CN116239597B

CN116239597B - Pyrimidine pyrrole derivative and medicinal composition and application thereof

Info

Publication number: CN116239597B
Application number: CN202111486590.XA
Authority: CN
Inventors: 徐石林; 蒙凌华; 吴非飞; 孙朴; 张利山; 孙姚良; 李慧钰; 徐瓓
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2021-12-07
Filing date: 2021-12-07
Publication date: 2024-08-06
Anticipated expiration: 2041-12-07
Also published as: CN116239597A

Abstract

本发明披露了一种式(Ⅰ)所示的嘧啶并吡咯类化合物或其药学上可接受的盐、立体异构体或其前药分子，其中各基团的定义如说明书中所述。本发明还披露了此类化合物的制备方法，及其作为HPK1抑制剂，用于治疗HPK1相关障碍或疾病的方法。 The present invention discloses a pyrimidopyrrole compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug molecule thereof, wherein the definitions of each group are as described in the specification. The present invention also discloses a method for preparing such a compound, and a method for using the compound as an HPK1 inhibitor to treat HPK1-related disorders or diseases.

Description

Pyrimidine pyrrole derivative and medicinal composition and application thereof

Technical Field

The invention belongs to the field of chemical medicines, and in particular relates to a preparation method and application of a pyrimidopyrrole compound and a medicinal composition thereof.

Background

Immunotherapy (IO) relies on enhancing autoimmune function to kill cancer cells and tumor tissue. Compared with the traditional operation, chemotherapy, radiotherapy and targeted therapy, the method can effectively improve the survival rate of patients. Although antibody-based immune checkpoint inhibitor drugs have made significant progress in the area of immunotherapy. However, there is still a general problem with immunotherapy, namely that the response rate varies greatly among different tumor types. In addition to identifying the development of new immune checkpoints, modulation of T cell function by small molecule drugs is yet another strategy for future immunotherapy.

HPK1, also known as MAP4K1, is a serine-threonine kinase that is expressed mainly in hematopoietic cells. When the TCR is activated, HPK1 in the cytoplasm is recruited to the plasma membrane, and the activated HPK1 phosphorylates the adaptor protein SLP76, thereby activating SLP76 as an adaptor site for the 14-3-3p protein, ultimately disrupting the stability of the TCR signaling complex and inhibiting activation and proliferation of T cells. In addition to the TCR pathway, HPK1 can negatively regulate T cell signaling through prostaglandin E2 (PGE 2) receptors.

Further studies have shown that HPK1 kinase can inhibit immune function in a variety of cells, including cd4+ T cells, cd8+ T cells, and Dendritic Cells (DCs). MAP4K1 knockout mice grow slower than wild type mice, and infiltrating T cells are more active and have stronger proliferation capacity. The group of studies at the university of Qinghua Liao Xue have also found that small molecule inhibitors of HPK1 and the corresponding PROTACs degradants both enhance the efficacy of CAR-T cell based immunotherapy. These works all demonstrate that HPK1 is expected to be a hot research target for T cell immunotherapy. Therefore, the development of safe and efficient HPK1 small molecule inhibitors has great research value.

Disclosure of Invention

The invention aims to provide an HPK1 small molecule inhibitor with a novel structure.

In a first aspect of the present invention there is provided a pyrimido-pyrrole compound of the formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a prodrug molecule thereof:

Wherein,

R ₁ is selected from the group consisting of: hydrogen, halogen, C ₁-C₆ alkyl, C ₁-C₆ fluoroalkyl, - (CH ₂)_mR₄), substituted OR unsubstituted 5-7 membered aromatic ring, substituted OR unsubstituted C ₃-C₈ cycloalkyl, substituted OR unsubstituted 5-7 membered heterocyclyl, -C (O) R ₅、-C(O)NHC₁-C₃ alkyl, -OR ₅、-NH₂、-NHR₅、-NHC(O)C₁-C₆ alkyl, -S (O) ₂C₁-C₆ alkyl, -S (O) C ₁-C₆ alkyl, -C (O) OC ₁-C₆ alkyl;

L is selected from the group consisting of: -O-, -S-, -NH-, -NC ₁-C₃ alkyl-, -SO-, -S (O) ₂ -, or L is a bond (i.e. R ₂ is directly attached to the parent core);

R ₂ is selected from the group consisting of: r ₂ is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-6 membered heteroaromatic ring, a substituted or unsubstituted 5-7 membered aromatic ring and 5-8 membered aromatic ring, a substituted or unsubstituted 4-7 membered saturated nitrogen-containing heterocyclic ring; wherein the 5-7 membered ring is a saturated ring, a partially unsaturated ring or an aromatic ring;

R ₃ is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 4-10 membered ring acene ring, a substituted or unsubstituted 5-6 membered heteroaryl ring, a substituted or unsubstituted 4-10 membered ring and a 5-6 membered heteroaryl ring; wherein the 4-10 membered ring is a saturated ring, a partially unsaturated ring or an aromatic ring;

r ₄ is selected from the group consisting of: cyano, alkynyl;

R ₅ is selected from the group consisting of: c ₁-C₃ alkyl, substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered heteroaryl ring;

m is selected from the group consisting of: 0.1 or 2;

The substituents refer to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, oxygen (=o), carboxyl, hydroxyl, amino, nitro, cyano, -S (O) ₂C₁-C₆ alkylamino (including alkylamino or cycloalkylamino), -S (O) ₂C₁-C₆ alkyl (including alkanyl or cycloalkyl), -P (O) (C ₁-C₆ alkyl) ₂、C₁-C₆ alkyl, C ₁-C₆ fluoroalkyl, C ₁-C₆ alkoxy, C ₁-C₆ alkylamino, C ₁-C₆ alkoxycarbonyl, C ₁-C₆ amido, C ₂-C₁₂ ester group; each of the foregoing groups may be unsubstituted or substituted with 1,2 or 3 group a substituents selected from the group consisting of: halogen, hydroxy, amino, C ₁-C₆ alkyl, C ₁-C₆ alkoxy, C ₃-C₇ cycloalkyl, C ₁-C₆ alkenyl, C ₁-C₆ alkynyl, 3-to 12-membered heterocyclyl, 5-to 6-membered aryl;

In each of the above groups, the aryl or heterocyclic group (as an independent substituent or as part of other substituents) may be substituted with 1 or more halogens;

Each saturated ring may be carbocyclic or heterocyclic;

The heteroatoms in each heterocycle are selected from N, O, S.

In another preferred embodiment, R ₃ is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 6-membered ring acene, a substituted or unsubstituted 10-membered ring acene, a substituted or unsubstituted 5-6-membered heteroaryl ring, a substituted or unsubstituted 6-membered ring 5-6-membered heteroaryl ring, a substituted or unsubstituted 10-membered ring 5-6-membered heteroaryl ring; wherein the 6-membered ring or 10-membered ring is a saturated ring, a partially unsaturated ring or an aromatic ring.

In another preferred embodiment, R ₃ has the structure shown in the following formula:

Wherein a ₁、A₂、A₃、A₄ and a ₅ are each independently selected from the group consisting of: H. halogen, C ₁-C₆ alkyl, C ₁-C₆ alkoxy, 3-12 membered heterocyclyl, 5-6 membered aryl; each of the foregoing groups may be unsubstituted or substituted with 1,2 or 3 group a substituents selected from the group consisting of: halogen, hydroxy, C ₁-C₆ alkyl, C ₁-C₆ alkoxy, C ₃-C₇ cycloalkyl, C ₁-C₆ alkenyl, C ₁-C₆ alkynyl, 3-12 membered heterocyclyl, 5-6 membered aryl;

Or a ₃ and a ₂ or a ₄ together with the two carbon atoms to which they are attached form A5-to 8-membered ring comprising 0, 1 or 2 heteroatoms (selected from nitrogen, oxygen or optionally oxidized sulfur) as ring members, and said ring being optionally substituted with one or more substituents a ₆; the A ₆ is selected from the following group: H. c ₁-C₄ alkyl; or two a ₆ together with the two carbon atoms to which they are attached form a 5 to 8 membered ring containing 0, 1 or 2 heteroatoms as one or more ring members;

x and Y are N or C; and when X is N, A ₁ is absent.

In another preferred embodiment, each of a ₁、A₂、A₃、A₄ and a ₅ is independently selected from the group consisting of: H. halogen, C ₁-C₆ alkyl, C ₁-C₆ alkoxy, N-dimethylaminoethoxy, N-dimethylaminopropoxy, 2- (N-methylpiperazinyl) ethoxy, 2- (N-acetylpiperazinyl) ethoxy, 2-morpholinylethoxy, 2-thiarphinylethoxy, 2-piperidylethoxy, 2-tetrahydropyrrolylethoxy, N-methylpiperazinyl, morpholinyl, thiarphinyl, piperidinyl, tetrahydropyrrolyl, imidazolyl, 3-N, N-dimethylpyrrolyl, 4-N, N-dimethylpiperidinyl, 4-acetylpiperazinyl, 1-methyl-4- (piperazin-4-substituted) piperidinyl, 4- (4-methylpiperazin-1-substituted) methyl, 1-methylpiperidin-4-amino, 4-piperazin-2-one, 1-methyl-4-piperazin-2-one.

In another preferred embodiment, when L is selected from the group consisting of-NH-, -N (C ₁-C₃ alkyl) -, or is directly attached to a C atom in R ₂, R ₂ has the structure shown below:

Wherein B ₁、B₂、B₃、B₄ and B ₅ are each independently selected from the group consisting of: H. halogen, amino, C ₁-C₄ alkyl, C ₁-C₄ alkoxy, C ₁-C₄ alkylamino, C ₁-C₄ hydroxy, -C (O) B ₆、-S(O)₂B₆、-S(O)B₆、-P(O)(B₆)₂; and B ₆ is selected from the group consisting of: c ₁-C₄ alkyl, C ₁-C₄ alkylamino; or B ₁ and B ₂ or B ₄ and B ₅ together with the two carbon atoms to which they are attached form a 5-to 8-membered ring containing 0, 1 or 2 heteroatoms as one or more ring members; the ring being optionally substituted with one or more substituents B ₇;

the B ₇ is selected from the following group: H. substituted or unsubstituted C1-C6 alkyl, or two B ₇ located on the same carbon atom, together form an oxygen atom (=o);

Z is N or C, and B ₃ is absent when Z is N.

In another preferred embodiment, when L is selected from the group consisting of directly attached to the N atom in R ₂, said R ₂ has the structure shown in the formula:

wherein each C ₁、C₂、C₃、C₄ is independently selected from the group consisting of: H. halogen, amino, C ₁-C₄ alkyl, C ₁-C₄ alkoxy, C ₁-C₄ alkylamino, C ₁-C₄ hydroxy;

D is selected from the group consisting of: hydrogen, C ₁-C₄ alkyl;

n is 0, 1,2 or 3;

m is 0,1, 2,3 or 4.

In another preferred embodiment, the compound has the structure of formula (II):

wherein each a ₁、A₂、A₃、A₄、A₅ is independently selected from the group consisting of: H. halogen, C ₁-C₆ alkyl, C ₁-C₆ alkoxy,

Or a ₃ and a ₂ or a ₄ together form a structure selected from the group consisting of:

In another preferred embodiment, R ₁ is selected from the group consisting of:

Wherein n is 0 or 1 or 2 or 3.

