CN116239597A - Pyrimidine pyrrole derivative and medicinal composition and application thereof - Google Patents

Pyrimidine pyrrole derivative and medicinal composition and application thereof Download PDF

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CN116239597A
CN116239597A CN202111486590.XA CN202111486590A CN116239597A CN 116239597 A CN116239597 A CN 116239597A CN 202111486590 A CN202111486590 A CN 202111486590A CN 116239597 A CN116239597 A CN 116239597A
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amino
methyl
tetrahydroisoquinolin
methoxy
pyrimidin
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徐石林
蒙凌华
吴非飞
孙朴
张利山
孙姚良
李慧钰
徐瓓
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention discloses a pyrimidopyrrole compound shown in formula (I) or pharmaceutically acceptable salt, stereoisomer or the like thereofProdrug molecules, wherein the definition of each group is as described in the specification. The invention also discloses methods for preparing such compounds, and methods for their use as HPK1 inhibitors for the treatment of HPK 1-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 research of the Liao Xue subject group of the university of Qinghua also found that small molecule inhibitors of HPK1 and corresponding PROTACs degradation agents can 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:
Figure BDA0003397746400000011
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 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 An alkyl group;
l is selected from the group consisting of: -O-, -S-, -NH-, -NC 1 -C 3 Alkyl-, -SO-, -S (O) 2 -, or L is a bond (i.e., R 2 Directly connected with the mother nucleus);
R 2 selected from the group consisting of: r is R 2 Selected from the group consisting of: substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered heteroaromatic ring, and the likeSubstituted or unsubstituted 5-7 membered ring and 5-8 membered aromatic ring, substituted or unsubstituted 4-7 membered saturated nitrogen-containing heterocycle; wherein the 5-7 membered ring is a saturated ring, a partially unsaturated ring or an aromatic ring;
R 3 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 Selected from the group consisting of: cyano, alkynyl;
R 5 selected from the group consisting of: c (C) 1 -C 3 An alkyl group, a substituted or unsubstituted benzene ring, a 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 atom (=o), carboxyl, hydroxyl, amino, nitro, cyano, -S (O) 2 C 1 -C 6 Alkylamino (including alkylamino or cycloalkylamino), -S (O) 2 C 1 -C 6 Alkyl (including alkanyl or cycloalkyl), -P (O) (C) 1 -C 6 Alkyl group 2 、C 1 -C 6 Alkyl, C 1 -C 6 Containing fluoroalkyl groups, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxycarbonyl group, C 1 -C 6 Amido, C 2 -C 12 An 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 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkenyl, C 1 -C 6 Alkynyl, 3-12 membered heterocyclyl, 5-6 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 is 3 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 is 3 Has a structure shown in the following formula:
Figure BDA0003397746400000021
wherein A is 1 、A 2 、A 3 、A 4 And A 5 Each independently selected from the group consisting of: H. halogen, C 1 -C 6 Alkyl, C 1 -C 6 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 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkenyl, C 1 -C 6 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 a 5-to 8-membered ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, and said ring is optionally substituted with one or more substituents A 6 Substitution; the A is 6 Selected from the group consisting of: H. c (C) 1 -C 4 An alkyl group; or two A 6 Together with the two carbon atoms to which they are attached form a chain containing 0, 1 or 2 heteroatoms as one or moreA 5 to 8 membered ring of ring members;
x and Y are N or C; and when X is N, A 1 Is not present.
In another preferred embodiment, the A 1 、A 2 、A 3 、A 4 And A 5 Each independently selected from the group consisting of: H. halogen, C 1 -C 6 Alkyl, C 1 -C 6 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 -C 3 Alkyl) -, or directly with R 2 When C atom of (B) is connected, R is 2 Has a structure shown in the following formula:
Figure BDA0003397746400000031
wherein B is 1 、B 2 、B 3 、B 4 And B 5 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, C 1 -C 4 Hydroxy, -C (O) B 6 、-S(O) 2 B 6 、-S(O)B 6 、-P(O)(B 6 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And B is 6 Selected from the group consisting of: c (C) 1 -C 4 Alkyl, C 1 -C 4 An alkylamino group; or B is a 1 And B 2 Or B 4 And B 5 Together with the two carbon atoms to which they are attached form a chain containing 0, 1 or 2 heteroatoms as oneA 5-to 8-membered ring of one or more ring members; the ring optionally being substituted with one or more substituents B 7 Substitution;
said B 7 Selected from the group consisting of: H. substituted or unsubstituted C1-C6 alkyl, or two B's on the same carbon atom 7 Together form an oxygen atom (=o);
z is N or C, and B when Z is N 3 Is not present.
