CN117003734A - Pyrimidine ring derivative and preparation method and application thereof - Google Patents

Pyrimidine ring derivative and preparation method and application thereof Download PDF

Info

Publication number
CN117003734A
CN117003734A CN202210454533.1A CN202210454533A CN117003734A CN 117003734 A CN117003734 A CN 117003734A CN 202210454533 A CN202210454533 A CN 202210454533A CN 117003734 A CN117003734 A CN 117003734A
Authority
CN
China
Prior art keywords
alkyl
cycloalkyl
heterocyclyl
aryl
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202210454533.1A
Other languages
Chinese (zh)
Inventor
周梦光
程超英
胡杜芬
林凌志
林文成
许英彪
邵林江
林承才
张盼盼
叶成
陈磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
Original Assignee
Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang Hisun Pharmaceutical Co Ltd, Shanghai Aryl Pharmtech Co Ltd filed Critical Zhejiang Hisun Pharmaceutical Co Ltd
Priority to CN202210454533.1A priority Critical patent/CN117003734A/en
Priority to PCT/CN2023/090548 priority patent/WO2023207960A1/en
Publication of CN117003734A publication Critical patent/CN117003734A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Abstract

The invention relates to a substituted pyrimido-ring derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in medicine. In particular, the invention relates to substituted pyrimido ring derivatives represented by the general formula (I), a preparation method and pharmaceutically acceptable salts thereof, and application thereof as therapeutic agents, particularly HPK1 inhibitors, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Pyrimidine ring derivative and preparation method and application thereof
Technical Field
The invention relates to a pyrimido-ring derivative, a preparation method thereof, a pharmaceutical composition containing the pyrimido-ring derivative and application of the pyrimido-ring derivative as a therapeutic agent, particularly as an HPK1 inhibitor.
Background
Hematopoietic progenitor kinase (HPK 1, also known as MAP4K 1) is a mammalian Ste 20-like serine/threonine kinase, which is the expression product of the gene MAP4K1, mainly in hematopoietic stem cells, belongs to mitogen activated protein kinase kinase family (MAP 4K), it has now been found that this family also includes 5 other members MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAP4K6.HPK1 is a protein of 97kDa in relative molecular weight, and is largely divided into 3 regions, the N-terminal Ste 20-like kinase region, the C-terminal kinase region and the middle 4 proline-rich regions (P1, P2, P3 and P4), which normally interact with the adaptor proteins containing SH2/SH3 regions, activating the transduction of a range of signal pathways.
When HPK1 is activated by a variety of upstream signaling factors, including epidermal growth factor, prostaglandin E2, tumor growth factor, erythropoietin, T cell receptors, B cell receptors, etc., a series of biological cascades are triggered. HPK1 can also interact with the adaptor protein SLP-76 family, CARD11, GRB2 family, CRK family and the like in the downstream signaling pathway to activate the JNK/SAPK signaling pathway of hematopoietic stem cells, thereby back-regulating the T cell pathway. Therefore, HPK1 is involved in regulating cell proliferation and apoptosis, and plays an important role in immunosuppression.
HPK1 acts as a kinase regulating immunosuppression and is a reverse regulator of T cell receptor, when T cell receptor is activated, HPK1 in cytoplasm recruits to the vicinity of cell membrane, activated HPK1 phosphorylates linker protein SLP76, activated SLP76 acts as docking site for T cell regulatory inhibitor protein 14-3-3, multiple proteins combine to form SLP76 complex, SLP76 complex induces ubiquitination degradation, finally leading to instability of T cell receptor signaling complex, thereby down regulating T cell signaling pathway and T cell proliferation.
However, T cells participate in an important process of anti-tumor immunity, and the antigen receptor of the T cells recognizes specific antibodies on tumor cells to directly kill the tumor cells; or indirectly kill tumor cells by activating macrophages and secreting other lymphokines. Therefore, inhibition of HPK1 can proliferate T cells and activate T cell signaling pathways, further enhancing tumor killing and inhibiting tumor growth. Since HPK1 plays an important role in immunomodulation, HPK1 can be used as a research direction for treating inflammatory responses, autoimmune diseases (e.g., systemic lupus erythematosus, psoriasis) and malignant tumors (e.g., acute myelogenous leukemia, bladder epithelial cancer, colon cancer, pancreatic cancer).