In another preferred embodiment, B ₁ is selected from the group consisting of:

Wherein n is 0 or 1 or 2 or 3; n is 0 or 1 or 2 or 3; * Is the site in the group attached to the adjacent carbon atom of the carbon in which the benzene ring is substituted.

In another preferred embodiment, the compound is selected from the group consisting of:

1) N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ -phenyl-7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine;

2) N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (o-tolyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine;

3) N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (tert-butyl) phenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine;

4) N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (o-fluorophenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine;

5) N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (o-chlorophenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine;

6) N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (trifluoromethyl) phenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine;

7) N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (o-methanoylphenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine;

8) N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (methoxy) phenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine;

9) N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (methoxymethyl) phenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine;

10 N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (isopropoxy) phenyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

11 N- (4- (indol-1-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine;

12 N- (4- (3, 4-dihydroquinolin-1 (2H) -yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine;

13 N- (4- (2, 3,4, 5-tetrahydro-1H-benzo [ b ] azapyridin-1-yl) -7H-pyrrole [2,3-d ] pyrimidin-2-yl) -6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine;

14 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzoic acid methyl ester;

15 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide;

16 N ⁴ - (2- (isopropylsulfonyl) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

17 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

18 N-ethyl-2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N-methylbenzenesulfonamide;

19 N, N-diethyl-2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

20 7- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) isoindol-1-one;

21 4- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) isoindol-1-one;

22 6-methoxy-2-methyl-N- (4-phenyl-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine;

232- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

24 2- ((5-chloro-2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

25 2- ((5-cyano-2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

26 2- ((5- (cyanomethyl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

27 2- ((5-acetyl-2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

28 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (thiophen-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

29 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (1H-pyrazol-4-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

30 N, N-dimethyl-2- ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

31 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dipropylbenzenesulfonamide;

32 N ⁴ - (2- (azetidin-1-ylsulfonyl) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

33 N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (pyrrolidin-1-ylsulfonyl) phenyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

34 N-isopropyl-2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N-toluenesulfonamide;

35 N- (sec-butyl) -2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N-toluenesulfonamide;

36 N ⁴ - (2- (cyclopropylsulfonyl) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

37 N ⁴ - (2- (cyclobutylsulfonyl) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

38 N ⁴ - (2- (tert-butoxy) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

39 2- ((5- (furan-3-yl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

40 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (1H-1, 2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

41 2- ((5- (isoxazol-4-yl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

42 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (thiazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

43 2- ((5- (2-chlorothien-3-yl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

44 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (3-methyl-1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

45 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (1-methyl-1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

46 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (3-oxocyclopentyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

47 2- ((5- (isoxazole-4-carbonyl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

48 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5-phenyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

49 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (pyridin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

50 2- ((5- (3-fluorophenyl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

51 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (pyridin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

52 2- ((5- (6-aminopyridin-3-yl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

53 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

54 N- (4- ((2- (N, N-dimethylsulfamoyl) phenyl) amino) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) acetamide;

55 4- ((2- (N, N-dimethylsulfamoyl) phenyl) amino) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -N-methyl-7H-pyrrole [2,3-d ] pyrimidine-5-carboxamide;

56 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (trifluoromethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

57 2- ((5-ethynyl-2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

58 N- (4- (2-aminopyridin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine;

59 N, N-dimethyl-2- ((2- ((4-morpholinophenyl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

60 N, N-dimethyl-2- ((2- ((4- (4-methyl-1, 4-diaza-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

61 2- ((2- ((4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

62 2- ((2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

63 N, N-dimethyl-2- ((2- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

64 2- ((2- ((3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

65 N, N-dimethyl-2- ((2- ((4-morpholinophenyl) amino) -5- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide

66 N, N-dimethyl-2- ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -5- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

67 N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (piperidin-1-ylsulfonyl) phenyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine

68 N ⁴ - (2-ethoxyphenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine

69 N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N4- (2-propoxyphenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine

70 2- ((2- ((6-Fluoro-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

71 2- ((2- ((6-chloro-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

72 2- ((2- ((7-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

73 N, N-dimethyl-2- ((2- ((3- (4-methylpiperazin-1-yl) phenyl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

74 2- ((2- ((2-ethyl-6-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

75 2- ((2- ((2-isopropyl-6-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

76 2- ((2- ((9-methoxy-1, 3,4,6,11 a-hexahydro-2H-pyridin [1,2-b ] isoquinolin-8-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

77 2- ((2- ((6-ethoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

78 N, N-dimethyl-2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

79 2- ((2, 5-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

80N, N-dimethyl-2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

81 2- ((2- ((2-methoxyphenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

82 2- ((2- ((5- (hydroxymethyl) -2-methoxyphenyl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

83 2- ((2- ((5- (2-hydroxypropan-2-yl) -2-methoxyphenyl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

84 N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (piperidin-1-ylsulfonyl) phenyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

85 2- ((2- ((7-methoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

86 2- ((2- ((2-cyclopropyl-6-methoxy-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

87 2- ((2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

88 2- ((2- ((4- (4-ethylpiperazin-1-yl) phenyl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

89 4- ((4- ((2- (N, N-dimethylsulfamoyl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -N- (1-methylpiperidin-4-yl) benzamide;

90 N, N-dimethyl-2- ((2- ((4- (morpholine-4-carbonyl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

91 N, N-dimethyl-2- ((2- ((2-methyl-4-morpholinophenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

92 N, N-dimethyl-2- ((2- ((4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide;

93 2- ((2- ((4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) amino) -7H pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

94 N- (tert-butyl) -2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N-toluenesulfonamide;

95 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N-methyl-N-neopentylbenzenesulfonamide;

96 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N-methyl-N-propylbenzenesulfonamide;

97 N-isobutyl-2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N-toluenesulfonamide;

98 1- ((2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) sulfonyl) -3-methylazetidin-3-ol;

99 N ⁴ - (2- ((3, 3-dimethylpyrrolidin-1-yl) sulfonyl) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

100 N ⁴ - (2- ((3, 3-dimethylazetidin-1-yl) sulfonyl) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

101 1- ((2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) sulfonyl) -4-methylpiperidin-4-ol;

102 N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (morpholinesulfonyl) phenyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

103 N ⁴ - (2- ((4, 4-dimethylpiperidin-1-yl) sulfonyl) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine;

104 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (2-oxo-1, 2-dihydropyridin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

105 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (1-methyl-6-oxo-1, 6-dihydropyridin-2-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

106 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (5-methylpyridin-3-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

107 2- ((5- (1, 3-dimethyl-2-oxo-1, 2-dihydropyridin-4-yl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide;

108 2- ((5- (3, 5-dimethylisoxazol-4-yl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide

109 2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (2-methylpyridin-3-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide

110 2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (4-methylpyridin-3-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide

111 N ⁴ - (3-fluorophenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine

112 N ⁴ - (3-chlorophenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine

113 N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (3- (trifluoromethyl) phenyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising: one or more of the compounds of formula I, pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof according to the first aspect of the present invention, and one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents.

In a third aspect, the present invention provides the use of a compound of formula I according to the first aspect of the invention, a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or a mixture thereof, for the preparation of a pharmaceutical composition for the treatment or prophylaxis of diseases associated with HPK1 activity or expression level.

In another preferred embodiment, the disease is selected from the group consisting of: lymphomas, blastomas, medulloblastomas, retinoblastomas, sarcomas, liposarcomas, synovial cell sarcomas, neuroendocrine tumors, carcinoid tumors, gastrinomas, islet cell carcinomas, mesotheliomas, schwannomas, auditory neuromas, meningiomas, adenocarcinomas, melanomas, leukemias or lymphoid malignancies, squamous cell carcinomas, epithelial squamous cell carcinomas, lung cancer, small cell lung cancer, non-small cell lung cancer, adenocarcinoma lung cancer, lung squamous carcinoma, peritoneal carcinoma, hepatocellular carcinoma, stomach cancer, intestinal cancer, pancreatic cancer, glioblastomas, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, merkel cell carcinoma, esophageal carcinoma, biliary tract tumors, head and neck cancer, and hematological malignancies.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Drawings

FIG. 1 shows the effect of some of the compounds of the present invention for inhibiting phosphorylation of SLP76 protein;

FIG. 2 shows the effect of some of the compounds of the present invention for inhibiting phosphorylation of SLP76 protein;

FIG. 3 shows the effect of some of the compounds of the present invention for inhibiting phosphorylation of SLP76 protein;

FIG. 4 shows the effect of some of the compounds of the present invention for inhibiting phosphorylation of SLP76 protein;

FIG. 5 shows the effect of some of the compounds of the present invention for inhibiting phosphorylation of SLP76 protein.

Detailed Description

The invention takes 2, 4-dichloro-7H-pyrrole [2,3-d ] pyrimidine as raw material, and prepares and synthesizes the compound shown in the formula (I) by using the known organic synthesis technology, and has HPK1 kinase inhibition activity.

Terminology

In the chemicals of the present invention, when any variable (e.g., R ₁, R, etc.) occurs more than once in any component, the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible provided that such combinations stabilize the compounds. The lines drawn from the substituents into the ring system indicate that the bond referred to may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atom adjacent to the ring. If the substituent itself is substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, as long as the structure is stabilized.

The term "alkyl" as used in the present invention is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C ₁-C₅" in "C ₁-C₅ alkyl" includes groups having 1, 2,3, 4, or 5 carbon atoms in a straight or branched chain arrangement. For example, "C ₁-C₅ alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.

The term "heterocycle" or "heterocyclyl" as used herein refers to a 5-to 6-membered aromatic or non-aromatic heterocycle containing 1 to 4 heteroatoms selected from O, N and S, and includes bicyclic groups. "heterocyclyl" thus includes the heteroaryl groups mentioned above, as well as the dihydro and tetrahydro analogs thereof. Further examples of "heterocyclyl" include, but are not limited to: imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, l, 4-dioxanyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl and tetrahydrothienyl, and N-oxides thereof. The attachment of the heterocyclic substituent may be through a carbon atom or through a heteroatom.

"Halogen" as used in the present invention means fluorine, chlorine, bromine and iodine.

Unless otherwise defined, alkyl, cycloalkyl, aryl and heterocyclyl substituents in the present invention may be unsubstituted or substituted. For example, (C ₁-C₆) alkyl may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclyl, such as morpholino, piperidinyl and the like.

The present invention includes the free forms of the compounds of formula (I), as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to an amine compound in a non-salt form. Included are pharmaceutically acceptable salts which include not only the exemplary salts of the specific compounds described herein, but also all of the typical pharmaceutically acceptable salts of the compounds of formula (i) in free form. The free form of the particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention such acid and base salts are otherwise pharmaceutically comparable to their respective free forms.

Stereoisomers as described herein include enantiomers, diastereomers and geometric forms. Some compounds of the invention have cycloalkyl groups which may be substituted on more than one carbon atom, in which case all geometric forms thereof, including cis and trans, and mixtures thereof, are within the scope of the invention.

Pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess of an inorganic or organic acid in the form of the desired salt in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases. Thus, pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention formed by the reaction of a basic compound of the invention with an inorganic or organic acid. For example, conventional nontoxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, and also salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

If the compounds of the present invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases, salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and the like. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guava, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

Since under physiological conditions the deprotonated acidic moiety, e.g. carboxyl, in the compound may be anionic, and this charge may then be balanced out by the protonated or alkylated basic moiety, e.g. tetravalent nitrogen atom, which is internally cationic, it should be noted that the compounds of the present invention are potentially internal salts or zwitterions.