In another preferred embodiment, when L is selected from the group consisting of R directly 2 When N atoms in (B) are connected, R is 2 Has a structure shown in the following formula:
Figure BDA0003397746400000032
wherein C is 1 、C 2 、C 3 、C 4 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, C 1 -C 4 A hydroxyl group;
d is selected from the group consisting of: hydrogen, C 1 -C 4 An alkyl group;
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):
Figure BDA0003397746400000033
/>
wherein A is 1 、A 2 、A 3 、A 4 、A 5 Each independently selected from the group consisting of: H. halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,
Figure BDA0003397746400000041
Or A 3 And A 2 Or A 4 Together form a structure selected from the group consisting of:
Figure BDA0003397746400000042
In another preferred embodiment, R is 1 Selected from the group consisting of:
Figure BDA0003397746400000043
/>
wherein n is 0 or 1 or 2 or 3.
In another preferred embodiment, said B 1 Selected from the group consisting of:
Figure BDA0003397746400000051
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-pyrrole [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-pyrrole [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-pyrrole [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-pyrrole [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-pyrrole [2,3-d ]]Pyrimidine-2, 4-diamine;
6)N 2 - (6-methyl)Oxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N 4 - (2- (trifluoromethyl) phenyl) -7H-pyrrole [2,3-d ]]Pyrimidine-2, 4-diamine;
7)N 2 - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N 4 - (o-methanolphenyl) -7H-pyrrole [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-pyrrole [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-pyrrole [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;
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-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-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-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-diamines
68)N 4 - (2-ethoxyphenyl) -N 2 - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d]Pyrimidine-2, 4-diamines
69)N 2 - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N4- (2-propoxyphenyl) -7H-pyrrole [2,3-d]Pyrimidine-2, 4-diamines
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;
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;
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-dimethyl azetidin-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-pyrrole [2,3-d]Pyrimidine-2, 4-diamines
112)N 4 - (3-chlorophenyl) -N 2 - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d]Pyrimidine-2, 4-diamines
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-diamines
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 chemical compounds of the present invention, when any variable (e.g., R 1 R, etc.) occur more than once in any component, then 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 means a bagIncluding branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, "C 1 -C 5 Alkyl "medium" C 1 -C 5 The definition of "includes groups having 1, 2, 3, 4, or 5 carbon atoms arranged in a straight or branched chain. For example, "C 1 -C 5 The alkyl group includes, in particular, 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 -C 6 ) The alkyl groups may be one, two or three selected from OH, halogen, alkoxyA dialkylamino group, or a heterocyclic group 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.
In another preferred embodiment, the compound is selected from the group consisting of:
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Figure BDA0003397746400000141
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Figure BDA0003397746400000151
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Figure BDA0003397746400000161
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Figure BDA0003397746400000171
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Figure BDA0003397746400000181
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Figure BDA0003397746400000191
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Figure BDA0003397746400000201
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Figure BDA0003397746400000211
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Figure BDA0003397746400000221
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Figure BDA0003397746400000231
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Figure BDA0003397746400000281
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Figure BDA0003397746400000291
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Figure BDA0003397746400000301
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Figure BDA0003397746400000311
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Figure BDA0003397746400000321
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:
Figure BDA0003397746400000331
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)
Figure BDA0003397746400000341
Step 1-1:2, 4-dichloro-7- (2-trimethylsiloxymethyl) -7H-pyrrolo [2,3-d ] pyrimidine (S2)
Figure BDA0003397746400000351
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.
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000352
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.
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000353
6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (92.2mg,0.48mmol 192.13), cesium carbonate (208.5mg,0.64mol 325.82), xantphos (37.03mg,0.064mol 578.62), pd were added sequentially to 3mL of toluene solution of Compound S3 (120mg,0.32mmol 374.13) at room temperature 2 (dba) 3 (29.3 mg,0.032mol 915.72). By N 2 After three times of pumping and discharging, the liquid is in N 2 The reaction was carried out at 100℃for 12h under an atmosphere. 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.
1 H NMR(500MHz,MeOD-d 6 )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 (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)
Figure BDA0003397746400000361
To a solution of compound S4 (30 mg,0.056 mmole 530.28) in 5mL DCM was added 2.5mL 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 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.
