm RT1 (min): 7.75) to yield compound I-38 as a white solid (4.3 mg, yield: 23.14%). MS (ESI) M/z [ M + H ]] ⁺ ＝571. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.45(s,1H),9.11(s,1H),9.01(d,J＝6.0Hz,1H),8.58(dd,J＝8.9,5.2Hz,1H),8.37(s,1H),8.04(d,J＝8.2Hz,1H),7.95(dd,J＝8.6,5.6Hz,2H),7.85(d,J＝8.3Hz,1H),4.33(d,J＝9.8Hz,1H),3.99(d,J＝11.0Hz,1H),3.89(d,J＝11.2Hz,1H),3.79(d,J＝11.3Hz,1H),3.56-3.78(m,6H),3.27-3.42(m,3H),2.92-3.10(m,7H),1.56-1.93(m,7H).

EXAMPLE 40 Synthesis of Compound I-39

Compound 1 (70mg, 0.087mmol, 1.0equiv) was dissolved in methylene chloride (4 mL), trifluoroacetic acid (1.5 mL) was added, nitrogen gas was purged into a reaction flask, and the reaction system was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified by high pressure preparative liquid phase (X Select CSH Prep C18OBD column, 19X 250mm,5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 24% to 34% B in 7 min; 34% B; wavelength: 254 220220nm, RT1 (min): 6.85) to yield compound I-39 as a white solid (22.5 mg, yield: 42.50%). MS (ESI) M/z [ M ]] ⁺ ＝604. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.26(s,1H),9.75(s,1H),9.26(s,1H),8.83-9.09(m,2H),8.18(d,J＝8.3Hz,1H),7.89-8.13(m,3H),7.82(d,J＝9.6Hz,1H),7.59(dd,J＝8.4,4.2Hz,1H),5.11(s,1H),4.10-4.20(m,2H),3.92-3.99(m,3H),3.65-3.92(m,6H),3.27-3.53(m,4H),3.02(d,J＝9.7Hz,4H),2.85-3.01(m,2H),1.85-1.90(m,2H),1.64-1.79(m,3H).

EXAMPLE 41 Synthesis of Compound I-40

Compound 1 (40mg, 0.050mmol,1.0 equiv) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction flask was purged with nitrogen and the reaction was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product obtained was subjected to a high pressure preparation of the liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 15% to 45% B within 7min, 45% B; the wavelength is 220nm; RT1 (min): 7.80) to give compound I-40 as a white solid (9.6 mg, yield: 31.0%). MS (ESI): M/z [ M + H ]] ⁺ ＝600. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.01(s,1H),9.04(s,1H),8.80(s,1H),7.96(dd,J＝8.2Hz,2.8Hz,1H),7.88(s,1H),7.82(d,J＝8.6Hz,2H),7.53-7.55(m,1H),7.19(dd,J＝8.7Hz,1.6Hz,1H),4.36(d,J＝9.9Hz,1H),3.98(d,J＝11.0Hz,2H),3.81-3.90(m,5H),3.47-3.62(m,5H),3.25(s,3H),3.19(s,3H),2.98-3.10(m,5H),2.82(s,3H),1.69-1.86(m,2H),1.58-1.67(m,3H).

EXAMPLE 42 Synthesis of Compound I-41

Compound 1 (80mg, 0.10mmol,1.0 equiv) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction flask was purged with nitrogen and the reaction was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product obtained was subjected to a high pressure preparation of the liquid phase (Xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 10% to 40% B within 7min, 40% B; the wavelength is 220nm; RT1 (min): 7.07) gave compound I-41 as a white solid (7.5 mg, yield: 11.93%). MS (ESI) M/z [ M ]] ⁺ ＝600. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.29(s,1H),9.11(s,1H),8.92(s,1H),8.22(s,1H),8.15(s,1H),8.03(d,J＝8.2Hz,1H),7.94(d,J＝8.2Hz,1H),7.82-7.90(m,2H),7.50(d,J＝7.9Hz,1H),4.67-4.74(m,4H),4.37(dd,J＝10.0,3.2Hz,1H),4.26(s,2H),4.16(s,2H),3.99(d,J＝10.9Hz,2H),3.81-3.92(m,3H),3.49-3.65(m,3H),2.95-3.01(m,3H),1.55-1.89(m,4H).

EXAMPLE 43 Synthesis of Compound I-42

Compound 1 (30mg, 0.029mmol, 1equiv) was dissolved in dichloromethane (3 mL), nitrogen was purged, and 2,6-lutidine (0.3 mL) and trifluoro pyridine were addedTrimethylsilyl methanesulfonate (0.3 mL). The reaction was stirred at 0 ℃ for half an hour and then at room temperature for 2 hours. After the reaction was completed, the reaction solution was dried by spinning, and the resulting crude product was purified by preparative high-pressure liquid phase (column: xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient from 24% to 54% within 8min, 54% by weight B; the wavelength is 220nm; RT1 (min): 7.32) gave compound I-42 as a white solid (7.3 mg, yield: 40.77%). MS (ESI) M/z [ M + H ]] ⁺ ＝612. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.15(s,1H),9.06(s,1H),8.87(s,1H),7.96-8.01(m,2H),7.84-7.90(m,2H),7.76(s,1H),7.52(d,J＝8.1Hz,1H),7.27(s,1H),4.32(d,J＝9.7Hz,1H),3.98(d,J＝10.8Hz,2H),3.88(d,J＝8.4Hz,1H),3.78(d,J＝10.8Hz,1H),3.52-3.54(m,6H),3.16-3.20(m,3H),2.99(s,5H),1.61-1.80(m,6H),0.90(s,9H).

EXAMPLE 44 Synthesis of Compound I-43

Compound 1 (50mg, 0.063mmol, 1equiv) was dissolved in methylene chloride (1 mL), trifluoroacetic acid (1 mL) was added, the reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction, the reaction solution was spin-dried. The crude product was subjected to high pressure to prepare a liquid phase (column: xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 20% to 50% within 7min, 50% by weight B; the wavelength is 220nm; RT1 (min): 7.50) gave compound I-43 as a white solid (3.4 mg, 9.01% yield). MS (ESI) M/z [ M + H ]] ⁺ ＝596. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.16(s,1H),9.07(s,1H),8.87(s,1H),7.77-8.02(m,5H),7.54(t,J＝7.7Hz,1H),7.28(d,J＝7.5Hz,1H),4.34(s,1H),3.99(d,J＝10.8Hz,2H),3.91-3.98(m,2H),3.40-3.57(m,6H),3.22(s,3H),3.02(s,5H),2.85-3.01(m,2H),1.62-1.89(m,6H),0.27-0.70(m,4H).

EXAMPLE 45 Synthesis of Compound I-44

Compound 1 (60mg, 0.079mmol, 1.0equiv) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, the inside of a reaction bottle was purged with nitrogen, and the reaction system was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction, the reaction solution was spin-dried. The crude product was purified by preparative liquid phase under high pressure (column: xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient 9%B to 39% B within 8min, 39% B; the wavelength is 220nm; RT1 (min): 7.65) gave compound I-44 as a white solid (8.6 mg, yield 19.17%). MS (ESI) M/z [ M + H ]] ⁺ ＝564. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.24(s,1H),9.14(s,1H),8.89(s,1H),8.07(d,J＝8.1Hz,1H),8.01(d,J＝7.9Hz,1H),7.92(d,J＝8.1Hz,2H),7.84(d,J＝7.7Hz,1H),7.72(d,J＝7.7Hz,2H),4.71(s,4H),4.56(s,2H),4.20-4.25(m,3H),3.99(d,J＝10.4Hz,2H),3.51-3.56(m,2H),3.19-3.22(m,2H),2.77-2.83(m,1H),1.52-1.92(m,11H).