Prodrugs of the present invention are those compounds of formula (i) which are suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and are effective for their intended use, and include acetal, ester, and zwitterionic forms. The prodrug is converted in vivo (e.g., by hydrolysis in blood) to the parent compound of the above formula.

The invention provides a pharmaceutical composition, which comprises a compound of a general formula (I), and further comprises pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials are selected from the following materials: carrier, diluent, binder, lubricant, wetting agent. Preferably, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I).

The compounds of the invention may be formulated as pharmaceutical compositions in the form: syrups, elixirs, suspensions, powders, granules, tablets, capsules, troches, aqueous solutions, creams, ointments, lotions, gels, emulsions and the like.

Cancers described herein include lymphomas, blastomas, medulloblastomas, retinoblastomas, sarcomas, liposarcomas, synovial cell sarcomas, neuroendocrine tumors, carcinoid tumors, gastrinomas, islet cell carcinomas, mesotheliomas, schwannomas, auditory neuroma, meningiomas, adenocarcinomas, melanomas, leukemias or lymphoid malignancies, squamous cell carcinomas, epithelial squamous cell carcinomas, lung carcinomas, small cell lung carcinomas, non-small cell lung carcinomas, adenocarcinoma lung carcinomas, lung squamous cell carcinomas, peritoneal carcinomas, hepatocellular carcinomas, stomach carcinomas, intestinal carcinomas, pancreatic carcinomas, glioblastomas, cervical carcinomas, ovarian carcinomas, liver carcinomas, bladder carcinomas, liver carcinomas, breast carcinomas, metastatic breast carcinomas, colon carcinomas, rectal carcinomas, colorectal carcinomas, uterine carcinomas, salivary gland carcinomas, kidney carcinomas, prostate carcinomas, vulval carcinomas, thyroid carcinomas, liver carcinomas, anal carcinomas, penile carcinomas, merkel cell carcinomas, esophageal carcinomas, biliary tract tumors, head and neck carcinomas, and hematological malignancies.

The invention discloses a pyrimidopyrrole compound or pharmaceutically acceptable salt, stereoisomer or prodrug molecule thereof which is used as an HPK1 inhibitor, reduces the activity of HPK1 kinase and is used for treating HPK1 related diseases.

synthesis of pyrrolopyrimidines

The compounds of the formula I-II according to the invention can be synthesized from 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine as starting material by the following two schemes:

Pharmaceutical composition and preparation thereof

In another aspect the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the compounds of formula I above, pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents. The auxiliary materials are, for example, odorants, flavoring agents, sweeteners and the like.

The pharmaceutical composition provided by the invention preferably contains 1-99% by weight of active ingredients, wherein the preferable proportion is that the compound shown in the general formula I is 65-99% by weight of the total weight of the active ingredients, and the rest is pharmaceutically acceptable carrier, diluent or solution or salt solution.

The compounds and pharmaceutical compositions provided herein may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols and the like, and may be presented in a suitable solid or liquid carrier or diluent and in a suitable sterilization apparatus for injection or infusion.

The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dose of the formulation formula comprises 1mg to 700mg of the compound of the general formula I, preferably 25mg to 300mg of the compound of the general formula I.

The compounds and pharmaceutical compositions of the present invention may be used clinically in mammals, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes of administration. Most preferably orally. Most preferably, the daily dosage is 50-1400mg/kg body weight, taken at one time, or 25-700mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Typically starting from a small dose, the dose is gradually increased until the most suitable dose is found.

The invention also provides an HPK1 inhibitor, which comprises one or more selected from the compounds shown in the general formula I, pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or a mixture thereof, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and/or diluents.

The compounds and compositions of the present invention are useful for the treatment and prevention of non-alcoholic fatty liver, liver fibrosis, diabetes, hyperlipidemia, multiple sclerosis (including recurrent multiple sclerosis, relapsing remitting multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, lupus erythematosus, crohn's disease, immune disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, and the like, associated with HPK1 inhibitors, including, but not limited to, various types of diabetes, hyperlipidemia, non-alcoholic fatty liver, liver fibrosis, multiple sclerosis, and the like.

Accordingly, in a further aspect, the present invention provides the use of a compound of formula I, a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixtures thereof as defined above in the manufacture of a medicament for the treatment of diseases associated with HPK1 agonists, such as tumour or immune diseases, which diseases specifically include (but are not limited to): acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, burkitt's lymphoma, follicular lymphoma, breast cancer, non-small cell lung cancer, melanoma, renal cancer, ovarian cancer, prostate cancer, colon cancer, and central nervous system tumor drugs, or autoimmune disease.

In yet another aspect, the present invention provides a method of treating a disease or condition associated with HPK1 activity or expression level, comprising administering to a patient in need thereof one or more compounds selected from the group consisting of compounds of formula I, pharmaceutically acceptable salts, racemates, R-isomers, S-isomers, and mixtures thereof.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Example 1

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ -phenyl-7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (Compound 1)

Step 1-1:2, 4-dichloro-7- (2-trimethylsiloxymethyl) -7H-pyrrolo [2,3-d ] pyrimidine (S2)

To a solution of compound S1 (5 g,26.7 mmol) in 50mL anhydrous DMF at 0deg.C was added 60% sodium hydride (1.6 g,40.05 mmol). The resulting mixture was stirred at 0℃for 0.5 h. 2- (trimethylsilyl) ethoxymethyl chloride (5.3g,32.04mmol,1.2eq 166.72) was then added at 0℃and the resulting solution was stirred at room temperature for 3 hours. The reaction was quenched with water (5 mL). The resulting mixture was extracted with ethyl acetate (200 ml x 3), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography gave the title compound (6.5 g, 77%) as a white solid.

¹H NMR(500MHz,MeOD-d₆)δ7.64(d,J＝3.7Hz,1H),6.67(d,J＝3.7Hz,1H),5.62(s,2H),3.56(t,J＝8.1Hz,2H),0.88(t,J＝8.1Hz,2H),0.08(s,9H).

Step 1-2: 2-chloro-N-phenyl-7- (2-trimethylsiloxymethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (S3)

To a solution of compound S2 (200 mg,0.63 mmol) in 10mL of dry t-butanol was added aniline (88.06 mg,0.95mmol,1.5 eq) and DIPEA (126.8mg,1.26mmol 2e.q) at room temperature. The resulting mixture was stirred at 100℃for 12h. After cooling to room temperature, the reaction solution was diluted with water (100 mL), then extracted with ethyl acetate (100 ml×3), and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography gave the title compound (120 mg, 51%) as a white solid.

¹H NMR(500MHz,MeOD-d₆)δ7.75(d,J＝7.7Hz,2H),7.36(t,J＝8.0Hz,2H),7.22(d,J＝3.7Hz,1H),7.11(d,J＝7.4Hz,1H),6.68(d,J＝3.6Hz,1H),5.53(s,2H),3.56(t,J＝8.1Hz,2H),0.87(t,J＝8.0Hz,2H),0.05(s,9H).

Step 1-3:N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ -phenyl-7- (2-trimethylsiloxymethyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (S4)

6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (92.2mg,0.48mmol 192.13) and cesium carbonate (208.5mg,0.64mol 325.82)、Xantphos(37.03mg,0.064mol 578.62)、Pd₂(dba)₃(29.3mg,0.032mol915.72). were sequentially added to 3mL of a toluene solution of compound S3 (120mg,0.32mmol 374.13) at room temperature, and after three times of pumping with N ₂, they were reacted at 100℃for 12 hours under an atmosphere of N ₂. The reaction solution was filtered and concentrated, and purified by silica gel column chromatography to give the title compound (30 mg, 17.8%) as a yellow oil.

¹H NMR(500MHz,MeOD-d₆)δ8.28(s,1H),7.67(d,J＝8.1Hz,2H),7.37(t,J＝7.6Hz,2H),7.12(t,J＝7.4Hz,1H),6.96(d,J＝3.6Hz,1H),6.69(s,1H),6.60(d,J＝3.5Hz,1H),5.48(s,2H),3.88(s,3H),3.60(t,J＝8.0Hz,2H),3.53(s,3H),2.91(t,J＝5.8Hz,2H),2.82(t,J＝5.8Hz,2H),2.51(s,3H),0.07(s,9H).

Step 1-4: n ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ -phenyl-7H-pyrrole [2,3-D ] pyrimidine-2, 4-diamine (Compound 1)

To a solution of compound S4 (30mg,0.056mmol 530.28) in 5mL of DCM was added 2.5mL of TFA at room temperature. The reaction was stirred at room temperature for 3h. The mixture was neutralized to ph=7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 ml×3), and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. To the crude product was added 5mL of NH ₃ in MeOH, and the reaction was stirred at room temperature for 12h. After concentration under pressure, purification by reverse phase column chromatography gave compound 1 (10 mg,44.4% 400.2) as a white solid.

¹H NMR(400MHz,MeOD-d₆)δ8.06(s,1H),7.58-7.51(m,4H),7.42(t,J＝7.6,1H),7.05(d,J＝3.5,1H),6.94(s,1H),6.66(s,1H),4.22–4.05(m,2H),3.93(s,3H),3.77-3.69(m,1H),3.46-3.35(m,1H),3.22-3.11(m,2H),3.05(s,3H).

MS(ESI,[M+H]⁺)m/z 401.2

Example 2

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (o-tolyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (Compound 2)

Synthetic method as in example 1

¹H NMR(400MHz,MeOD-d₆)δ8.02(brs,1H),7.48-7.40(m,4H),7.04(s,1H),6.89(s,1H),6.52(brs,1H),4.11–4.02(m,2H),3.91(s,3H),3.77-3.70(m,1H),3.41-3.36(m,1H),3.24-3.11(m,2H),3.05(s,3H),2.31(s,3H).

MS(ESI,[M+H]⁺)m/z 415.3

Example 3

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (tert-butyl) phenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine (Compound 3)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.13(brs,1H),7.74(d,J＝8.0Hz,1H),7.56(t,J＝8.3Hz,1H),7.45(t,J＝7.3Hz,1H),7.35(d,J＝6.7Hz,1H),7.05(s,1H),6.92(s,1H),4.27–4.04(m,2H),3.93(s,3H),3.79-3.68(m,1H),3.45-3.38(m,1H),3.26-3.15(m,2H),3.08(s,3H),1.42(s,9H).

MS(ESI,[M+H]⁺)m/z 457.4

Example 4

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (ortho-fluorophenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine (Compound 4)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ7.95(s,1H),7.61(t,J＝8.0Hz,1H),7.55-7.50(m,1H),7.41-7.36(m,2H),7.07(d,J＝3.6Hz,1H),6.91(s,1H),6.63(s,J＝1H),4.08–4.00(m,2H),3.92(s,3H),3.76-3.68(m,1H),3.43-3.35(m,1H),3.24-3.09(m,2H),3.05(s,3H).