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000362
Synthetic method as in example 1
1 H NMR(400MHz,MeOD-d 6 )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-pyrrole [2,3-d ]]Pyrimidine-2, 4-diamines (compounds3)
Figure BDA0003397746400000371
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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 - (o-fluorophenyl) -7H-pyrrole [2,3-d ]]Pyrimidine-2, 4-diamine (Compound 4)
Figure BDA0003397746400000372
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000373
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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-pyrrole [2,3-d ]]Pyrimidine-2, 4-diamine (Compound 6)
Figure BDA0003397746400000381
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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-methanolphenyl) -7H-pyrrole [2,3-d ]]Pyrimidine-2, 4-diamine (Compound 7)
Figure BDA0003397746400000382
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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-pyrrole [2,3-d ]]Pyrimidine-2, 4-diamine (Compound 8)
Figure BDA0003397746400000391
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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-pyrrole [2,3-d ]]Pyrimidine-2, 4-diamine (Compound 9)
Figure BDA0003397746400000392
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000393
Synthetic method as in example 1
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000401
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Synthetic method as in example 1
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000402
Synthetic method as in example 1
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000411
Synthetic method as in example 1
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000412
Synthetic method as in example 1
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000413
Synthetic method as in example 1
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000421
Synthetic method as in example 1
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000422
Synthetic method as in example 1
1 H NMR(500MHz,CDCl 3 -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)
Figure BDA0003397746400000431
Synthetic method as in example 1
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000432
Synthetic method as in example 1
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000433
/>
Synthetic method as in example 1
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000441
Synthetic method as in example 1
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000442
Step 22-1: -chloro-4-phenyl-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrole [2,3-d ] pyrimidine
Figure BDA0003397746400000443
To a solution of compound S2 (200 mg,0.63 mmol) in 5mL of toluene at room temperature were added phenylboronate (128.6 mg,0.63 mmol), potassium carbonate (174 mg,1.26 mol), pd (PPh) 3 ) 4 (73 mg,0.063 mol). By N 2 After three times of pumping and discharging, the liquid is in N 2 The reaction was carried out at 100℃for 12h under an atmosphere. The reaction solution was filtered and concentrated, and purified by silica gel column chromatography to give the title compound (100 mg, 44%).
1 H NMR(400MHz,CDCl 3 -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.
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000451
Step 23-1:2, 4-dichloro-5-iodo-7H-pyrrole [2,3-d ] pyrimidine (S5)
Figure BDA0003397746400000452
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.
1 H NMR(500MHz,CDCl 3 -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)
Figure BDA0003397746400000453
The title compound was synthesized in a similar manner to that described in step 1-1 of example 1.
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000461
The title compound was synthesized in a similar manner to that described in step 1-2 of example 1.
1 H NMR(400MHz,CDCl 3 -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)
Figure BDA0003397746400000462
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). By N 2 After three times of pumping and discharging, the liquid is in N 2 The reaction was carried out at 100℃for 24 hours under an atmosphere. The reaction solution was filtered and concentrated, and purified by silica gel column chromatography to give the title compound (30 mg, 37.5%).
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000463
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.
Figure BDA0003397746400000471
The title compound was synthesized in a similar manner to that described in steps 1-4 of example 1.
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000472
The synthesis was as in example 23.
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000473
/>
The synthesis was as in example 23.
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000481
Step 26-1:2- ((2-chloro-5- (cyanomethyl) -7- (2-trimethylsilylethoxymethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide
Figure BDA0003397746400000482
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). By N 2 After three times of pumping and discharging, the liquid is in N 2 The reaction was carried out at 100℃for 24 hours under an atmosphere. 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.
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000491
The synthesis was as in example 23.
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000492
The synthesis was as in example 23.
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000493
/>
The synthesis was as in example 23.
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000501
The synthesis was as in example 1.
1 H NMR(500MHz,MeOD-d 6 )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)
Figure BDA0003397746400000502
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)
Figure BDA0003397746400000511
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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-pyrrolo [2,3-d]Pyrimidine-2, 4-diamine (Compound 33)
Figure BDA0003397746400000512
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000521
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000522
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000523
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The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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)
Figure BDA0003397746400000531
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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 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 (compound 39)
Figure BDA0003397746400000532
The synthesis was as in example 23.
1 H NMR(400MHz,MeOD-d 6 )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 44
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)
Figure BDA0003397746400000541
The synthesis was as in example 44.
1H NMR(400MHz,MeOD-d 6 )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 45
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)
Figure BDA0003397746400000542
The synthesis was as in example 23.
1H NMR(400MHz,MeOD-d 6 )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 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 (compound 48)
Figure BDA0003397746400000543
The synthesis was as in example 48.
1 H NMR(400MHz,MeOD-d 6 )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 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 (compound 49)
Figure BDA0003397746400000551
The synthesis was as in example 23.