EXAMPLE 46 Synthesis of Compound I-45

Compound 1 (20mg, 0.027mmol, 1.0eq) was dissolved in methylene chloride (1 mL), trifluoroacetic acid (1 mL) was added, nitrogen gas was placed in a reaction flask, and the reaction system was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction was completed, the reaction solution was spin-dried. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient from 14% to 39% within 8min, 39% B; the wavelength is 220nm; RT1 (min): 7.60 Compound I-45 was obtained as a white solid (3.8 mg, yield 25.04%). MS (ESI) M/z [ M + H ]] ⁺ ＝550. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.29(s,1H),9.06(s,1H),8.91(s,1H),8.07(s,1H),7.99(d,J＝8.2Hz,1H),7.90(d,J＝8.4Hz,2H),7.83(d,J＝8.4Hz,1H),7.72(d,J＝8.4Hz,2H),4.71(s,4H),4.56(s,2H),4.50(t,J＝7.3Hz,1H),4.25(s,2H),3.97-4.00(m,2H),3.53(t,J＝10.4Hz,2H),3.25-330(m,2H),2.86-2.91(m,1H),2.09-2.18(m,1H),1.62-1.88(m,7H).

EXAMPLE 47 Synthesis of Compound I-46

Compound 1 (40mg, 0.060mmol,1.0 equiv) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, the reaction flask was purged with nitrogen, and the reaction system was stirred at room temperature for 1 hour. After the reaction, the reaction solution was spin-dried. The resulting crude product was purified by preparative high pressure liquid phase (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 25% to 55% by weight B within 7min, 55% by weight B; the wavelength is 220nm; RT1 (min): 7.78) gave compound I-46 as a white solid (3.3 mg, yield: 9.32%). MS (ESI) M/z [ M + H ]] ⁺ ＝564. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.20(s,1H),9.01(s,1H),8.88(s,1H),8.06(s,1H),7.71-8.00(m,6H),4.71(s,4H),4.56(s,2H),4.24(s,2H),3.94-4.01(m,4H),3.47-3.52(m,2H),1.70-1.85(m,8H),1.23-1.25(m,3H).

EXAMPLE 48 Synthesis of Compounds I-47

Compound 1 (40mg, 0.062mmol, 1.0equiv) was dissolved in methylene chloride (6 mL), and trifluoroethylene was addedAcid (2 mL), nitrogen was purged into the reaction flask, and the reaction was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified by preparative high pressure liquid phase (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 25% to 55% by weight B within 7min, 55% by weight B; the wavelength is 220nm; RT1 (min): 7.78) gave compound I-47 as a white solid (6.2 mg, yield: 23.49%). MS (ESI) M/z [ M + H ]] ⁺ ＝538. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.21(s,1H),9.01(s,1H),8.86(s,1H),7.99-8.07(m,1H),7.83-7.89(m,4H),7.72(d,J＝8.4Hz,2H),4.71(s,4H),4.57(s,2H),4.25(s,2H),3.98-4.01(m,2H),3.70(s,2H),3.45-3.50(m,2H),3.29-3.31(m,1H),2.25(s,6H),1.71–1.78(m,4H).

EXAMPLE 49 Synthesis of Compound I-48

Compound 1 (20mg, 0.026mmol, 1.0equiv) was dissolved in methylene chloride (1 mL), trifluoroacetic acid (1 mL) was added, nitrogen gas was purged into the reaction flask, and the reaction system was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction, the reaction solution was spin-dried. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 18% to 43% in 8min, 43% by weight B; the wavelength is 220nm; RT1 (min): 7.62) gave compound I-48 as a white solid (11.0 mg, yield 73.85%). MS (ESI) M/z [ M + H ]] ⁺ ＝580. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.23(s,1H),9.10(s,1H),8.88(s,1H),8.07(s,1H),8.01(d,J＝8.2Hz,1H),7.91(d,J＝8.1Hz,2H),7.84(d,J＝8.3Hz,1H),7.72(d,J＝8.1Hz,2H),4.71(s,4H),4.57(s,2H),4.25(s,3H),3.86-4.00(m,3H),3.52-3.64(m,4H),3.20(t,J＝11.6Hz,1H),3.01(d,J＝12.4Hz,1H),2.55-2.63(m,1H),1.59-1.82(m,4H),1.09(d,J＝6.1Hz,3H).

EXAMPLE 50 Synthesis of Compounds I-49

Compound 1 (11mg, 0.019mmol, 1.0equiv) was dissolved in methanol (3 mL) in an 8mL sealed tube, nitrogen gas was blown in, an aqueous solution of formaldehyde (2.4mg, 0.080mmol, 4.11equiv) was added, and the reaction system was stirred at room temperature for 1 hour. After disappearance of the starting material, sodium cyanoborohydride (2.5mg, 0.040mmol, 2.05equiv) was added and the reaction mixture was stirred at room temperature for 4h. After the reaction, the reaction solution was dried by spinning, and the obtained crude product was purified by preparative high-pressure liquid phase (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient of 5%B to 35% in 7min, 35% by weight B; wavelength is 220nm; RT1 (min): 7.18) gave compound I-49 as a white solid (1.8 mg, yield: 13.81%). MS (ESI) M/z [ M + H ]] ⁺ ＝580. ¹ HNMR(400MHz,DMSO-d ₆ ):δ(ppm)12.22(s,1H),9.03(s,1H),8.88(s,1H),8.00-8.07(m,2H),7.86-7.91(m,3H),7.72(d,J＝8.1Hz,2H),4.71(s,4H),4.56(s,2H),4.25(s,2H),3.98-4.01(m,2H),3.68-3.86(m,6H),3.49-3.56(m,2H),2.89(d,J＝11.2Hz,1H),2.03(s,2H),1.76-1.93(m,2H),1.61-1.64(m,2H),1.24(s,2H).

EXAMPLE 51 Synthesis of Compound I-50

Compound 1 (60mg, 0.078mmol, 1.0equiv) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, the inside of a reaction bottle was purged with nitrogen, and the reaction system was stirred at room temperature for 1 hour in a nitrogen atmosphere. After the reaction, the reaction solution was spin-dried. The resulting crude product was purified by preparative high pressure liquid phase (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Flow ofThe mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 25% to 55% by weight B within 7min, 55% by weight B; the wavelength is 220nm; RT1 (min): 7.78) gave compound I-50 (10.2 mg, yield: 22.84%). MS (ESI) M/z [ M + H ]] ⁺ ＝570. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.18(s,1H),9.10(s,1H),8.88(s,1H),8.00-8.03(m,2H),7.82-7.90(m,3H),7.51-7.53(m,2H),4.64(s,1H),4.31(d,J＝9.9Hz,1H),3.99(d,J＝10.8Hz,2H),3.77-3.90(m,2H),3.47-3.61(m,6H),3.23-3.31(m,1H),3.12(s,3H),2.98-3.10(m,2H),1.65-1.81(m,4H),1.19(s,6H),0.97(s,1H).

EXAMPLE 52 Synthesis of Compound I-51

Compound 1 (30mg, 0.038mmol, 1.0equiv) was dissolved in methylene chloride (1 mL), trifluoroacetic acid (1 mL) was added, the nitrogen gas was purged into the reaction flask, and the reaction system was stirred at room temperature for 1 hour in a nitrogen atmosphere. After the reaction, the reaction solution was spin-dried. The crude product was purified by preparative high pressure liquid phase (column: xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 13% to 43% by weight in 8min, 43% by weight; the wavelength is 220nm; RT1 (min): 7.58) gave compound I-51 as a white solid (10.0 mg, yield 44.27%). MS (ESI) M/z [ M + H ]] ⁺ ＝582. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.19(s,1H),9.10(s,1H),8.87(s,1H),8.00-8.04(m,2H),7.82-7.90(m,3H),7.48(s,2H),5.33(s,1H),4.31(d,J＝9.2Hz,1H),3.87-4.00(m,6H),3.36-3.58(m,8H),3.01(s,3H),1.98-2.03(m,3H),1.61-1.81(m,7H).