Even though only two compounds are currently in clinical use as inhibitors against the HPK1 target, CFI-402411 (second phase) from Treadwell and BGB-15025 (first phase) from baji shenzhou, respectively, but facing the tumor, the field of fight is not in progress, and medical workers are not in the hope of being in the position of being in the arms, more and more medical companies have been added to this campaign today, such as Nimbus Therapeutics and aro medicine. The HPK1 inhibitor is taken as a research direction of a comparison front, and immune response related to T cells is brought about when tumors are treated, so that the HPK1 inhibitor which is safer and more effective is needed to be found, the risk in the treatment process is reduced, and the pain of patients is reduced.
Disclosure of Invention
The invention relates to a compound shown in a general formula (I) or a stereoisomer, a tautomer or pharmaceutically acceptable salt thereof:
wherein:
ring a is selected from the following groups:
x is selected from CR a Or N;
R a 、R b the same or different, each independently selected from hydrogen, halogen, hydroxy, amino, alkyl, alkoxy or cyano; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;
R 3 the same or different are each independently selected from the group consisting of hydrogen atom, hydroxy group, halogen, Alkyl, cyano, alkoxy, cycloalkyl, heterocyclyl or-NR c R d Wherein said alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with one or more halo, amino, hydroxy, cyano, alkyl or alkoxy substituents;
R c 、R d identical or different, each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, -C (O) R 4 or-S (O) 2 R 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, cycloalkyl or heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, hydroxy, cyano, alkyl or alkoxy;
l is selected from the group consisting of bond, -C (O) -, -OC (O) -, -SC (O) -, -CH 2 C (O) -or-NR e C(O)-；
R e Selected from hydrogen atoms or alkyl groups;
ring B is selected from fused ring, aryl, heteroaryl, cycloalkyl or heterocyclyl;
R 1 identical or different, each independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or fused ring, wherein said alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or fused ring is optionally further substituted with one or more R A Substituted;
each R A Identical OR different, each independently selected from alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 4 、-C(O)R 4 、-C(O)OR 4 、-NHC(O)R 4 、-NHC(O)OR 4 、-NR 5 R 6 、-C(O)NR 5 R 6 、-CH 2 NHC(O)OR 4 、-CH 2 NR 5 R 6 、-P(O)R 5 R 6 、-S(O) r NR 5 R 6 or-S (O) r R 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR 4 、-C(O)R 4 、-C(O)OR 4 、-NHC(O)R 4 、-NHC(O)OR 4 、-NR 5 R 6 、-C(O)NR 5 R 6 、-CH 2 NHC(O)OR 4 、-CH 2 NR 5 R 6 or-S (O) r R 4 Is substituted by a substituent of (2);
alternatively, two R A Together with the attached carbon atom, form a-C (=o) -;
R 2 identical OR different, each independently selected from the group consisting of hydrogen, alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 4 、-C(O)R 4 、-C(O)OR 4 、-NHC(O)R 4 、-NHC(O)OR 4 、-NR 5 R 6 、-C(O)NR 5 R 6 、-CH 2 NHC(O)OR 4 、-CH 2 NR 5 R 6 or-S (O) r R 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more R B Substituted;
alternatively, two R 2 Together with the attached carbon atom, form a-C (=o) -;
each R B Identical OR different, each independently selected from alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 4 、-C(O)R 4 、-C(O)OR 4 、-NHC(O)R 4 、-NHC(O)OR 4 、-NR 5 R 6 、-C(O)NR 5 R 6 、-CH 2 NHC(O)OR 4 、-CH 2 NR 5 R 6 or-S (O) r R 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR 4 、-C(O)R 4 、-C(O)OR 4 、-NHC(O)R 4 、-NHC(O)OR 4 、-NR 5 R 6 、-C(O)NR 5 R 6 、-CH 2 NHC(O)OR 4 、-CH 2 NR 5 R 6 or-S (O) r R 4 Is substituted by a substituent of (2);
alternatively, two R B Together with the attached carbon atom, form a-C (=o) -;
R 4 each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl group, heterocyclic group, aryl group, heteroaryl, =o, -C (O) R 7 、-C(O)OR 7 、-OC(O)R 7 、-NR 8 R 9 、-C(O)NR 8 R 9 、-SO 2 NR 8 R 9 or-NR 8 C(O)R 9 Is substituted by a substituent of (2);
R 5 and R is 6 Each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 7 、-C(O)OR 7 、-OC(O)R 7 、-NR 8 R 9 、-C(O)NR 8 R 9 、-SO 2 NR 8 R 9 or-NR 8 C(O)R 9 Is substituted by a substituent of (2);
alternatively, R 5 And R is 6 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 7 、-C(O)OR 7 、-OC(O)R 7 、-NR 8 R 9 、-C(O)NR 8 R 9 、-SO 2 NR 8 R 9 or-NR 8 C(O)R 9 Is substituted by a substituent of (2);
R 7 、R 8 and R is 9 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;
m is selected from 0, 1, 2, 3, 4 or 5; and is also provided with
r is 0, 1 or 2.