MS(ESI,[M+H]⁺)m/z 419.4

Example 5

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (o-chlorophenyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (5)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.0(s,1H),7.73-7.71(m,1H),7.68-7.65(m,1H),7.55-7.53(m,2H),7.07(d,J＝3.6Hz,1H),6.91(s,1H),6.59(s,J＝1H),4.13–4.04(m,2H),3.94(s,3H),3.81-3.65(m,1H),3.48-3.38(m,1H),3.27-3.11(m,2H),3.07(s,3H).

MS(ESI,[M+H]⁺)m/z 435.3.

Example 6

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (trifluoromethyl) phenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine (Compound 6)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.00(d,J＝7.84Hz,1H),7.90(m,2H),7.78(d,J＝7.7Hz,1H),7.71(d,J＝7.8Hz,1H),7.07(d,J＝3.6Hz,1H),6.91(s,1H),6.50(s,J＝1H),4.15–4.01(m,2H),3.92(s,3H),3.79-3.69(m,1H),3.45-3.37(m,1H),3.28-3.18(m,1H),3.16-3.12(m,1H),3.08(s,3H).

MS(ESI,[M+H]⁺)m/z 469.4

Example 7

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (o-methanoylphenyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (Compound 7)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.01(s,1H),7.70(d,J＝7.2Hz,1H),7.57-7.48(m,3H),7.05(d,J＝3.5Hz,1H),6.90(s,1H),6.53(s,1H),4.68(s,2H),4.15–3.98(m,2H),3.91(s,3H),3.80-3.68(m,1H),3.45-3.35(m,1H),3.25-3.08(m,2H),3.05(s,3H).

MS(ESI,[M+H]⁺)m/z 431.4

Example 8

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (methoxy) phenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine (Compound 8)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.20(s,1H),7.50(t,J＝7,4Hz,1H),7.26(d,J＝8.3Hz,1H),7.07(d,J＝3.5Hz,1H),6.92(s,1H),7.07(d,J＝Hz,1H),6.90(d,J＝2.8Hz,1H),6.60(s,J＝1H),4.32–4.10(m,2H),3.91(s,3H),3.87(s,3H),3.79-3.68(m,1H),3.49-3.36(m,1H),3.27-3.11(m,2H),3.06(s,3H).

MS(ESI,[M+H]⁺)m/z 431.3.

Example 9

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (methoxymethyl) phenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine (Compound 9)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ7.50-7.45(m,2H),7.34(s,2H),7.23(d,J＝8.6Hz,1H),7.13(d,J＝8.6Hz,1H),6.94(d,J＝3.4Hz,1H),6.36-6.17(br,1H),4.60–4.50(m,1H),4.43(s,2H),4.31–4.14(m,1H),3.83(s,3H),3.66-3.47(m,2H),3.33(s,3H),,3.09-3.06(m,2H),2.97(s,3H).

MS(ESI,[M+H]⁺)m/z 445.4

Example 10

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (isopropoxy) phenyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (Compound 10)

Synthetic method as in example 1

¹H NMR(400MHz,MeOD-d₆)δ8.21(s,1H),7.49-7.44(m,2H),7.23(d,J＝8Hz,1H),7.11(t,J＝8Hz,1H),7.07(d,J＝2.8Hz,1H),6.90(d,J＝2.8Hz,1H),6.57(s,J＝1H),4.71–4.65(m,1H),4.30–4.07(m,2H),3.91(s,3H),3.76-3.66(m,1H),3.50-3.35(m,1H),3.23-3.10(m,2H),3.06(s,3H),1.21(d,J＝7.36Hz,6H).

MS(ESI,[M+H]⁺)m/z 459.5.

Example 11

N- (4- (indol-1-yl) -7H-pyrrole [2,3-d ] pyrimidin-2-yl) -6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (compound 11)

Synthetic method as in example 1

¹H NMR(500MHz,MeOD-d₆)δ8.13(d,J＝8.6Hz,1H),7.72(s,1H),7.92(s,1H),7.32(d,J＝8.6Hz,1H),7.11-7.09(m,1H),7.07-7.06(m,1H),6.79(d,J＝3.7Hz,1H),4.59(t,J＝8.3Hz,2H),4.45-4.14(m,2H),3.91(s,3H),3.85-3.68(m,2H),3.55-3.36(m,2H),3.31-3.18(m,2H),3.06(s,3H).

MS(ESI,[M+H]⁺)m/z 427.3

Example 12

N- (4- (3, 4-dihydro-quinolin-1 (2H) -yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (compound 12)

Synthetic method as in example 1

¹H NMR(400MHz,MeOD-d₆)δ8.16(s,1H),7.39-7.36(m,2H),7.32-7.23(m,2H),6.96(s,1H),6.92(d,J＝3.6Hz,1H),5.83(s,1H),4.39-4.21(m,2H),4.17(t,J＝6.6Hz,2H),3.95(s,3H),3.80-3.70(m,1H),3.46-3.34(m,1H),3.28-3.09(m,2H),3.06(s,3H),2.83(t,J＝6.4Hz,2H),2.15-2.08(m,2H).

MS(ESI,[M+H]⁺)m/z 441.4

Example 13

N- (4- (2, 3,4, 5-tetrahydro-1H-benzo [ b ] azapyridin-1-yl) -7H-pyrrole [2,3-d ] pyrimidin-2-yl) -6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (compound 13)

Synthetic method as in example 1

¹H NMR(400MHz,MeOD-d₆)δ8.10(s,1H),7.50-7.47(m,2H),7.41-7.37(m,1H),7.32(d,J＝7.6Hz,1H),7.01(s,1H),6.62(s,1H),5.09-5.05(m,1H),4.52-4.34(m,3H),3.97(s,3H),3.81-3.66(m,1H),3.49-3.35(m,2H),3.25-3.13(m,2H),3.07(s,3H),2.82-2.75(m,2H),2.14-1.99(m,3H),1.61-1.52(m,1H).

MS(ESI,[M+H]⁺)m/z 455.4

Example 14

Methyl 2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzoate (compound 14)

Synthetic method as in example 1

¹H NMR(500MHz,MeOD-d₆)δ8.51(d,J＝8.3Hz,1H),δ8.15(d,J＝9.1Hz,1H),8.05(s,1H),7.68(t,J＝8.4Hz,1H),7.31(t,J＝7.6Hz,1H),7.09(d,J＝3.6Hz,1H),6.97(s,1H),6.62(d,J＝3.5Hz,1H),4.35–4.24(m,2H),3.95(s,3H),3.94(s,3H),3.85-3.75(m,1H),3.50-3.40(m,1H),3.29-3.15(m,2H),3.08(s,3H).

MS(ESI,[M+H]⁺)m/z 459.2

Example 15

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (compound 15)

Synthetic method as in example 1

¹H NMR(500MHz,MeOD-d₆)δ8.28-8.26(m,1H),7.98(s,1H),7.84-7.79(m,1H),7.71(t,J＝7.8Hz,1H),7.48(t,J＝7.6Hz,1H),7.06(d,J＝4.0Hz,1H),6.98(s,1H),6.56(d,J＝3.5Hz,1H),4.26-4.19(m,2H),3.95(s,3H),3.84-3.75(m,2H),3.49-3.39(m,1H),3.21-3.16(m,1H),3.09(s,3H),1.89(d,J＝13.5Hz,6H).

MS(ESI,[M+H]⁺)m/z 477.3

Example 16

N ⁴ - (2- (isopropylsulfonyl) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (Compound 16)

Synthetic method as in example 1

¹H NMR(500MHz,MeOD-d₆)δ8.30(d,J＝8Hz,1H),8.06(dd,J＝8.0Hz、1Hz,1H),8.05(s,1H),7.86(td,J＝7.8Hz、1.5Hz,1H),7.57(t,J＝7.8Hz,1H),7.10(d,J＝3.5Hz,1H),7.00(s,1H),6.53(d,J＝3.5Hz,1H),4.31-4.14(m,2H),3.95(s,3H),3.83-3.74(m,1H),3.47-3.43(m,1H),3.40(t,J＝6.8Hz,1H),3.28-3.15(m,2H),3.09(s,3H),1.26(d,J＝7.0Hz,6H).

MS(ESI,[M+H]⁺)m/z 507.3

Example 17

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 17)

Synthetic method as in example 1

¹H NMR(500MHz,CDCl₃-d)δ12.30(brs,1H),10.07(s,1H),8.40(d,J＝8.5Hz,1H),8.21(s,1H),7.92(dd,J＝7.5Hz、1Hz,1H),7.68(td,J＝8.2Hz、1.5Hz,1H),7.64(s,1H),7.41(t,J＝7.5Hz,1H),7.00-6.98(m,1H),6.67(s,1H),6.42(s,1H),4.50(d,J＝15Hz,1H),3.96(s,1H),3.92(s,3H),3.83-3.75(m,1H),3.51-3.41(m,1H),3.25-3.15(m,1H),3.15-3.09(m,1H),2.99(s,3H),2.78(s,6H).

MS(ESI,[M+H]⁺)m/z 508.3

Example 18

N-ethyl-2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N-methylbenzenesulfonamide (compound 18)

Synthetic method as in example 1

¹H NMR(500MHz,MeOD-d₆)δ8.06-8.03(m,2H),7.97(s,1H),7.79(t,J＝7.7Hz,1H),7.58(t,J＝7.5Hz,1H),7.07(d,J＝3.6Hz,1H),6.92(s,1H),6.53(d,J＝3.5Hz,1H),4.23-4.21(m,2H),3.91(s,3H),3.76-3.71(m,1H),3.46-3.35(m,1H),3.27-3.20(m,1H),3.15-3.11(m,3H),3.06(s,3H),2.72(s,3H),1.04(t,J＝7.2Hz,3H).

MS(ESI,[M+H]⁺)m/z 522.3

Example 19

N, N-diethyl-2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide (compound 19)

Synthetic method as in example 1

¹H NMR(500MHz,MeOD-d₆)δ8.12(d,J＝8.0Hz,1H),8.04-8.03(m,2H),7.76(t,J＝7.6Hz,1H),7.52(t,J＝7.5Hz,1H),7.07(d,J＝3.6Hz,1H),6.91(s,1H),6.52(d,J＝3.5Hz,1H),4.22-4.14(m,2H),3.92(s,3H),3.78-3.70(m,1H),3.43-3.36(m,1H),3.26-3.22(m,4H),3.20-3.11(m,2H),3.06(s,3H),1.02(t,J＝7.1Hz,6H).

MS(ESI,[M+H]⁺)m/z 536.3

Example 20

7- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) isoindol-1-one (compound 20)

Synthetic method as in example 1

¹H NMR(400MHz,MeOD-d₆)δ8.26(s,1H),7.41(t,J＝7.7Hz,1H),7.16(d,J＝3.7Hz,1H),7.02(d,J＝3.8Hz,1H),6.87(s,1H),6.81(d,J＝7.3Hz,1H),6.72(d,J＝8.2Hz,1H),5.16(s,2H),4.54-4.49(m,1H),4.30-4.25(m,1H),3.93(s,3H),3.77(brs,1H),3.51-3.38(m,1H),3.26-3.16(m,2H),3.10(s,3H).

MS(ESI,[M+H]⁺)m/z 456.38

Example 21

4- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) isoindol-1-one (compound 21)

Synthetic method as in example 1

¹H NMR(400MHz,MeOD-d₆)δ8.30(s,1H),7.35(t,J＝7.7Hz,1H),7.23(d,J＝7.4Hz,1H),7.18(d,J＝3.6Hz,1H),7.05-7.03(m,2H),6.88(s,1H),5.11(s,2H),4.55-4.51(m,1H),4.32-4.28(m,1H),3.92(s,3H),3.75(brs,1H),3.48-3.37(m,1H),3.23-3.14(m,2H),3.08(s,3H).