EXAMPLE 53 Synthesis of Compound I-52

Compound 1 (30mg, 0.038mmol, 1.0equiv) was dissolved in methylene chloride (1 mL), trifluoroacetic acid (1 mL) was added, the nitrogen gas was purged into the reaction flask, and the reaction system was stirred at room temperature for 1 hour in a nitrogen atmosphere. After the reaction was completed, the reaction solution was spin-dried. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 19% to 44% B within 8min, 44% B; the wavelength is 254nm; RT1 (min): 7.43) gave compound I-52 as a white solid (6.6 mg, 29.34% yield). MS (ESI) M/z [ M + H ]] ⁺ ＝582. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.19(s,1H),9.10(s,1H),8.88(s,1H),8.00-8.04(m,2H),7.82-7.90(m,3H),7.48-7.50(m,2H),4.32(s,1H),3.99(d,J＝11.1Hz,2H),3.71-3.89(m,4H),3.52-3.61(m,8H),3.21-3.34(m,1H),3.01(s,3H),2.98(s,2H),1.85-2.01(m,1H),1.65-1.72(m,4H),1.24-1.31(m,2H).

EXAMPLE 54 Synthesis of Compound I-53

Compound 1 (60mg, 0.077mmol, 1.0eq) was dissolved in methylene chloride (6 mL), trifluoroacetic acid (2 mL) was added, nitrogen gas was placed in a reaction flask, and the reaction system was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction, the reaction solution was spin-dried. The resulting crude product was purified by preparative high pressure liquid phase (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 25% to 55% by weight B within 7min, 55% by weight B; the wavelength is 220nm; RT1 (min): 7.78) gave compound I-53 as a white solid (11.6 mg, yield: 27.66%). MS (ESI) M/z [ M + H ]] ⁺ ＝584. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.18(s,1H),9.11(s,1H),8.88(s,1H),8.03(s,1H),8.05(d,J＝8.0Hz,2H),7.82-7.90(m,3H),7.49(d,J＝7.9Hz,2H),4.31(s,1H),3.99(d,J＝10.9Hz,2H),3.90(dd,J＝10.8,3.0Hz,1H),3.79(d,J＝10.8Hz,1H),3.41-3.67(m,6H),3.19(s,3H),3.07(s,3H),2.98(s,2H),1.60–1.85(m,4H),1.19(s,6H),0.95(s,1H).

EXAMPLE 55 Synthesis of Compound I-54

Compound 1 (60mg, 0.077mmol, 1.0equiv) was dissolved in methylene chloride (6 mL), trifluoroacetic acid (2 mL) was added, nitrogen gas was charged into a reaction flask, and the reaction system was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction, the reaction solution was spin-dried. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH _3· H ₂ O), mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 20% to 45% within 8min, 45% by weight B; the wavelength is 254nm; RT1 (min): 8.67) gave compound I-54 as a white solid (1.9 mg, yield: 5.94%). MS (ESI) M/z [ M ]] ⁺ ＝578. ¹ H NMR(400MHz,CD ₃ OD-d ₄ ):δ(ppm)8.96(s,2H),7.87-7.91(m,2H),7.79(d,J＝8.4Hz,2H),4.81-4.90(m,5H),4.63-4.70(m,4H),4.39(s,2H),4.11(d,J＝11.4Hz,2H),3.63(t,J＝11.5Hz,3H),2.06-2.10(m,2H),1.78-1.93(m,6H),1.31-1.43(m,8H),0.92(s,1H).

EXAMPLE 56 Synthesis of Compound I-55

Compound 1 (60mg, 0.077mmol,1.0 equiv) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, nitrogen gas was charged into a reaction flask, and the reaction system was stirred at room temperature under nitrogen atmosphere for 1 hour. After the reaction, the reaction solution was spin-dried. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH _3· H ₂ O), mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 20% to 45% within 8min, 45% by weight B; the wavelength is 254nm; RT1 (min): 8.67) gave compound I-55 as a white solid (2.2 mg, yield: 6.55%). MS (ESI) M/z [ M ]] ⁺ ＝578. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)8.97(s,2H),7.87-7.92(m,5H),7.79(d,J＝8.4Hz,2H),4.66-4.87(m,4H),4.63-4.66(m,4H),4.39(s,2H),4.11(d,J＝11.4Hz,2H),3.63(t,J＝11.5Hz,3H),1.92-1.93(m,2H),1.78-1.89(m,7H),1.38-1.42(m,4H),0.92-1.00(m,1H).

EXAMPLE 57 Synthesis of Compound I-56

Compound 1 (60mg, 0.077mmol, 1equiv) was dissolved in methylene chloride (6 mL), trifluoroacetic acid (2 mL) was added, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 16% to 41% B within 8min, 41% B; the wavelength is 254nm; RT1 (min): 7.68) gave compound I-56 as a white solid (9.8 mg, yield: 21.76%). MS (ESI) M/z [ M + H ]] ⁺ ＝580. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.16(s,1H),9.07(s,1H),8.92(s,1H),7.99-8.01(m,2H),7.83(d,J＝8.3Hz,1H),7.73(s,1H),7.73-7.82(m,1H),7.37(d,J＝7.6Hz,1H),4.67-4.72(m,4H),4.31(d,J＝9.7Hz,1H),4.23(s,2H),4.17(s,2H),3.99(d,J＝10.9Hz,2H),3.90(dd,J＝11.0,3.1Hz,1H),3.79(d,J＝10.8Hz,1H),3.45-3.61(m,4H),2.97-3.20(m,1H),2.89-2.97(m,2H),2.41(s,3H),1.63-1.85(m,4H),1.24(s,1H).

EXAMPLE 58 Synthesis of Compound I-57

Compound 1 (60mg, 0.075mmol, 1equiv) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient from 28% to 49% B within 8min, 49% B; the wavelength is 254nm; RT1 (min): 7.50) gave compound I-57 as a white solid (21 mg, yield: 46.44%). MS (ESI) M/z [ M + H ]] ⁺ ＝598. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.13(s,1H),9.07(s,1H),8.92(s,1H),7.99-8.01(m,2H),7.82(d,J＝8.2Hz,1H),7.67–7.71(m,2H),7.21-7.23(m,1H),4.31(d,J＝9.9Hz,1H),3.99(d,J＝11.0Hz,2H),3.90(dd,J＝11.2,3.1Hz,1H),3.79(d,J＝10.8Hz,1H),3.40-3.68(m,6H),3.18(s,4H),2.84-3.13(m,6H),2.32(s,3H),1.62-1.81(m,4H),1.21(s,5H),0.98(s,1H).

EXAMPLE 59 Synthesis of Compound I-58

Compound 1 (100mg, 0.149mmol, 1equiv) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient from 25% to 50% B within 8min, 50% B; the wavelength is 254nm; RT1 (min): 7.53) gave compound I-58 as a white solid (33.4 mg, yield: 36.95%). MS (ESI) M/z [ M + H ]] ⁺ ＝570. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.10(s,1H),8.99(s,1H),8.95(s,1H),7.94-8.01(m,2H),7.82(d,J＝8.2Hz,1H),7.63-7.68(m,2H),7.23(d,J＝7.8Hz,1H),3.99(d,J＝10.4Hz,2H),3.68(s,2H),3.59(s,2H),3.47(dd,J＝11.4,2.7Hz,2H),3.27(dd,J＝7.1,5.9Hz,2H),3.18(s,1H),3.09(s,2H),3.05(s,1H),2.91(s,2H),2.32(s,2H),2.24(s,6H),1.65-1.80(m,4H),1.21(s,4H),0.98(s,1H).