1 H NMR(400MHz,MeOD-d 6 )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 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 (compound 50)
Figure BDA0003397746400000552
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 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 (compound 51)
Figure BDA0003397746400000561
The synthesis was as in example 23.
1 H NMR(400MHz,MeOD-d 6 )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 52
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)
Figure BDA0003397746400000562
The synthesis was as in example 23.
1 H NMR(400MHz,MeOD-d 6 )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 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 (compound 53)
Figure BDA0003397746400000571
The synthesis was as in example 23.
1 H NMR(400MHz,MeOD-d 6 )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 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 (compound 58)
Figure BDA0003397746400000572
The synthesis was as in example 23.
1 H NMR(400MHz,MeOD-d 6 )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 59
N, N-dimethyl-2- ((2- ((4-morpholinophenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide (compound 59)
Figure BDA0003397746400000573
The synthesis was as in example 23.
1 H NMR(400MHz,MeOD-d 6 )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 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 (compound 60)
Figure BDA0003397746400000581
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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 61
2- ((2- ((4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (61)
Figure BDA0003397746400000582
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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 62
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)
Figure BDA0003397746400000591
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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 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 (compound 63)
Figure BDA0003397746400000592
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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 64
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)
Figure BDA0003397746400000601
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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 65
N, N-dimethyl-2- ((2- ((4-morpholinophenyl) amino) -5- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzenesulfonamide (65)
Figure BDA0003397746400000602
The synthesis was as in example 1.
1 H NMR(400MHz,MeOD-d 6 )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 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 (102)
Figure BDA0003397746400000603
The synthesis was as in example 1.
MS(ESI,[M+H] + )m/z 550.3
Example 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 (106)
Figure BDA0003397746400000611
The synthesis was as in example 2.
MS(ESI,[M+H] + )m/z 599.3
Example 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 (109)
Figure BDA0003397746400000612
The synthesis was as in example 2.
MS(ESI,[M+H] + )m/z 599.3
Example 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 (110)
Figure BDA0003397746400000613
The synthesis was as in example 2.
MS(ESI,[M+H] + )m/z 599.3
Example 111
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)
Figure BDA0003397746400000621
The synthesis was as in example 1.
MS(ESI,[M+H] + )m/z 419.3
Example 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-diamines
Figure BDA0003397746400000622
The synthesis was as in example 1.
MS(ESI,[M+H] + )m/z 469.3
EXAMPLE 114 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. A kind of electronic deviceThen 10mM magnesium acetate is added [ gamma- ] 33 P]ATP was started and incubated at room temperature for 40 min before 0.5% phosphate was added to stop the reaction. 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 rate of the kinase by the compound at different concentrations, the compound was introduced into Prism software and IC was calculated 50 Values. IC (integrated circuit) 50 The inhibition was plotted against the logarithmic concentration.
TABLE 2 results of HPK1 kinase Activity experiments
Figure BDA0003397746400000623
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Figure BDA0003397746400000631
Figure BDA0003397746400000641
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Example 115 Effect of 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 5min.
(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 116ELISA detection of Jurkat cell viability and culture supernatant IL-2 concentration
The specific operation method is as follows:
plate, dosing, and ELISA sample collection
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 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 application are incorporated by reference 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 claims appended hereto.

Claims (10)

1. A pyrimido-pyrrole compound of the formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a prodrug molecule thereof:
Figure FDA0003397746390000011
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 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 An alkyl group;
l is selected from the group consisting of: -O-, -S-, -NH-, -NC 1 -C 3 Alkyl-, -SO-, -S (O) 2 -, or L is a bond (i.e., R 2 Directly connected with the mother nucleus);
R 2 selected from the group consisting of: r is R 2 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 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 Selected from the group consisting of: cyano, alkynyl;
R 5 selected from the group consisting of: c (C) 1 -C 3 An alkyl group, a substituted or unsubstituted benzene ring, a 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 atom (=o), carboxyl, hydroxyl, amino, nitro, cyano, -S (O) 2 C 1 -C 6 AlkanolamineRadicals (including alkylamino or cycloalkylamino), -S (O) 2 C 1 -C 6 Alkyl (including alkanyl or cycloalkyl), -P (O) (C) 1 -C 6 Alkyl group 2 、C 1 -C 6 Alkyl, C 1 -C 6 Containing fluoroalkyl groups, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxycarbonyl group, C 1 -C 6 Amido, C 2 -C 12 An 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 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkenyl, C 1 -C 6 Alkynyl, 3-12 membered heterocyclyl, 5-6 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.