MS(ESI,[M+H]⁺)m/z 456.4

Example 22

6-Methoxy-2-methyl-N- (4-phenyl-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (compound 22)

Step 22-1: -chloro-4-phenyl-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrole [2,3-d ] pyrimidine

To a solution of compound S2 (200 mg,0.63 mmol) in 5mL of toluene was added phenyl borate (128.6 mg,0.63 mmol), potassium carbonate (174 mg,1.26 mol) and Pd (PPh ₃)₄ (73 mg,0.063 mol) in this order at room temperature, and the mixture was reacted under N ₂ for 12 hours at 100 ℃ under N ₂ atmosphere, and the reaction mixture was filtered and concentrated, followed by purification by silica gel column chromatography to give the title compound (100 mg, 44%).

¹H NMR(400MHz,CDCl₃-d)δ8.12-8.10(m,2H),7.54-7.53(m,3H)7.38(d,J＝3.6Hz,1H),6.86(d,J＝3.7Hz,1H),5.64(s,2H),3.57(t,J＝8.2Hz,2H),0.94(t,J＝8.2Hz,2H),-0.04(s,9H).

Example 22 was then synthesized in a similar manner to that described in steps 1-3, 1-4 of example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.46(s,1H),8.05-8.03(m,2H),7.73-7.69(m,3H),7.50(d,J＝3.8Hz,1H),6.98(s,1H),6.85(d,J＝3.8Hz,1H),4.57-4.53(m,1H),4.35-4.30(m,1H),3.98(s,3H),3.81-3.75(m,1H),3.47-3.40(m,1H),3.28-3.12(m,2H),3.12(s,3H).

MS(ESI,[M+H]⁺)m/z 386.4

Example 23

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 23)

Step 23-1:2, 4-dichloro-5-iodo-7H-pyrrole [2,3-d ] pyrimidine (S5)

To a solution of compound S1 (1 g,5.34 mmol) in 10mL anhydrous DMF at room temperature was added NIS (1.4 g,6.41mmol,1.2 eq). And the resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, water (100 mL) was added for dilution, followed by extraction with ethyl acetate (200 ml×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography on silica gel afforded the title compound (1.2 g, 72%) as a white solid.

¹H NMR(500MHz,CDCl₃-d)δ10.35(brs,1H),7.56(s,1H).

Step 23-2:2, 4-dichloro-5-iodo-7- (2-trimethylsiloxymethyl) -7H-pyrrole [2,3-d ] pyrimidine (S6)

The title compound was synthesized in a similar manner to that described in step 1-1 of example 1.

¹H NMR(500MHz,MeOD-d₆)δ7.88(s,1H),5.60(s,2H),3.59(d,J＝8.0Hz,2H),0.90(d,J＝7.9Hz,1H),-0.05(s,9H).

Step 23-3:2- ((2-chloro-5-iodo-7- (2-trimethylsiloxymethyl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (S7)

The title compound was synthesized in a similar manner to that described in step 1-2 of example 1.

¹H NMR(400MHz,CDCl₃-d)δ9.42(s,1H),8.13(d,J＝8.3Hz,1H),7.88(d,J＝8.0Hz,1H),7.63(t,J＝8.54Hz,1H),7.30-7.27(m,2H),5.52(s,2H),3.57(t,J＝8.3Hz,2H),2.70(s,6H),0.94(t,J＝8.3Hz,2H),-0.03(s,9H).

Step 23-4:2- ((2-chloro-5-methyl-7- (2-trimethylsiloxymethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (S8)

Compound S7 (100 mg,0.16 mmol), methylboronic acid (14.4 mg,0.24 mmol) were dissolved in dioxane (1 mL) and water (0.5 mL) at room temperature, to which was added sequentially potassium acetate (31 mg,0.32 mol), XPhos Pd G3 (1.4 mg,0.016 mol). After three times of pumping with N ₂, the reaction was carried out at 100℃for 24 hours under an atmosphere of N ₂. The reaction solution was filtered and concentrated, and purified by silica gel column chromatography to give the title compound (30 mg, 37.5%).

¹H NMR(500MHz,MeOD-d₆)δ8.44(d,J＝9.3Hz,1H),7.88(d,J＝8.0Hz,1H),7.72(t,J＝7.9Hz,1H),7.35(t,J＝8.2Hz,1H),7.14(s,1H),5.52(s,2H),3.58(t,J＝8.0Hz,2H),2.69(s,6H),2.58(s,3H),0.91(t,J＝8.0Hz,2H),-0.03(s,9H).

Step 23-5:2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5-methyl-7- (2-trimethylsiloxymethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (S9)

The title compound was synthesized in a similar manner to that described in steps 1-3 of example 1.

Step 23-6:2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 23)

MS(ESI,[M+H]⁺)m/z 652.5.

The title compound was synthesized in a similar manner to that described in steps 1-4 of example 1.

¹H NMR(500MHz,MeOD-d₆)δ8.16(d,J＝8.8Hz,1H),7.94(dd,J＝8.8Hz、1.5Hz,1H),7.92(s,1H),7.74(td,J＝8.8Hz、1.5Hz,1H),7.48(t,J＝8.8Hz,1H),6.92(s,1H),6.82(s,1H),4.12(d,J＝15Hz,2H),3.91(s,3H),3.79-3.70(m,1H),3.45-3.35(m,1H),3.27-3.19(m,1H),3.17-3.09(m,1H),3.05(s,3H),2.69(s,6H),2.51(s,3H).

MS(ESI,[M+H]⁺)m/z 522.3.

Example 24

2- ((5-Chloro-2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 24)

The synthesis was as in example 23.

¹H NMR(500MHz,MeOD-d₆)δ8.26(d,J＝8.1Hz,1H),8.20(s,1H),7.93(d,J＝8.0Hz,1H),7.72(t,J＝8.5Hz,1H),7.40(d,J＝7.6Hz,1H),7.04(s,1H),6.85(s,1H),4.16-4.13(m,2H),3.92(s,3H),3.77-3.72(m,1H),3.44-3.36(m,1H),3.20-3.10(m,2H),,3.04(s,3H),2.70(s,6H).

MS(ESI,[M+H]⁺)m/z 542.2

Example 25

2- ((5-Cyano-2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 25)

The synthesis was as in example 23.

¹H NMR(500MHz,MeOD-d₆)δ8.21(s,1H),8.15(d,J＝9.15Hz,1H),7.81(s,1H),7.75(t,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),6.86(s,1H),4.71–4.65(m,1H),4.15(d,J＝5Hz,2H),3.92(s,3H),3.78-3.71(m,1H),3.42-3.36(m,1H),3.24-3.19(m,1H),3.13-3.10(m,1H),3.05(s,3H),2.70(s,6H).

MS(ESI,[M+H]⁺)m/z 533.4.

Example 26

2- ((5- (Cyanomethyl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 26)

Step 26-1:2- ((2-chloro-5- (cyanomethyl) -7- (2-trimethylsilylethoxymethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide

Compound S7 (100 mg,0.16 mmol), isoxazole-4-boronic acid (27 mg,0.24 mmol) were dissolved in 1mL dioxane and 0.5mL water at room temperature, to which was added sequentially potassium acetate (31 mg,0.32 mol), XPhos Pd G3 (1.4 mg,0.016 mol). After three times of pumping with N ₂, the reaction was carried out at 100℃for 24 hours under an atmosphere of N ₂. The reaction solution was filtered and concentrated, and purified by silica gel column chromatography to give the title compound (30 mg, 36%).

Example 26 was then synthesized in a similar manner to that described in steps 1-3, 1-4 of example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.32(d,J＝8.2Hz,1H),8.17(s,1H),7.90(d,J＝9.1Hz,1H),7.73(t,J＝7.9Hz,1H),7.40(t,J＝7.5Hz,1H),7.07(s,1H),6.89(s,1H),4.23-4.13(m,4H),3.93(s,3H),3.80-3.71(m,1H),3.48-3.39(m,1H),3.27-3.13(m,2H),3.05(s,3H),2.69(s,6H).

MS(ESI,[M+H]⁺)m/z 547.4

Example 27

2- ((5-Acetyl-2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 27)

The synthesis was as in example 23.

¹H NMR(400MHz,MeOD-d₆)δ8.07(m,2H),8.01(s,1H),7.81(td,J＝7.8Hz、2.6Hz,1H),7.77(td,J＝8.1Hz、1.4Hz,1H),7.59(td,J＝6.9Hz、1.4Hz,1H),6.84(s,1H),3.98(s,2H),3.90(s,3H),3.74-3.68(m,1H),3.39-3.36(m,1H),3.22-3.13(m,1H),3.11-3.08(m,1H),3.04(s,3H),2.67(s,6H),2.55(s,3H).

MS(ESI,[M+H]⁺)m/z 550.3

Example 28

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (thiophen-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 28)

The synthesis was as in example 23.

¹H NMR(500MHz,MeOD-d₆)δ8.04-8.01(m,2H),7.90(dd,J＝9.9Hz、1.7Hz,1H),7.75(td,J＝9.97Hz、1.9Hz,1H),7.57-7.55(m,1H),7.50-7.49(m,1H),7.45(t,J＝10.2Hz,1H),7.28(dd,J＝6.2Hz、3.8Hz,1H),7.09(s,1H),6.88(s,1H),4.05(s,2H),3.92(s,3H),3.77-3.69(m,1H),3.47-3.35(m,1H),3.22-3.10(m,2H),3.04(s,3H),2.50(s,6H).

MS(ESI,[M+H]⁺)m/z 590.3

Example 29

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (1H-pyrazol-4-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 29)

The synthesis was as in example 23.

¹H NMR(400MHz,MeOD-d₆)δ8.11-8.08(m,2H),7.88(d,J＝8.8Hz,1H),7.73(t,J＝7.7Hz,1H),7.41(t,J＝7.7Hz,1H),7.01(s,1H),6.88(s,1H),4.08(s,2H),3.93(s,3H),3.79-3.72(m,1H),3.47-3.36(m,1H),3.22-3.13(m,2H),3.05(s,3H),2.52(s,6H).

MS(ESI,[M+H]⁺)m/z 574.5

Example 30

N, N-dimethyl-2- ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide (compound 30)

The synthesis was as in example 1.

¹H NMR(500MHz,MeOD-d₆)δ8.43(d,J＝8.0Hz,1H),7.91(d,J＝8.0Hz,1H),7.66(t,J＝8.6Hz,1H),7.47(d,J＝8.8Hz,2H),7.40(t,J＝8.0Hz,1H),7.03-7.01(m,3H),6.48(d,J＝3.2Hz,1H),4.81-4.64(m,5H),3.09-3.05(m,2H),2.99(s,3H),2.67(s,6H),2.04(s,1H).

MS(ESI,[M+H]⁺)m/z 507.3

Example 31

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dipropylbenzenesulfonamide (compound 31)

The synthesis was as in example 1.