EXAMPLE 60 Synthesis of Compound I-59

Compound 1 (60mg, 0.077mmol, 1equiv) was dissolved in methylene chloride (6 mL), trifluoroacetic acid (2 mL) was added, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 19% to 40% B within 8min, 40% B; the wavelength is 220nm; RT1 (min): 7.70) gave compound I-59 as a white solid (8.3 mg, yield: 18.41%). MS (ESI) M/z [ M ]] ⁺ ＝584. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.35(s,1H),9.11(s,1H),8.73(s,1H),7.94-7.97(m,3H),7.82(d,J＝8.3Hz,1H),7.56–7.58(m,2H),4.71(s,4H),4.59(s,2H),4.17-4.38(m,3H),3.98(d,J＝10.8Hz,2H),3.88(dd,J＝11.1,3.1Hz,1H),3.78(d,J＝10.8Hz,1H),3.41-3.57(m,4H),3.17-3.32(m,1H),2.97(s,2H),1.61–1.80(m,4H). ¹⁹ F NMR(376MHz,DMSO-d ₆ ):δ(ppm)-114.36.

EXAMPLE 61 Synthesis of Compound I-60

Compound 1 (80mg, 0.099mmol, 1equiv) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1.5 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. After the reaction is finished, rotatingThe reaction solution was dried. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 18% to 43% within 8min, 43% B; the wavelength is 254nm; RT1 (min): 7.62) gave compound I-60 as a white solid (15.8 mg, yield: 26.23%). MS (ESI) M/z [ M + H ]] ⁺ ＝606. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.15(s,1H),9.03(s,1H),8.83(s,1H),8.02(s,1H),7.99(d,J＝8.0Hz,1H),7.83(d,J＝8.3Hz,1H),7.60(d,J＝7.8Hz,1H),7.32(d,J＝7.9Hz,1H),7.24(s,1H),4.67-4.73(m,4H),4.30-4.32(m,1H),4.25(s,2H),4.16(s,2H),3.92-3.99(m,2H),3.90(d,J＝10.0Hz,1H),3.79(d,J＝11.0Hz,1H),3.34-3.57(m,4H),3.21(s,1H),3.05-3.19(m,1H),2.98-3.00(m,2H),2.14–2.16(m,1H),1.62–1.80(m,4H),0.96-1.08(m,2H),0.77-0.92(m,2H).

EXAMPLE 62 Synthesis of Compound I-61

Compound 1 (80mg, 0.101mmol, 1equiv) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 15% to 40% B within 8min, 40% B; the wavelength is 254nm; RT1 (min): 7.57) gave compound I-61 as a white solid (20.9 mg, yield: 34.59%). MS (ESI) M/z [ M + H ]] ⁺ ＝596. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.19(s,1H),9.07(s,1H),8.92(s,1H),8.07(s,1H),7.99(d,J＝8.2Hz,1H),7.82(d,J＝8.3Hz,1H),7.43(d,J＝8.5Hz,2H),7.38(d,J＝8.2Hz,1H),4.66–4.73(m,4H),4.29-4.31(m,1H),4.19(s,2H),4.14(s,2H),3.90-3.97(m,5H),3.89(dd,J＝11.1,3.0Hz,1H),3.78(d,J＝10.1Hz,1H),3.52-3.62(m,3H),3.43-3.48(m,1H),3.18-3.20(m,1H),2.96-3.00(m,2H),1.62–1.81(m,4H).

EXAMPLE 63 Synthesis of Compound I-62

Compound 1 (80mg, 0.101mmol, 1equiv) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, and the reaction flask was purged with nitrogen and stirred at room temperature for 0.5 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 19% to 40% B within 8min, 40% B; the wavelength is 254nm; RT1 (min): 7.48) gave compound I-62 as a white solid (13.0 mg, 21.67% yield). MS (ESI) M/z [ M + H ]] ⁺ ＝594. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.09(s,1H),9.05(s,1H),8.96(s,1H),7.99(d,J＝8.3Hz,1H),7.94(s,1H),7.82(d,J＝8.3Hz,1H),7.52(s,2H),4.67-4.74(m,4H),4.30(d,J＝9.8Hz,1H),4.26(s,2H),3.81-3.97(m,5H),3.78-3.80(m,1H),3.43-3.66(m,4H),3.01–3.19(m,1H),2.94-3.00(m,2H),2.28(s,6H),1.62–1.81(m,4H).

EXAMPLE 64 Synthesis of Compound I-63

Compound 1 (120mg, 0.144mmol, 1equiv) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 0.5 hours. And after the reaction is finished, spin-drying the reaction solution. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient from 22% to 42% in 8min B,42%B; the wavelength is 254nm; RT1 (min): 7.52) gave compound I-63 as a white solid (25.5 mg, yield: 27.69%). MS (ESI) M/z [ M + H ]] ⁺ ＝634. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.46(s,1H),9.09(s,1H),8.95(s,1H),8.23(s,1H),8.16–8.18(m,2H),8.01(d,J＝8.2Hz,1H),7.84(d,J＝8.3Hz,1H),7.63(d,J＝8.4Hz,1H),4.66-4.74(m,4H),4.25-4.30(m,1H),4.25(s,2H),4.10(s,2H),3.99(d,J＝10.9Hz,2H),3.89(dd,J＝11.2,3.1Hz,1H),3.79(d,J＝10.0Hz,1H),3.45-3.61(m,4H),3.11-3.24(m,1H),2.86–3.01(m,2H),1.54-1.78(m,4H). ¹⁹ F NMR(376MHz,DMSO-d6):δ(ppm)-58.62。

EXAMPLE 65 Synthesis of Compound I-64

Compound 1 (60mg, 0.074mmol, 1equiv) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 0.5 hours. And after the reaction is finished, spin-drying the reaction solution. The crude product was purified by preparative high pressure liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 20% to 45% within 8min, 45% by weight B; the wavelength is 254nm; RT1 (min): 7.50) gave compound I-64 as a white solid (10.0 mg, yield: 22.16%). MS (ESI) M/z [ M + H ]] ⁺ ＝608. ¹ H NMR(400MHz,DMSO-d ₆ ):δ(ppm)12.16(s,1H),9.03(s,1H),8.89(s,1H),8.02(s,1H),7.97(d,J＝8.3Hz,1H),7.84(d,J＝8.3Hz,1H),7.79(s,1H),7.63(d,J＝7.9Hz,1H),7.32(d,J＝8.0Hz,1H),4.67-4.72(m,4H),4.25-4.31(m,1H),4.24(s,2H),4.11(s,2H),3.99(d,J＝11.2Hz,1H),3.90(d,J＝10.5Hz,1H),3.30-3.58(m,4H),3.19-3.23(m,2H),2.86-3.09(m,2H),1.65-1.78(m,4H),1.30(s,3H),1.28(s,3H),1.24(s,1H).

EXAMPLE 66 Synthesis of Compound I-65

Compound 1 (50mg, 0.064mmol, 1.0equiv) was dissolved in methylene chloride (2 mL), and trifluoroacetic acid (2 mL) was added thereto, and the reaction flask was purged with nitrogen and stirred at room temperature for 0.5 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 18% to 40% B within 8min, 40% B; the wavelength is 254nm; RT1 (min): 7.68) gave compound I-65 (7.8 mg, 20.93% yield) as a white solid, MS (ESI): M/z [ M + H ]]+＝580.1H NMR(400MHz,DMSO-d6):δ(ppm)12.15(s,1H),9.08(s,1H),8.47(s,1H),7.91(d,J＝8.3Hz,1H),7.72–7.81(m,2H),7.63(s,1H),7.50–7.59(m,2H),4.69-4.72(m,4H),4.56(s,1H),4.24(s,3H),3.98(d,J＝11.1Hz,2H),3.87(d,J＝11.0,2H),3.55-3.62(m,4H),3.38–3.48(m,1H),3.20(s,1H),2.95(s,2H),2.42(s,2H),1.70(s,2H),1.58-1.62(m,2H).