2. A compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, or a prodrug molecule thereof, wherein R 3 Has a structure shown in the following formula:
Figure FDA0003397746390000021
wherein A is 1 、A 2 、A 3 、A 4 And A 5 Each independently selected from the group consisting of: H. halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, 3-12 membered heterocyclyl, 5-6 membered aryl; each of the above groups may be unsubstituted or substituted with 1, 2 or 3 substituents of group A selected from the group consisting of: halogen, hydroxy, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkenyl, C 1 -C 6 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 a 5-to 8-membered ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, and said ring is optionally substituted with one or more substituents A 6 Substitution; the A is 6 Selected from the group consisting of: H. c (C) 1 -C 4 An alkyl group; or two A 6 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;
x and Y are N or C; and when X is N, A 1 Is not present.
3. A compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, or a prodrug molecule thereof, wherein when L is selected from the group consisting of-NH-, -N (C 1 -C 3 Alkyl) -, or directly with R 2 When C atom of (B) is connected, R is 2 Has a structure shown in the following formula:
Figure FDA0003397746390000022
wherein B is 1 、B 2 、B 3 、B 4 And B 5 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, C 1 -C 4 Hydroxy, -C (O) B 6 、-S(O) 2 B 6 、-S(O)B 6 、-P(O)(B 6 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And B is 6 Selected from the group consisting of: c (C) 1 -C 4 Alkyl, C 1 -C 4 An alkylamino group; or B is a 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 comprising 0, 1 or 2 heteroatoms as one or more ring members; the ring optionally being substituted with one or more substituents B 7 Substitution;
said B 7 Selected from the group consisting of: H. substituted or unsubstituted C1-C6 alkyl, or two B's on the same carbon atom 7 Together form an oxygen atom (=o);
z is N or C, and B when Z is N 3 Is not present.
4. A compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, or a prodrug molecule thereof, wherein when L is selected from the group consisting of R directly 2 When N atoms in (B) are connected, R is 2 Has a structure shown in the following formula:
Figure FDA0003397746390000023
wherein C is 1 、C 2 、C 3 、C 4 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, C 1 -C 4 A hydroxyl group;
d is selected from the group consisting of: hydrogen, C 1 -C 4 An alkyl group;
n is 0, 1, 2 or 3;
m is 0, 1, 2, 3 or 4.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, or a prodrug molecule thereof, wherein the compound has the structure of formula (II):
Figure FDA0003397746390000031
wherein A is 1 、A 2 、A 3 、A 4 、A 5 Each independently selected from the group consisting of: H. halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,
Figure FDA0003397746390000032
Or A 3 And A 2 Or A 4 Together form a structure selected from the group consisting of:
Figure FDA0003397746390000033
6. the compound of claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof, or a prodrug molecule thereof, wherein R 1 Selected from the group consisting of:
H. halogen, halogen,
Figure FDA0003397746390000041
/>
Figure FDA0003397746390000042
Wherein n is 0 or 1 or 2 or 3.
7. The compound of claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof, or a prodrug molecule thereof, wherein B 1 Selected from the group consisting of:
H. halogen, halogen,
Figure FDA0003397746390000043
Figure FDA0003397746390000044
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.
8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, or a prodrug molecule thereof, wherein 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-pyrrole [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-pyrrole [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-pyrrole [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-pyrrole [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-pyrrole [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-pyrrole [2,3-d ]]Pyrimidine-2, 4-diamine;
7)N 2 - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N 4 - (o-methanolphenyl) -7H-pyrrole [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-pyrrole [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-pyrrole [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;
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-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-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-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-diamines
68)N 4 - (2-ethoxyphenyl) -N 2 - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d]Pyrimidine-2, 4-diamines
69)N 2 - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N4- (2-propoxyphenyl) -7H-pyrrole [2,3-d]Pyrimidine-2, 4-diamines
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;
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;
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-dimethyl azetidin-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-pyrrole [2,3-d]Pyrimidine-2, 4-diamines
112)N 4 - (3-chlorophenyl) -N 2 - (6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -7H-pyrrole [2,3-d]Pyrimidine-2, 4-diamines
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.
9. A pharmaceutical composition, said pharmaceutical composition comprising: a compound of formula I as defined in claim 1, one or more of its pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof, together with one or more pharmaceutically acceptable carriers, excipients, adjuvants, and/or diluents.
10. The use of a compound of formula I according to claim 1, in the form of 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 which are associated with HPK1 activity or expression level.
CN202111486590.XA 2021-12-07 2021-12-07 Pyrimidine pyrrole derivative and medicinal composition and application thereof Pending CN116239597A (en)

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