1H NMR(400MHz,MeOD-d6)8.26(d,J＝8.6Hz,1H),8.14(s,1H),8.00(d,J＝9.2Hz,1H),7.74(t,J＝8.0Hz,1H),7.44(t,J＝8.0Hz,1H),7.06(d,J＝4.7Hz,1H),6.90(s,1H),6.50(d,J＝4.7Hz,1H),4.23-4.13(m,2H),3.93(s,3H),3.80-3.70(m,1H),3.46-3.36(m,1H),3.25-3.13(m,2H),3.10-3.06(m,7H),1.46-1.41(m,4H),0.67(t,J＝7.3Hz,6H).

MS(ESI,[M+H]+)m/z 564.3

Example 32

N ⁴ - (2- (azetidin-1-ylsulfonyl) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (Compound 32)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.44(d,J＝8.9Hz,1H),8.20(s,1H),7.99(dd,J＝8.0Hz、1.5Hz,1H),7.80(dd,J＝7.8Hz、1.6Hz,1H),7.46(t,J＝8.2Hz,1H),7.05(d,J＝3.6Hz,1H),6.92(s,1H),6.46(d,J＝4.6,1H),4.33-4.19(m,2H),3.94(s,3H),3.79(t,J＝7.6Hz,4H),3.77-3.72(m,1H),3.44-3.40(m,2H),3.24-3.13(m,1H),3.07(s,3H),2.09-2.01(m,3H).

MS(ESI,[M+H]+)m/z 520.4

Example 33

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (pyrrolidin-1-ylsulfonyl) phenyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (Compound 33)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.26-8.16(m,1H),8.10-7.99(m,2H),7.78(t,J＝7.7Hz,1H),7.57-3.48(m,1H),7.06(d,J＝3.6Hz,1H),6.93(s,1H),6.50(s,1H),4.28-4.11(m,2H),3.92(d,J＝4.4Hz,3H),3.81-3.71(m,1H),3.45-3.37(m,1H),3.24-3.12(m,6H),3.07(s,3H),1.72-1.68(m,4H).

MS(ESI,[M+H]⁺)m/z 534.5。

Example 34

N-isopropyl-2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N-toluenesulfonamide (compound 34)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.19-8.07(m,1H),8.08(d,J＝8.0Hz,2H),7.78(t,J＝7.8Hz,1H),7.54-7.51(m,1H),7.10(d,J＝3.6Hz,1H),6.94(s,1H),6.55(d,J＝3.5,1H),4.23-4.17(m,2H),4.10-4.06(m,1H),3.95(s,3H),3.81-3.72(m,1H),3.46-3.37(m,1H),3.26-3.20(m,2H),3.08(s,3H),0.96(d,J＝6.7Hz,6H).

MS(ESI,[M+H]⁺)m/z 536.4。

Example 35

N- (sec-butyl) -2- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N-toluenesulfonamide (compound 35)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.19(d,J＝8.1Hz,2H),8.05-8.01(m,2H),7.74(t,J＝8.5Hz,1H),7.48(t,J＝8.5Hz,1H),7.08(d,J＝3.6Hz,1H),6.92(s,1H),6.55(d,J＝3.6,1H),4.25-4.13(m,2H),3.92(s,3H),3.80-3.72(m,2H),3.44-3.37(m,1H),3.24-3.10(m,2H),3.06(s,3H),2.65(s,3H),1.37-1.29(m,2H),0.86(d,J＝6.6Hz,3H),0.67(t,J＝7.4Hz,3H).

MS(ESI,[M+H]⁺)m/z 550.5

Example 36

N ⁴ - (2- (cyclopropylsulfonyl) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (Compound 36)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.12-8.08(m,2H),8.03(s,1H),7.85(d,J＝8.5Hz,1H),7.61(d,J＝8.1Hz,1H),7.09(d,J＝3.6Hz,1H),6.92(s,1H),6.51(d,J＝3.6Hz,1H),4.21-4.09(m,2H),3.92(s,3H),3.45-3.38(m,1H),3.24-3.14(m,2H),3.06(s,3H),2.77-2.72(m,1H),1.20-1.18(m,2H),1.01-0.98(m,2H).

MS(ESI,[M+H]⁺)m/z 505.3

Example 37

N ⁴ - (2- (cyclobutylsulfonyl) phenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (Compound 37)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.17(d,J＝8.0Hz,1H),8.07(d,J＝8.0Hz,1H),7.95(s,1H),7.83(t,J＝8.5Hz,1H),7.56(t,J＝7.7Hz,1H),7.07(d,J＝3.6Hz,1H),6.92(s,1H),6.50(d,J＝3.6Hz,1H),4.23-4.11(m,2H),4.05(t,J＝8.2Hz,1H),3.92(s,3H),3.79-3.69(m,1H),3.49-3.35(m,1H),3.24-3.15(m,2H),3.06(s,3H),2.50-2.39(m,2H),1.96-1.89(m,2H).

MS(ESI,[M+H]⁺)m/z 519.3

Example 38

2- ((5- (Furan-3-yl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 39)

The synthesis was as in example 23.

¹H NMR(400MHz,MeOD-d₆)δ8.08-8.05(m,2H),7.91(dd,J＝8.0Hz、1.5Hz,1H),7.76-7.72(m,2H),7.63(t,J＝1.7Hz,1H),7.44(td,J＝7.7Hz、1.1Hz,1H),7.04(s,1H),6.88(s,1H),6.64-6.63(m,1H),4.07(s,2H),3.93(s,3H),3.79-3.72(m,1H),3.43-3.35(m,1H),3.22-3.10(m,2H),3.05(s,3H),2.54(s,6H).

MS(ESI,[M+H]⁺)m/z 574.4

Example 39

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (3-methyl-1H-pyrazol-4-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 44)

The synthesis was as in example 39.

1H NMR(400MHz,MeOD-d₆)δ8.15(d,J＝8.2Hz,1H),8.02(s,1H),7.86(d,J＝8.0Hz,2H),7.79(s,1H),7.72(t,J＝8.4,1H),7.41((t,J＝8.4,1H),7.01(s,1H),6.92(s,1H),4.13-4.11(m,2H),3.93(s,3H),3.79-3.71(m,1H),3.45-3.39(m,1H),3.23-3.13.(m,2H),3.05(s,3H),2.56(s,6H),2.32(s,3H).

MS(ESI,[M+H]+)m/z 588.4

Example 40

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (1-methyl-1H-pyrazol-4-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 45)

The synthesis was as in example 23.

1H NMR(400MHz,MeOD-d₆)δ8.10(d,J＝7.5Hz,1H),7.97(s,1H),7.87(d,J＝8.0Hz,1H),7.82(s,1H),7.71(d,J＝8.6,1H),7.60(s,1H),7.42(t,J＝8.2Hz,1H),7.01(s,1H),6.90(s,1H),4.12-4.06(m,2H),3.95(s,3H),3.91(s,3H),3.78-3.70(m,1H),3.43-3.36(m,1H),3.24-3.10(m,2H),3.04(s,3H),2.55(s,6H).

MS(ESI,[M+H]+)m/z 588.5

Example 41

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5-phenyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 48)

The synthesis was as in example 41.

¹H NMR(400MHz,MeOD-d₆)δ8.25(t,J＝8.2Hz,1H),8.21(s,1H),8.03(dd,J＝8.0Hz、1.4Hz,1H),7.82(td,J＝7.8Hz、1.5Hz,1H),7.76(d,J＝7.3Hz,2H),7.56(t,J＝7.6Hz,1H),7.48(t,J＝7.7Hz,2H),7.36(t,J＝7.4Hz,1H),6.92(s,1H),6.83(s,1H),4.26-4.20(m,2H),3.95(s,3H),3.77-3.73(m,1H),3.47-3.37(m,1H),3.26-3.15(m,2H),2.75(s,3H).

MS(ESI,[M+H]⁺)m/z 584.5

Example 42

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (pyridin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 49)

The synthesis was as in example 23.

¹H NMR(400MHz,MeOD-d₆)δ9.03(s,1H),8.77(d,J＝6.2Hz,1H),8.66(d,J＝8.3Hz,1H),8.35(d,J＝7.5Hz,1H),8.26(s,1H),8.07-8.03(m,1H),7.77(d,J＝8.0Hz,1H),7.73(t,J＝7.8Hz,1H),7.39(s,1H),7.33(t,J＝7.8Hz,1H),6.89(s,1H),6.83(s,1H),4.23-4.19(m,2H),3.93(s,3H),3.80-3.72(m,1H),3.44-3.37(m,1H),3.25-3.13(m,2H),3.05(s,3H),2.49(s,6H).

MS(ESI,[M+H]⁺)m/z 585.4

Example 43

2- ((5- (3-Fluorophenyl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 50)

The synthesis was as in example 23.

1H NMR(400MHz,MeOD-d6)δ8.35(d,J＝8.2Hz,1H),8.25(s,1H),7.97(d,J＝8.0Hz,1H),7.78(t,J＝8.6,1H),7.57(d,J＝8.0Hz,1H),7.50-7.43(m,3H),7.06(t,J＝9.4,1H),6.89(s,1H),6.84(s,1H),4.29-4.15(m,2H),3.94(s,3H),3.79-3.70(m,1H),3.45-3.36(m,1H),3.23-3.14(m,2H),3.07(s,3H),2.72(s,6H).

MS(ESI,[M+H]+)m/z 602.5

Example 44

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (pyridin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 51)

The synthesis was as in example 23.

¹H NMR(400MHz,MeOD-d₆)δ8.72(d,J＝6.8Hz,2H),8.35(d,J＝8.4Hz,1H),8.26(s,1H),8.15(d,J＝6.7,2H),7.82(d,J＝9.4Hz,1H),7.75(t,J＝8.4Hz,1H),7.73(s,1H),7.36(t,J＝8.2,1H),6.90(s,1H),4.25-4.20(m,2H),3.95(s,3H),3.79-3.72(m,2H),3.45-3.39(m,1H),3.25-3.19(m,1H),3.06(s,3H),2.49(s,6H).

MS(ESI,[M+H]⁺)m/z 585.4

Example 45

2- ((5- (6-Aminopyridin-3-yl) -2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 52)

The synthesis was as in example 23.

¹H NMR(400MHz,MeOD-d₆)δ8.36(d,J＝8.2Hz,1H),8.30(s,1H),8.07(d,J＝11.3Hz,1H),7.98(s,1H),7.80(d,J＝9.4Hz,1H),7.72(t,J＝7.8Hz,1H),7.32(t,J＝7.8Hz,1H),7.17(s,1H),7.10(d,J＝9.2Hz,1H),6.89(s,1H),4.24-4.20(m,2H),3.94(s,3H),3.79-3.72(m,1H),3.44-3.39(m,1H),3.23-3.18(m,2H),3.05(s,3H),2.54(s,6H).

MS(ESI,[M+H]⁺)m/z 600.4

Example 46

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 53)

The synthesis was as in example 23.

¹H NMR(400MHz,MeOD-d₆)δ8.27(d,J＝10.5Hz,1H),8.21(s,1H),7.85(dd,J＝8.0Hz、1.4Hz,1H),7.74(t,J＝7.6,1H),7.71(d,J＝7.0,1H),7.36(t,J＝8.2,1H),7.30(s,1H),6.87(s,1H),6.66(s,1H),6.62(dd,J＝6.9Hz、3.0Hz,1H),4.17-4.16(m,2H),3.93(s,3H),3.78-3.71(m,1H),3.61(s,3H),3.44-3.36(m,1H),3.23-3.10(m,2H),3.05(s,3H),2.50(s,6H).