EXAMPLE 67 Synthesis of Compounds I-66

Compound 1 (10mg, 0.014mmol, 1.0equiv) was dissolved in methylene chloride (2 mL), and trifluoroacetic acid (2 mL) was added thereto, and the reaction flask was purged with nitrogen and stirred at room temperature for 0.5 hours. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 20% to 40% B within 8min, 40% B; the wavelength is 220nm; RT1 (min): 7.77) gave compound I-66 (1.0 mg, 13.75% yield) as a white solid, MS (ESI): M/z [ M + H ]]+＝499.1H NMR(400MHz,CD3OD-d4):δ(ppm)9.13(s,1H),8.60(s,1H),8.42–8.46(m,1H),7.81-7.88(m,4H),7.36–7.39(m,1H),6.97(t,J＝7.5Hz,1H),4.43-4.62(m,3H),4.08-4.11(m,2H),3.89–3.97(m,2H),3.53-3.89(m,4H),3.09–3.18(m,3H),1.71-1.83(m,2H).19F NMR(376MHz,CD3OD-d4):-114.92.

EXAMPLE 68 Synthesis of Compound I-67

Compound 1 (40mg, 0.059mmol, 1.0equiv) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 10% to 40% B within 7min, 40% B; the wavelength is 220nm; RT1 (min): 7.28) gave compound I-67 as a white solid (10 mg, yield: 34.86%). MS (ESI) M/z [ M + H ]]+＝482.1H NMR(400MHz,DMSO-d6):δ(ppm)12.44(s,1H),9.20(s,1H),8.97-9.02(m,2H),8.48(s,1H),8.34(s,1H),8.26(s,1H),8.12(d,J＝7.6Hz,1H),7.87(d,J＝8.2Hz,1H),7.71(d,J＝8.0Hz,1H),4.40(s,1H),3.98-4.01(m,2H),3.91-3.94(m,1H),3.81-3.83(m,1H),3.55-3.62(m,4H),3.28-3.33(m,1H),2.99-3.03(m,2H),1.65-1.82(m,4H).

EXAMPLE 69 Synthesis of Compound I-68

Compound 1 (30mg, 0.043mmol, 1.0equiv) was dissolved in methylene chloride (5 mL), and trifluoroacetic acid (3 mL) was added thereto, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phaseB is ACN; the flow rate is 60mL/min; a gradient from 19% to 40% B within 8min, 40% B; the wavelength is 254nm; RT1 (min): 7.83) gave compound I-68 as a white solid (5.7 mg, yield: 26.43%). MS (ESI) M/z [ M + H ]]+＝495.1H NMR(400MHz,DMSO-d6):δ(ppm)12.01(s,1H),9.06(s,1H),8.85(s,1H),8.21(s,1H),7.87-8.09(m,4H),7.61-7.76(m,2H),4.30(d,J＝10.0Hz,1H),3.99(d,J＝11.1Hz,2H),3.89(s,3H),3.78(d,J＝11.0Hz,1H),3.43-3.61(m,4H),3.22-3.33(m,1H),2.97(s,2H),1.62-1.79(m,4H).

EXAMPLE 70 Synthesis of Compound I-69

Compound 1 (20mg, 0.028mmol, 1.0equiv) was dissolved in methylene chloride (3 mL), trifluoroacetic acid (2 mL) was added, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 30% to 60% within 7min, 60% B; the wavelength is 220nm; RT1 (min): 7.25) gave compound I-69 as a white solid (4.2 mg, yield: 28.92%). MS (ESI) M/z [ M + H ]]+＝516.1H NMR(400MHz,DMSO-d6):δ(ppm)12.67(s,1H),9.32(s,1H),9.17(s,1H),8.50(s,1H),7.88-8.06(m,4H),7.38-7.43(m,1H),4.38-4.43(m,1H),3.94-4.01(m,3H),3.83-3.85(m,1H),3.63-3.68(m,1H),3.53-3.59(m,3H),3.33-3.44(m,1H),3.04-3.10(m,2H),1.64-1.82(m,4H).19FNMR(376MHz,DMSO-d6):δ(ppm)-117.17.

EXAMPLE 71 Synthesis of Compound I-70

Compound 1 (20mg, 0.029mmol, 1.0equiv) was dissolved in dichloromethaneTrifluoroacetic acid (3 mL) was added to the solution (5 mL), and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 25% to 45% B within 8min, 45% B; the wavelength is 220nm; RT1 (min): 7.58) gave compound I-70 as a white solid (4.7 mg, yield: 33.12%). MS (ESI) M/z [ M + H ]]+＝481.1H NMR(400MHz,DMSO-d6):δ(ppm)12.20(s,1H),11.97(s,1H),9.18(s,1H),8.97(s,1H),8.15-8.19(m,3H),7.85-7.92(m,2H),7.04-7.07(m,2H),4.02(s,1H),3.72-4.02(m,4H),3.53-3.64(m,4H),3.04-3.33(m,2H),1.64-1.84(m,4H).

EXAMPLE 72 Synthesis of Compound I-71

Compound 1 (20mg, 0.029mmol, 1.0equiv) was dissolved in methylene chloride (4 mL), trifluoroacetic acid (2 mL) was added, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 28% to 48% B within 8min, 48% B; the wavelength is 220nm; RT1 (min): 6.85) gave compound I-71 as a white solid (3.9 mg, yield: 26.71%). MS (ESI) M/z [ M + H ]]+＝495.1H NMR(400MHz,DMSO-d6):δ(ppm)12.38(s,1H),9.16(s,1H),8.74(s,1H),8.27(s,1H),7.97-8.04(m,3H),7,81-7.83(m,1H),7.12-7.15(m,1H),6.83(s,1H),4.32(s,1H),3.95-4.01(m,2H),3.90(s,3H),3.77-3.88(m,2H),3.47-3.60(m,5H),3.31-3.29(m,1H),2.97-3.05(m,2H),1.64-1.87(m,4H).

EXAMPLE 73 Synthesis of Compound I-72

Compound 1 (15mg, 0.022mmol, 1.0equiv) was dissolved in methylene chloride (2 mL), trifluoroacetic acid (2 mL) was added, the reaction flask was purged with nitrogen, and the mixture was stirred at room temperature for 0.5 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient of 5%B to 40% in 7min, 40% B; wavelength is 220nm; RT1 (min): 7.67) gave compound I-72 (3.7 mg, yield: 34.05%) as a white solid, MS (ESI): M/z [ M + H ]]+＝482.1H NMR(400MHz,DMSO-d6):δ(ppm)13.27(s,1H),12.47(s,1H),9.36(s,1H),9.20(s,1H),8.37(d,J＝8.0Hz,1H),8.26(d,J＝7.9Hz,1H),7.87-8.05(m,3H),7.20-7.25(m,1H),4.41(s,1H),3.75-4.00(m,4H),3.45-3.62(m,2H),3.05(s,2H),1.64-1.90(m,4H),1.24(s,1H).

EXAMPLE 74 Synthesis of Compound I-73

Compound 1 (30mg, 0.038mmol, 1.0equiv) was dissolved in methylene chloride (6 mL), and trifluoroacetic acid (2 mL) was added thereto, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 10% to 35% B within 8min, 35% B; the wavelength is 220nm; RT1 (min): 11.58) gave compound I-73 as a white solid (0.5 mg, 1.1% yield). MS (ESI) M/z [ M + H ]]+＝496.1H NMR(400MHz,CD3OD-d4):δ(ppm)9.36(s,1H),9.18(s,1H),8.38–8.44(m,1H),8.28(s,1H),8.13(d,J＝7.9Hz,1H),7.99(d,J＝8.3Hz,1H),7.89(d,J＝8.3Hz,1H),7.39(d,J＝8.0Hz,1H),4.48(dd,J＝10.2,3.4Hz,1H),4.15(s,3H),4.09-4.13(m,2H),3.90–4.03(m,2H),3.58-3.71(m,4H),3.11-3.29(m,3H),1.72-2.01(m,4H),1.32-1.39(m,1H),0.96-1.01(m,1H).