MS(ESI,[M+H]⁺)m/z 615.6

Example 47

N- (4- (2-aminopyridin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (compound 58)

The synthesis was as in example 23.

¹H NMR(400MHz,MeOD-d₆)δ8.55(s,1H),8.03(d,J＝6.7Hz,1H),7.78(s,1H),7.64(d,J＝6.7Hz,1H),7.40(d,J＝3.7Hz,1H),6.94(s,1H),6.80(d,J＝3.7Hz,1H),4.56-4.53(m,1H),4.37-4.33(m,1H),4.00(s,3H),3.82-3.75(m,1H),3.47-3.39(m,1H),3.29-3.17(m,2H),3.10(s,3H).

MS(ESI,[M+H]⁺)m/z 402.4

Example 48

N, N-dimethyl-2- ((2- ((4-morpholinophenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide (compound 59)

The synthesis was as in example 23.

¹H NMR(400MHz,MeOD-d₆)δ8.30(d,J＝8.1Hz,1H),7.93(d,J＝9.4Hz,1H),7.69(t,J＝9.8Hz,1H),7.49-3.45(m,3H),7.16-7.04(m,3H),6.51(d,J＝3.44Hz,1H),4.03-3.91(m,5H),2.68(s,1H),2.66(s,6H).

MS(ESI,[M+H]⁺)m/z 494.4

Example 49

N, N-dimethyl-2- ((2- ((4- (4-methyl-1, 4-diaza-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide (compound 60)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.45(d,J＝8.3Hz,1H),7.91(d,J＝9.3Hz,1H),7.66(t,J＝7.8Hz,1H),7.43-7.36(m,3H),7.30(d,J＝3.4Hz,1H),6.84(d,J＝8.6Hz,2H),6.46(d,J＝3.4Hz,1H),3.88-3.54(m,7H),3.39-3.35(m,2H),2.98(s,3H),2.68(s,6H),2.39-2.23(m,3H).

MS(ESI,[M+H]⁺)m/z 521.3

Example 50

2- ((2- ((4- (4- (Dimethylamino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (61)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.41(d,J＝11.8Hz,1H),7.91(d,J＝9.2Hz,1H),7.66(t,J＝8.5Hz,1H),7.44-7.41(m,3H),7.30(d,J＝3.4Hz,1H),6.84(d,J＝8.6Hz,2H),6.46(d,J＝3.4Hz,1H),3.88-3.54(m,7H),3.39-3.35(m,2H),2.98(s,3H),2.68(s,6H),2.39-2.23(m,3H).

MS(ESI,[M+H]⁺)m/z 535.4

Example 51

2- ((2- ((2-Methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 62)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.31(d,J＝8.0Hz,1H),7.79(d,J＝9.3Hz,1H),7.70(d,J＝8.0Hz,1H),7.69(t,J＝8.0Hz,1H),7.45(t,J＝8.0Hz,1H),7.02(d,J＝3.6Hz,1H),6.75(d,J＝2.5Hz,1H),6.56(d,J＝8.8Hz,1H),6.50(d,J＝3.4Hz,1H),2.89(s,3H),3.85-3.59(m,4H),3.10-3.05(m,2H),3.00(s,3H),2.68(s,6H).

MS(ESI,[M+H]⁺)m/z 537.4

Example 52

N, N-dimethyl-2- ((2- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide (compound 63)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.61(d,J＝8.0Hz,1H),8.04(dd,J＝9.2Hz、2.8Hz,1H),7.93(dd,J＝8.0Hz、1.4Hz,1H),7.79-7.75(m,2H),7.45-7.39(m,2H),7.20(d,J＝3.6Hz,1H),6.50(d,J＝3.6Hz,1H),3.68-3.40(m,8H),2.99(s,3H),2.68(s,6H).

MS(ESI,[M+H]⁺)m/z 508.5

Example 53

2- ((2- ((3-Methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (compound 64)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.42(d,J＝8.2Hz,1H),7.92(d,J＝8.2Hz,1H),7.65(t,J＝7.8Hz,1H),7.43(t,J＝7.8Hz,1H),7.30(d,J＝2.2Hz,1H),7.12(dd,J＝7.8Hz、1.6Hz,1H),7.04(d,J＝3.6Hz,1H),6.96(d,J＝8.4Hz,1H),6.48(d,J＝3.5Hz,1H),3.81(s,1H),3.64-3.55(m,4H),3.37-3.28(m,2H),3.13-3.02(m,2H),3.00(s,3H),2.70(s,6H).

MS(ESI,[M+H]⁺)m/z 537.5

Example 54

N, N-dimethyl-2- ((2- ((4-morpholinophenyl) amino) -5- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide (65)

The synthesis was as in example 1.

¹H NMR(400MHz,MeOD-d₆)δ8.16(d,J＝8.2Hz,1H),7.83-7.82(m,3H),7.69(t,J＝7.8Hz,1H),7.52(d,J＝7.8Hz,2H),7.40(t,J＝8.1Hz,1H),7.14(d,J＝7.8Hz,2H),7.01(s,1H),3.95-3.93(m,4H),2.53(s,6H).

MS(ESI,[M+H]⁺)m/z 560.3

Example 55

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (2- (morpholinesulfonyl) phenyl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (102)

The synthesis was as in example 1.

MS(ESI,[M+H]⁺)m/z 550.3

Example 56

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (5-methylpyridin-3-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (106)

The synthesis was as in example 2.

MS(ESI,[M+H]⁺)m/z 599.3

Example 57

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (2-methylpyridin-3-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (109)

The synthesis was as in example 2.

MS(ESI,[M+H]⁺)m/z 599.3

Example 58

2- ((2- ((6-Methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -5- (4-methylpyridin-3-yl) -7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (110)

The synthesis was as in example 2.

MS(ESI,[M+H]⁺)m/z 599.3

Example 59

N ⁴ - (3-fluorophenyl) -N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d ] pyrimidine-2, 4-diamine (111)

The synthesis was as in example 1.

MS(ESI,[M+H]⁺)m/z 419.3

Example 60

N ² - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N ⁴ - (3- (trifluoromethyl) phenyl) -7H-pyrrolo [2,3-d ] pyrimidine-2, 4-diamine

The synthesis was as in example 1.

MS(ESI,[M+H]⁺)m/z 469.3

EXAMPLE 61 test of the inhibition of HPK1 kinase by Compounds of the invention

All synthetic final compounds were assayed for inhibition of HPK1 by Eurofins. The compound kinase half-inhibitory concentration was detected by radioisotope-labeled ATP method.

The specific operation method comprises the following steps: HPK1 kinase, 8mM MOPS (pH=7), 0.02mM EDTA and 0.33mg/mL myelin basic protein were added as substrates and 9 concentration gradients of compound and control were added for co-incubation, respectively, in the microwell plates. The reaction was then started by adding 10mM magnesium acetate and [ gamma- ³³ P ] -ATP, and after incubation at room temperature for 40 minutes, the reaction was stopped by adding 0.5% phosphoric acid. Then 10. Mu.L of the reaction solution was spotted on the P30 filter pad and washed 4 times with 0.425% phosphoric acid for 4 minutes each. Dried and dissolved in methanol before scintillation counting. After measuring the inhibition of kinase by the compounds at different concentrations, the compounds were introduced into Prism software and IC ₅₀ values were calculated. IC ₅₀ was obtained by plotting the percent inhibition and the logarithmic concentration values.

TABLE 1 results of HPK1 kinase Activity experiments

Effect of example 62 Compounds on phosphorylation of HPK1 downstream protein SLP76

The specific operation method is as follows:

Seed, drug and protein collection sample

1. Jurkat cells were collected, washed once with 1640 medium, centrifuged and counted in 1640 for resuspension

2. 12-Well plates were seeded at a density of 1X106/mL with 1mL per well

3. After 5h, DMSO or a compound to be tested with different concentrations is added, and after 10min, 1 mug/mL anti-human CD3 is added for 1h.

4. Cellular proteins were collected and BCA quantified.

(1) Cells were collected into 1.5mL centrifuge tubes. Centrifuge at 4℃at 5000rpm for 5 min.

(2) The supernatant was discarded, washed 2 times with 1mL of precooled PBS, and centrifuged under the same conditions as above.

(3) The supernatant was discarded, the cells were pelleted, 100. Mu.L RIPA was added to each tube for additional strength, mixed well, and lysed on ice for 15min.

(4) Centrifugation was performed at 20000g for 20min at 4 ℃. After the precipitated material was picked out, BCA quantification was performed on the remaining protein solution, and all samples were prepared as protein solutions with the same protein concentration.

(5) 5 XSDS was added. Boiling at 100deg.C for 12min, and preserving at-20deg.C

Western Blot

1. Centrifuging the thawed sample in a centrifuge, and mixing by vortexing

2. Preparing upper layer glue and lower layer glue, placing the glue plate into an electrophoresis tank, and adding TGS.

3. Removing comb, loading protein ladder (product number 26616) 5 μl, and loading sample 10 μl

4. And (3) adding TGS, running the gel at 80V, and adjusting the sample to 120V after entering the lower gel. The running time is about 2 hours.

5. Transfer film, about 1.5h.

6. After the film transfer is finished, the strip is cut, and the positions are as follows: SLP76 (cat# 4958S), p-SLP76 Ser376 (cat# 76384S): molecular weight 76; beta-action (cat# 60008-1-1G): molecular weight 43

7. TBST (Tunnel boring mill) dissolved skimmed milk powder, and room temperature 1h sealing strip on shaking table

8. The bands were incubated with SLP76, p-SLP76 Ser376, and beta-Actin primary antibody, respectively, on a shaker for 1h at room temperature.

9. The strip was washed 3 times with TBST for 10min each.

10. The bands were incubated with the corresponding secondary antibodies (murine antibody,. Beta. -action, rabbit antibody: SLP76 and p-SLP76 Ser 376) for 1h at room temperature on a shaker.

11. TBST was washed 3 times for 10min each.

12. The ECL luminescence solution was subjected to band color development.

The results are shown in fig. 1-5, and the results show that the compounds of the invention can significantly inhibit the phosphorylation of SLP76 protein.

EXAMPLE 63ELISA detection of Jurkat cell viability and culture supernatant IL-2 concentration

The specific operation method is as follows:

plate, dosing, and ELISA sample collection

2. 12-Well plates were seeded at a density of 1.5X106/mL with 1mL per well

3. After 5h, DMSO or compounds with different concentrations are added, after 10min, 1 mug/mL anti-human CD3 is added for 24h

4. Uniformly mixing cells in each hole, sucking 100 mu L of cells in a 96-well plate, adding 1640 culture solution into one hole as a blank control, adding 10 mu L of CCK8 into each hole, incubating for 1-4h in a 37-degree incubator, reading a light absorption value at 450nm, and taking the obtained value as the relative cell viability of each sample, wherein each blank control hole OD450 is deducted from each sample hole OD 450; the remaining cells were collected in a 1.5mL centrifuge tube for subsequent handling.

ELISA detection of culture supernatant IL-2 concentration

1. The cells were blown and mixed well in the wells and collected into 1.5mL centrifuge tubes. 5000g,4℃and 20 min. The supernatant was transferred to a new 1.5mL centrifuge tube.