EXAMPLE 75 Synthesis of Compounds I-74

Compound 1 (30mg, 0.038mmol, 1.0equiv) was dissolved in methylene chloride (6 mL), and trifluoroacetic acid (2 mL) was added thereto, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 10% to 35% B within 8min, 35% B; wavelength is 220nm; RT1 (min): 11.58) gave compound I-74 as a white solid (1 mg, 1.92% yield). MS (ESI) M/z [ M + H ]]+＝481.1H NMR(400MHz,CD3OD-d4):δ(ppm)9.12(d,J＝8.8Hz,2H),8.50(d,J＝7.9Hz,1H),8.36(s,1H),8.01(d,J＝8.0Hz,2H),7.89(d,J＝8.3Hz,1H),7.61(d,J＝8.0Hz,1H),7.36(t,J＝8.0Hz,1H),6.96(d,J＝8.5Hz,1H),4.50(d,J＝9.4Hz,1H),3.98-4.12(m,4H),3.62-3.79(m,4H),3.11-3.3(m,3H),1.62-1.98(m,4H),1.25-1.39(m,1H),0.89-1.01(m,1H).

EXAMPLE 76 Synthesis of Compound I-75

Compound 1 (20mg, 0.024mmol, 1.0equiv) was dissolved in methylene chloride (2 mL), and trifluoroacetic acid (2 mL) was added thereto, and the reaction flask was purged with nitrogen and stirred at room temperature for 0.5 hours. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Shield RP18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient of gradient25-to 50-percent B within 8min, 50-percent B; the wavelength is 254nm; RT1 (min): 6.88) gave compound I-75 (9.1 mg, 71.70% yield) as a white solid, MS (ESI): M/z [ M + H ]]+＝517.1H NMR(400MHz,DMSO-d6):δ(ppm)12.87(s,1H),12.41(s,1H),9.25(s,1H),9.09(s,1H),8.57(s,1H),8.15-8.28(m,2H),7.94(s,1H),7.16(s,1H),3.91-4.01(m,6H),3.65-3.76(m,6H),1.67-1.83(m,4H),1.24(s,1H).

EXAMPLE 77 Synthesis of Compound I-76

Compound 1 (10mg, 0.014mmol, 1.0equiv) was dissolved in methylene chloride (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction flask was purged with nitrogen and stirred at room temperature for 0.5 hours. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 30% to 60% within 7min, 60% by weight B; the wavelength is 220nm; RT1 (min): 7.85) gave compound I-76 (3.4 mg, 46.47% yield) as a white solid, MS (ESI): M/z [ M + H ]]+＝533.1H NMR(400MHz,DMSO-d6):δ(ppm)12.52(s,1H),9.14(s,1H),9.05(s,1H),8.31(s,1H),8.23(d,J＝8.5Hz,1H),8.12(d,J＝8.5Hz,1H),8.05(d,J＝8.4Hz,1H),7.87(d,J＝8.0Hz,2H),4.33(s,1H),3.92-4.01(m,3H),3.67-3.81(m,3H),3.48-3.54(m,3H),2.99-3.12(m,2H),1.63-1.91(m,4H),1.24(s,1H).

EXAMPLE 78 Synthesis of Compound I-77

Compound 1 (20mg, 0.027mmol, 1.0equiv) was dissolved in methylene chloride (5 mL), and trifluoroacetic acid (3 mL) was added thereto, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. After the reaction is finished, rotatingThe reaction solution was dried. The resulting crude product was purified using a high pressure preparative liquid phase (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient from 39% to 52% within 8min, 52% B; the wavelength is 254nm; RT1 (min): 7.28) gave compound I-77 as a white solid (0.7 mg, yield: 4.67%). MS (ESI) M/z [ M + H ]]+＝534.1H NMR(400MHz,DMSO-d6):δ(ppm)12.60(s,1H),9.12(s,1H),9.98(s,1H),8.89(s,1H),8.40(s,1H),8.08(d,J＝8.2Hz,1H),7.88(d,J＝8.0Hz,2H),4.33(d,J＝10.1Hz,1H),3.82-4.01(m,4H),3.81(d,J＝11.0Hz,1H),3.70(d,J＝10.6Hz,1H),3.49-3.53(m,2H),2.98-3.34(m,2H),1.63-1.81(m,4H),1.24(s,1H).

EXAMPLE 79 Synthesis of Compound I-78

Compound 1 (20mg, 0.027mmol, 1.0equiv) was dissolved in methylene chloride (5 mL), and trifluoroacetic acid (3 mL) was added thereto, and the reaction flask was purged with nitrogen and stirred at room temperature for 1 hour. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 35% to 65% in 7min, 65% by weight B; the wavelength is 220nm; RT1 (min): 7.22) gave compound I-78 as a white solid (3.3 mg, yield: 21.19%). MS (ESI) M/z [ M + H ]]+＝533.1H NMR(400MHz,DMSO-d6):δ(ppm)12.72(s,1H),9.53(s,1H),9.11(s,1H),8.57(s,1H),7.87–8.09(m,3H),7.63(d,J＝7.9Hz,1H),7.40(d,J＝7.9Hz,1H),4.35(s,1H),3.94-4.01(m,3H),3.75-3.90(m,2H),3.52-3.59(m,3H),3.21-3.33(m,1H),2.98-3.17(m,2H),1.59-1.92(m,4H).

EXAMPLE 80 Synthesis of Compound I-79

Compound 1 (10mg, 0.014mmol, 1.0equiv) was dissolved in methylene chloride (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction flask was purged with nitrogen and stirred at room temperature for 0.5 hour. And after the reaction is finished, spin-drying the reaction solution. The crude product obtained was purified using a high pressure preparative liquid phase (column: xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; a gradient from 20% to 45% B within 7min, 45% B; the wavelength is 220nm; RT1 (min): 7.43) gave compound I-79 as a white solid (2.8 mg, yield 38.20%) MS (ESI): M/z [ M + H ]]+＝513.1H NMR(400MHz,DMSO-d6):δ(ppm)12.45(s,1H),9.29(s,1H),9.12(s,1H),8.25(s,1H),7.95(d,J＝8.3Hz,1H),7.87(d,J＝8.2Hz,1H),7.65(d,J＝8.6Hz,1H),7.11(s,1H),6.79(d,J＝8.5Hz,1H),5.38(s,2H),4.34(d,J＝9.1Hz,1H),3.92-4.01(m,2H),3.82-3.84(m,2H),3.61-3.70(m,2H),3.34-3.59(m,4H),2.93-3.11(m,2H),1.64-1.81(m,4H).

EXAMPLE 81 Synthesis of Compound I-80

Compound 1 (10mg, 0.015mmol, 1.0equiv) was dissolved in methylene chloride (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction flask was purged with nitrogen and stirred at room temperature for 0.5 hours. And after the reaction is finished, spin-drying the reaction solution. The resulting crude product was purified using a high pressure preparative liquid phase (column: xbridge Prep OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) The mobile phase B is ACN; the flow rate is 60mL/min; gradient from 12% to 37% in 8min, 37% by weight B; the wavelength is 254nm; RT1 (min): 8.02) gave compound I-80 (1.0 mg, 14.06% yield) as a white solid, MS (ESI): M/z [ M + H ]]+＝483.1H NMR(400MHz,DMSO-d6):δ(ppm)12.53(s,1H),9.38(s,1H),9.25(s,1H),9.17(s,1H),9.11(d,J＝8.0Hz,1H),8.38(s,1H),8.28(s,1H),7.92(d,J＝8.3Hz,2H),4.44(s,1H),4.00(d,J＝11.0Hz,2H),3.93(d,J＝11.5Hz,1H),3.82(d,J＝11.1Hz,1H),3.41-3.69(m,4H),3.34(s,2H),1.64-1.83(m,4H),1.24(s,1H).

Effect embodiment: biological experiment method

Test compounds were dissolved in 100% DMSO, the stock concentration was 10mM. The test was started at 10 μ M, diluted in a three-fold gradient, ten concentration data points, and repeated twice for each point.

ADP-Glo is adopted in the experiment of inhibiting the activity of the compound on HPK1 kinase ^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 HPK1 kinase at 25 ℃ for 15min and the reaction was started by adding substrate and ATP. After 1 hour of reaction at 25 ℃, ADP-Glo was added ^TM Reagents, stop reaction and incubate for 1 hour at 25 ℃. 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

Wherein A represents IC ₅₀ IC is not less than 0.01nM ₅₀ Less than 5nM; b represents IC ₅₀ IC is 5nM or less ₅₀ < 10nM; c represents IC ₅₀ IC is 10nM or less ₅₀ < 100nM; d represents IC ₅₀ Is 100 or less IC ₅₀ ＜200nM。

Claims

1. A compound having the structure of formula I:

wherein

-CH ₂ -, -C ≡ C-, -CH = CH-, or-NH-C (= O) -;

R ^a 、R ^b And R ^c Each independently selected from H, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, -C _1-6 alkylene-C _1-6 Alkoxy, -C _1-6 alkylene-C _3-8 Cycloalkyl, -C _1-6 Alkylene- (3-to 8-membered heterocyclic group), C _6-10 Aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl radical, C _1-6 Alkylene radical, C _1-6 Alkoxy radical, C _6-10 Aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, NO ₂ 、-NR ^a R ^b Or C _1-6 Alkyl substituent substitution; said C is _1-6 Two adjacent substituents in an alkylene group optionally form C together with the atom to which they are attached _3-8 A cycloalkyl group;

R ^x selected from CN, halogen, -C (= O) NR ^8a R ^8b 、-CH ₂ NR ^8c R ^8d 、Het ^a 、Het ^b 、-CH ₂ -Het ^a 、-CH ₂ -Het ^b 、C _1-6 Alkyl or C _3-6 Cycloalkyl radical, said C _1-6 Alkyl or C _3-6 Cycloalkyl is optionally substituted by 1 or 2 substituents independently selected from halogen, OH, CN or-O-C _1-4 Alkyl substituent;

or, R ^8a And R ^8b Or R ^8c And R ^8d Together with the N atom to which they are attached form a 4-12 membered heterocyclyl comprising 1N atom and optionally 1 or 2 additional heteroatoms independently selected from N, O or S; wherein said heterocyclyl is optionally substituted on one or more C atoms by 1,2 or 3 substituents independently selected from OH, CN, halogen, R ⁹ 、-OR ⁹ 、-S(＝O) ₂ R ⁹ 、-C(＝O)R ⁹ 、-NR ^6c R ^6d or-C (= O) NR ^6a R ^6b Substituted with a substituent of (1); wherein said heterocyclyl is optionally substituted on the N atom by 1 or 2 substituents independently selected from R ⁹ 、-S(＝O) ₂ R ⁹ 、-C(＝O)R ⁹ or-C (= O) NR ^6a R ^6b Substituted with a substituent of (1);

Het ^a is composed of

R ^13a is H;

R ^13b selected from H, oxo or C _1-4 An alkyl group;

R ^14a selected from H, C _1-4 Alkyl or C _3-6 A cycloalkyl group;

or, R ^13b And R ^14b Together with the atoms to which they are attached form a 5-12 membered heteroaryl or 4-12 membered heterocyclyl, each of which comprises 1N atom and optionally 1 or 2 additional heteroatoms independently selected from N, O or S; wherein said heteroaryl or heterocyclyl is optionally substituted on one or more C atoms by 1,2 or 3 substituents independently selected from OH, CN, halogen, R ⁷ 、-OR ⁷ 、-S(＝O) ₂ R ⁷ 、-C(＝O)R ⁷ 、-NR ^6c R ^6d 、-C(＝O)NR ^6a R ^6b Or Het ^c Substituted with the substituent(s); wherein said heteroaryl or heterocyclyl is optionally substituted on the optional additional N atom by 1 or 2 atomsSelected from R ⁷ 、-S(＝O) ₂ R ⁷ 、-C(＝O)R ⁷ 、-C(＝O)NR ^6a R ^6b Or Het ^d Substituted with the substituent(s);

in the direction of R ^13b When the dotted bond is R ^13b And R ^14b Together form a ring optionally present as a bond;

each R ¹⁰ Independently selected from H or C _1-4 An alkyl group;

each Het ^c Independently of one another, contain 1,2 or 3A 4-12 membered heterocyclyl of heteroatoms independently selected from N, O or S;

2. A compound or pharmaceutically acceptable form thereof according to claim 1, wherein

w is selected from N or CR ⁵ ，R ⁵ Selected from H, F, cl or methyl;

q is selected from N or CR ¹⁵ ，R ¹⁵ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) F, cl, methyl, methoxy, ethoxy, or propenyl;

L ¹ selected from single bond, NH or O;

R ² selected from phenyl, pyridyl, imidazopyridineA phenyl, pyridyl, imidazopyridinyl, pyrrolopyridinyl, oxazolyl, pyridotriazolyl, benzimidazolyl, benzothiazolyl, pyrrolopyrimidinyl, thienopyridinyl, thienopyrimidinyl or pyrazinotriazolyl group, optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from F, cl, br, oxo, methyl, CN, NO ₂ Methoxy, isopropyl, cyclopropyl, -CF ₃ 、-C(＝O)NR ^a R ^b 、-NR ^a R ^b 、

R ^x is selected from

Is selected from

3. A compound according to claim 1, or a pharmaceutically acceptable form thereof, which is a compound having the structure of formula I-a 1:

wherein A, Q, Z, W、R ² 、R ³ And L ¹ As defined in claim 1.

4. A compound or pharmaceutically acceptable form thereof according to claim 3, wherein

A is selected from N or CR ⁴ ，R ⁴ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl or C _3-6 A cycloalkyl group; said C is _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl or C _3-6 Cycloalkyl is optionally substituted with one or more halo;

preferably, R ⁴ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-4 Alkyl radical, C _2-4 Alkenyl or C _1-4 An alkoxy group; said C is _1-4 Alkyl radical, C _2-4 Alkenyl or C _1-4 Alkoxy is optionally substituted with one or more F, cl or Br;

more preferably, R ⁴ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) F, cl, br, methyl, propenyl or methoxy.

5. A compound or pharmaceutically acceptable form thereof according to claim 3 or 4, wherein

W is selected from N or CR ⁵ ，R ⁵ Selected from H, halogen or C _1-4 An alkyl group;

preferably, R ⁵ Selected from H, F, cl or methyl.

6. A compound or pharmaceutically acceptable form thereof according to any one of claims 3-5, wherein

Q is selected from N or CR ¹⁵ ，R ¹⁵ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl or C _3-6 A cycloalkyl group; said C is _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl or C _3-6 Cycloalkyl groups optionally substituted by one or moreHalogen substitution;

preferably, R ¹⁵ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-4 Alkyl radical, C _2-4 Alkenyl or C _1-4 An alkoxy group; said C is _1-4 Alkyl radical, C _2-4 Alkenyl or C _1-4 Alkoxy is optionally substituted with one or more F, cl or Br;

more preferably, R ¹⁵ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) F, cl, methyl, methoxy, propenyl, or ethoxy.

7. A compound or pharmaceutically acceptable form thereof according to any one of claims 3-6, wherein

Z is selected from N or CR ¹ ，R ¹ Selected from H, halogen, OH, NH ₂ 、-NH(CH ₃ )、C _1-4 Alkyl radical, C _3-6 Cycloalkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl or C _1-4 Alkoxy radical, said C _1-4 Alkyl radical, C _3-6 Cycloalkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl or C _1-4 Alkoxy is optionally substituted with one or more halo;

preferably, R ¹ Selected from H, F, cl, br, methyl, ethyl, isopropyl, cyclopropyl, ethenyl, ethynyl, methoxy, or ethoxy, said methyl, ethyl, isopropyl, cyclopropyl, ethenyl, ethynyl, methoxy, or ethoxy being optionally substituted with one or more F, cl or Br.