2. Working fluid and standard substances are prepared.

(1) The working fluid required in the subsequent step includes:

1x dilution 10mL

200ML of 1 Xwashing solution

Preparing standard mother solution 1000pg/mL

1 Xdilution as Blank wells (Blank) 100. Mu.L/well

(2) The standard stock solution (1000 pg/mL) was subjected to gradient dilution to prepare a gradient standard.

3. The micro-pore plate is clamped on a bottom plate, and Jurkat cell supernatants after different concentrations of standard substances, blank and different compounds are respectively added into corresponding holes, 100 mu L/hole is provided with 2 compound holes.

4. The well plate was sealed with a sealing plate film paper and incubated for 2h at room temperature.

5. Preparation of 1X detection antibody (40X stock solution was prepared as 1X, and 1X dilution was used)

6. After incubation time, the liquid in the well was aspirated. Add 300. Mu.L/well of wash. After each washing, the liquid in the hole is poured off, the plate is buckled on the filter paper in a reverse way, the residual liquid is beaten out, and the beating is performed for several times until almost no water stain exists on the filter paper.

7. The antibody was diluted 100. Mu.L/well. Plates were sealed with a sealing plate membrane and incubated for 2h at room temperature.

8. 1 XSA-HRP was prepared 5min before the end of incubation, 1 Xwas prepared from 40 Xstock solution, and 1 Xdilution was used.

9. The plate washing operation in step 6 is repeated. After washing, 100. Mu.L/well of SA-HRP was added and incubated at room temperature for 20min in the absence of light.

10. The color reagent was prepared 3min before the incubation was completed. The color developer A and the color developer B are mixed in equal volumes.

11. The plate washing operation in step 6 is repeated. After washing, 100 mu L/hole of color reagent is added, and the mixture is incubated for 20min at room temperature in a dark place.

12. Adding stop solution 50 mu L/hole, and changing the solution in the hole from blue to yellow

13. And reading the plate by an enzyme label instrument. Taking 450nm as a detection wavelength and 540nm as a reference wavelength, calculating OD450-OD540 of each hole, subtracting the Blank hole OD450-OD540 from each hole, normalizing to the relative activity of the cells, and taking the last calculated value as the relative IL-2 concentration of the sample.

The results show that the compounds of the present invention are less cytotoxic and that the compounds of the present invention increase secretion of inflammatory factor IL-2, in addition to some compounds.

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

1. A pyrimidopyrrole compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof:

in,

R ₁ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -(CH ₂ ) _m R ₄ , substituted or unsubstituted 5-7 membered aromatic ring, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, -C(O)R ₅ , -C(O)NHC ₁ -C ₃ alkyl, -OR ₅ , -NH ₂ , -NHR ₅ , -NHC(O)C ₁ -C ₆ alkyl, -S(O) ₂ C ₁ -C ₆ alkyl, -S(O)C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl;

L is selected from the following group: -NH-, or L is a chemical bond;

_R2 is selected from the following group: substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered heteroaromatic ring, substituted or unsubstituted 5-7 membered ring and 5-8 membered aromatic ring, substituted or unsubstituted 4-7 membered saturated nitrogen-containing heterocyclic ring; wherein the 5-7 membered ring is a saturated ring, a partially unsaturated ring or an aromatic ring;

_R3 is

X and Y are each independently C;

wherein A ₁ , A ₂ and A ₅ are each independently H, halogen, or C ₁ -C ₆ alkoxy;

A ₃ and A ₄ together form a structure selected from the following group, wherein * indicates the site of attachment to the substituted carbon atom of the benzene ring:

R ₄ is selected from the group consisting of cyano, alkynyl;

R ₅ is selected from the following group: C ₁ -C ₃ alkyl, substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered heteroaromatic ring;

m is selected from the group consisting of 0, 1 or 2;

The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, =O, carboxyl, hydroxyl, amino, nitro, cyano, -S(O) _2C1 _-C6 _alkylamino , -S(O) _2C1 _-C6 _alkyl , -P(O)( _C1 - _C6 alkyl) ₂ , C1 _- _C6 alkyl, _C1 - _C6 fluorinated alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylamino, _C1 - _C6 alkoxycarbonyl, _C2 - _C12 ester; each of the above groups is unsubstituted or substituted by 1, 2 or 3 substituents of Group A, and the substituents of Group A are selected from the group consisting of halogen, hydroxyl, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkenyl, _C1 - _C6 alkynyl;

In the above groups, as an independent substituent or as part of other substituents, the aryl or heterocyclic group is optionally substituted by one or more halogens;

Each saturated ring is a carbocyclic ring or a heterocyclic ring;

The heteroatom in each heterocycle is selected from N, O and S.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A ₃ and A ₄ together form a structure selected from the following group, wherein * indicates the site of attachment to the substituted carbon atom of the benzene ring:

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein when L is selected from -NH-, or is a chemical bond, the R ₂ has a structure as shown in the following formula:

wherein _B1 , _B2 , _B3 , _B4 and _B5 are each independently selected from the group consisting of H, halogen, amino, _C1 - _C4 alkyl, C1- _C4 alkoxy, _C1 -C4 alkylamino, _C1 - _C4 hydroxy, -C(O) _B6 , -S(O) _2B6 _, -S(O) _B6 , -P(O)( _B6 ) ₂ ; and _B6 is selected from the group consisting of _C1 - _C4 alkyl, _C1 - _C4 _alkylamino ; or _B1 and _B2 together with the two carbon atoms to which they are attached form a 5- to 8-membered ring comprising 0, 1 or 2 heteroatoms as one or more _ring members; the ring is optionally substituted by one or more substituents _B7 ; or

_B4 and _B5 together with the two carbon atoms to which they are attached form a 5- to 8-membered ring containing 0, 1 or 2 heteroatoms as one or more ring members; said ring is optionally substituted with one or more substituents _B7 ;

The B ₇ is selected from the following group: H, unsubstituted or halogenated C1-C6 alkyl, or two B ₇ located on the same carbon atom together form =O;

Z is N or C, and when Z is N, B ₃ is absent.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein when L is a chemical bond, the R ₂ has a structure as shown in the following formula:

wherein C ₁ , C ₂ , C ₃ , and C ₄ are each independently selected from the group consisting of H, halogen, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylamino, and C ₁ -C ₄ hydroxyl;

D is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl;

n is 0, 1, 2 or 3;

m is 0, 1, 2, 3 or 4.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (II):

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from the group consisting of:

Wherein, n is 0 or 1 or 2 or 3.

7. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein said B ₁ is selected from the group consisting of:

Wherein, n is 0 or 1 or 2 or 3; m is 0 or 1 or 2 or 3.

8. A compound selected from the group consisting of:

1) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -phenyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

2) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(o-tolyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

3) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(2-(tert-butyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

4) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(o-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

5) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(o-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

6) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(2-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

7) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(o-methylolphenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

8) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(2-(methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

9) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(2-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

10) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(2-(isopropoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

11) N-(4-(Indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine;

12) N-(4-(3,4-dihydroquinolin-1(2H)-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine;

13) N-(4-(2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine;

14) methyl 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzoate;

15) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;

16) N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

17) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

18) N-ethyl-2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide;

19) N,N-diethyl-2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide;

20) 7-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)isoindol-1-one;

21) 4-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)isoindol-1-one;

22) 6-methoxy-2-methyl-N-(4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-amine;

23) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

24) 2-((5-chloro-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

25) 2-((5-cyano-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

26) 2-((5-(cyanomethyl)-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

27) 2-((5-acetyl-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrole

[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

28) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(thiophen-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

29) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

31) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dipropylbenzenesulfonamide;

32) N ⁴ -(2-(azetidin-1-ylsulfonyl)phenyl)-N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

33) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(2-(pyrrolidin-1-ylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

34) N-isopropyl-2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrole

[2,3-d]pyrimidin-4-yl)amino)-N-toluenesulfonamide;

35) N-(sec-butyl)-2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-toluenesulfonamide;

36) N ⁴ -(2-(cyclopropylsulfonyl)phenyl)-N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

37) N ⁴ -(2-(cyclobutylsulfonyl)phenyl)-N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

38) N ⁴ -(2-(tert-Butoxy)phenyl)-N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

39) 2-((5-(Furan-3-yl)-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

40) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

41) 2-((5-(isoxazol-4-yl)-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

42) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(thiazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

43) 2-((5-(2-chlorothien-3-yl)-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

44) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(3-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

45) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

46) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(3-oxocyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

47) 2-((5-(isoxazole-4-carbonyl)-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

48) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

49) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

50) 2-((5-(3-fluorophenyl)-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

51) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

52) 2-((5-(6-aminopyridin-3-yl)-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

53) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(1-methyl-2-oxy-1,2-dihydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

54) N-(4-((2-(N,N-dimethylsulfamoyl)phenyl)amino)-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)acetamide;

55) 4-((2-(N,N-dimethylsulfamoyl)phenyl)amino)-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

56) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

57) 2-((5-ethynyl-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrole

[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

58) N-(4-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine;

67) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(2-(piperidin-1-ylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

68) N ⁴ -(2-ethoxyphenyl)-N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

69) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N 4-(2-propoxyphenyl)-7H pyrrolo[2,3-d]pyrimidine-2,4-diamine

70) 2-((2-((6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

71) 2-((2-((6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

72) 2-((2-((7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

74) 2-((2-((2-ethyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

75) 2-((2-((2-isopropyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

76) 2-((2-((9-methoxy-1,3,4,6,11,11a-hexahydro-2H-pyridin[1,2-b]isoquinolin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

77) 2-((2-((6-ethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

78) N,N-dimethyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide;

79) 2-((2-((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

80) N,N-dimethyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide;

84) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(2-(piperidin-1-ylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

85) 2-((2-((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

86) 2-((2-((2-cyclopropyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

94) N-(tert-butyl)-2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-toluenesulfonamide;

95) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-methyl-N-neopentylbenzenesulfonamide;

96) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-methyl-N-propylbenzenesulfonamide;

97) N-isobutyl-2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-toluenesulfonamide;

98) 1-((2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)sulfonyl)-3-methylazetidin-3-ol;

99) N ⁴ -(2-((3,3-dimethylpyrrolidin-1-yl)sulfonyl)phenyl)-N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

100) N ⁴ -(2-((3,3-dimethylazetidin-1-yl)sulfonyl)phenyl)-N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

101) 1-((2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)sulfonyl)-4-methylpiperidin-4-ol;

102) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(2-(morpholinesulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

103) N ⁴ -(2-((4,4-dimethylpiperidin-1-yl)sulfonyl)phenyl)-N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

104) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(2-oxy-1,2-dihydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

105) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(1-methyl-6-oxy-1,6-dihydropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

106) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

107) 2-((5-(1,3-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

108) 2-((5-(3,5-dimethylisoxazol-4-yl)-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

109) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(2-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

110) 2-((2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(4-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

111) N ⁴ -(3-fluorophenyl)-N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

112) N ⁴ -(3-chlorophenyl)-N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine;

113) N ² -(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ⁴ -(3-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine.

9. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises: one or more of the compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt or a mixture thereof, and one or more pharmaceutically acceptable carriers.

10. Use of the compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt or a mixture thereof, characterized in that it is used for preparing a pharmaceutical composition for treating or preventing a disease associated with HPK1 activity or expression; and the disease is cancer.