8. A compound or pharmaceutically acceptable form thereof according to any one of claims 3-7, wherein

R ³ Selected from H, OH, NH ₂ 、-NH(CH ₃ ) Halogen, C _1-4 Alkyl radical, C _3-6 Cycloalkyl or C _1-4 Alkoxy radical, said C _1-4 Alkyl radical, C _3-6 Cycloalkyl or C _1-4 Alkoxy is optionally substituted with one or more halo;

preferably, R ³ Selected from H, OH, F, cl, br, methyl, ethyl, cyclopropyl,Methoxy or ethoxy, said methyl, ethyl, cyclopropyl, methoxy or ethoxy being optionally substituted with one or more F, cl or Br.

9. A compound or pharmaceutically acceptable form thereof according to any one of claims 3-8, wherein L ₁ Selected from the group consisting of a single bond, NH, O, C (= O) or

Preferably, L ₁ Selected from a single bond, NH or O.

10. A compound or pharmaceutically acceptable form thereof according to any one of claims 3-9, wherein

R ² Is selected from C _6-10 Aryl, 5-8 membered heterocyclyl or 5-12 membered heteroaryl, said C _6-10 Aryl, 5-8 membered heterocyclyl or 5-12 membered heteroaryl optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from halogen, oxo, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 5-8 membered heterocyclyl, C _6-10 Aryl, 5-12 membered heteroaryl, CN, NO ₂ 、C _1-4 Alkoxy, -C (= O) R ^a 、-C(＝O)OR ^a 、-C(＝O)NR ^a R ^b 、-NR ^a R ^b 、-NR ^a C(＝O)R ^b 、-NR ^a C(＝O)NR ^b R ^c or-NR ^a C(＝O)OR ^b Said C is _1-4 Alkyl radical, C _3-6 Cycloalkyl, 5-8 membered heterocyclyl, C _6-10 Aryl, 5-12 membered heteroaryl or C _1-4 Alkoxy is optionally substituted by one or more groups independently selected from halogen, oxo, CN, NO ₂ Or C _1-4 Alkyl substituent substitution;

or two adjacent R ⁶ Together with the atoms to which they are attached form a 5-8 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S, said 5-8 membered heterocyclyl optionally substituted with one or more R ¹⁶ Substituted, each R ¹⁶ Independently selected from halogen, oxo, C _1-4 Alkyl radical, C _3-6 CycloalkanesA group, a 5-to 8-membered heterocyclic group, C _6-10 Aryl, 5-12 membered heteroaryl, CN, NO ₂ 、C _1-4 Alkoxy, -C (= O) R ^a 、-C(＝O)OR ^a 、-C(＝O)NR ^a R ^b 、-NR ^a R ^b 、-NR ^a C(＝O)R ^b 、-NR ^a C(＝O)NR ^b R ^c or-NR ^a C(＝O)OR ^b ，

R ^a 、R ^b And R ^c Each independently selected from H, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, -C _1-4 alkylene-C _1-4 Alkoxy, -C _1-4 alkylene-C _3-6 Cycloalkyl, -C _1-4 Alkylene- (5-to 8-membered heterocyclic group), C _6-10 Aryl, 5-8 membered heterocyclyl or 5-12 membered heteroaryl, said C _1-4 Alkyl radical, C _3-6 Cycloalkyl, -C _1-4 alkylene-C _1-4 Alkoxy, -C _1-4 alkylene-C _3-6 Cycloalkyl, -C _1-4 Alkylene- (5-to 8-membered heterocyclic group), C _6-10 Aryl, 5-8 membered heterocyclyl or 5-12 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, NO ₂ 、-NR ^a R ^b Or C _1-6 Alkyl substituent substitution; said C is _1-4 Two adjacent substituents in an alkylene group optionally form C together with the atom to which they are attached _3-6 A cycloalkyl group;

or, R ^a And R ^b 、R ^b And R ^c Or R ^a And R ^c Together with the atoms to which they are attached form a 4-12 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S; said 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, oxo, CN, NO ₂ 、-NR ^a R ^b 、C _1-4 Alkyl or C _1-4 Substituent of alkoxy;

preferably, R ² Is selected from C _6-10 Aryl or 5-12 membered heteroaryl, said C _6-10 Aryl or 5-12 membered heteroaryl optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from halogen, oxo, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 5-8 membered heterocyclyl, 5-12 membered heteroaryl, CN, NO ₂ 、C _1-4 Alkoxy, -C (= O) NR ^a R ^b or-NR ^a R ^b Said C is _1-4 Alkyl radical, C _3-6 Cycloalkyl, 5-8 membered heterocyclyl, 5-12 membered heteroaryl or C _1-4 Alkoxy is optionally substituted by one or more groups independently selected from halogen, oxo, CN, NO ₂ Or C _1-4 Alkyl substituent substitution;

or, R ^a And R ^b Together with the atoms to which they are attached form a 4-8 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S; said 4-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, oxo, CN, NO ₂ 、-NR ^a R ^b 、C _1-4 Alkyl or C _1-4 Substituent substitution of alkoxy;

more preferably, R ² Selected from phenyl, pyridyl, imidazopyridinyl, pyrrolopyridyl, oxazolyl, triazolyl, pyridotriazolyl, benzimidazolyl, benzothiazolyl, pyrrolopyrimidinyl, thienopyridinyl, thienopyrimidinyl or pyrazinotriazolyl, optionally substituted with one or more R ⁶ Substituted, each R ⁶ Independently selected from F, cl, br, oxo, methyl, CN, NO ₂ Methoxy, isopropyl, cyclopropyl, -CF ₃ 、NH ₂ 、

particularly preferably, substituted R ₂ Is selected from

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable form thereof, which is a compound having the structure of formula I-a2, formula I-a3 or formula I-a4, or a pharmaceutically acceptable form thereof:

wherein A, Q, Z, W, R ² And R ³ As defined in claims 1-10.

12. A compound according to claim 11, or a pharmaceutically acceptable form thereof, which is a compound having the structure of formula I-a2-1, formula I-a3-1 or formula I-a4-1, or a pharmaceutically acceptable form thereof:

wherein A, Q, Z, W, R ² And R ³ As defined in claim 11.

13. A compound according to claim 11, or a pharmaceutically acceptable form thereof, which is a compound having the structure of formula I-a2-2, formula I-a3-2 or formula I-a4-2, or a pharmaceutically acceptable form thereof:

wherein A, Q, Z, W, R ² And R ³ As defined in claim 11.

14. The compound according to any one of claims 1-11, or a pharmaceutically acceptable form thereof, that is a compound having the structure of formula I-a5, formula I-a6, or formula I-a7, or a pharmaceutically acceptable form thereof:

wherein R is ² As defined in claims 1-11.

15. A compound according to claim 14, or a pharmaceutically acceptable form thereof, which is a compound having the structure of formula I-a5-1, formula I-a6-1, or formula I-a7-1, or a pharmaceutically acceptable form thereof:

wherein R is ² As defined in claim 14.

16. A compound according to claim 14, or a pharmaceutically acceptable form thereof, which is a compound having the structure of formula I-a5-2, formula I-a6-2, or formula I-a7-2, or a pharmaceutically acceptable form thereof:

wherein R is ² As defined in claim 14.

17. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable form thereof, selected from the following compounds, or pharmaceutically acceptable forms thereof:

18. a pharmaceutical composition comprising a compound according to any one of claims 1-17, or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.

19. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by HPK 1.

20. The use according to claim 19, wherein the disease is cancer.

21. The use of claim 19, wherein the disease is selected from non-small cell lung cancer, squamous cell carcinoma, cancer of the head and neck, cancer of the oral cavity, cancer of the pharynx, cancer of the thyroid gland, cancer of the esophagus, stomach 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, cancer of the peritoneum, endometrial cancer, uterine corpus carcinoma, cervical cancer, kidney cancer, renal pelvis cancer, prostate cancer, bladder cancer, neurofibromatosis, bone cancer, brain cancer, testicular cancer, glioma, skin cancer, melanoma, cell tumors and sarcoma, multiple myeloma, leukemia, non-hodgkin's lymphoma, or myelodysplastic syndrome.