In a preferred embodiment of the present invention, a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (II), (III), (IV), (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
wherein: ring B, L, R 1 ～R 3 、R a 、R b And m is as defined in claim 1.
In a preferred embodiment of the invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 Selected from aryl, heteroaryl, heterocyclyl or fused ring, wherein said aryl, heteroaryl, heterocyclyl or fused ring is optionally further substituted with one or more substituents selected from alkyl, halogen, hydroxy, amino, hydroxyalkyl, =o, -P (O) R 5 R 6 、-S(O) r NR 5 R 6 or-S (O) r R 4 Is substituted by a substituent of (2);
wherein said R 4 、R 5 、R 6 Each independently selected from a hydrogen atom or an alkyl group; r is 0, 1 or 2.
Preferred embodiments of the invention are compounds of the general formula (I), (II), (III), (IV) or (V) or a derivative thereofIsomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 1 Selected from the following groups:
in a preferred embodiment of the invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L is selected as a bond.
In a preferred embodiment of the invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of-C (O) -, -OC (O) -and-NR e C (O) -; wherein said R e Selected from hydrogen atoms or methyl groups.
In a preferred embodiment of the invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of:
in a preferred embodiment of the invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 Identical or different, each independently selected from hydrogen, alkyl, halogen, cyano, alkoxy, cycloalkyl, heterocyclyl or-C (O) NR 5 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with one or more R B Substituted; wherein said R 5 、R 6 Each independently selected from a hydrogen atom or an alkyl group;
alternatively, two R 2 Together with the attached carbon atom, form a-C (=o) -;
R B identical or different, each independently selected from alkyl, halogen, hydroxy, cyano, alkoxy, cycloalkyl or heterocyclyl, wherein the alkaneThe group, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with one or more substituents selected from alkyl, halogen, cyano, hydroxy, amino, alkoxy, haloalkyl, hydroxyalkyl or haloalkoxy.
In a preferred embodiment of the invention, a compound of the general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, whereinSelected from the following groups:
in a preferred embodiment of the invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from amino or halogen.
In a preferred embodiment of the invention, the compounds of formula (I) are selected from:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Note that: if there is a difference between the drawn structure and the name given to the structure, the drawn structure will be given greater weight.
Still further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.
The invention provides an application of a compound shown in a general formula (I), (II), (III), (IV) or (V) or a stereoisomer, a tautomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing an HPK1 inhibitor.
The invention also provides the use of a compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease mediated by HPK1, wherein the disease mediated by HPK1 is preferably an inflammatory, autoimmune or tumour, wherein the autoimmune disease is preferably systemic lupus erythematosus or psoriasis; wherein the tumor is preferably a hematological malignancy or a solid malignancy; wherein the tumour is more preferably selected from acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, oesophageal cancer, stomach cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer and multiple myeloma.
The invention further provides an application of the compound shown in the general formula (I), (II), (III), (IV) or (V) or stereoisomer, tautomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating inflammation, autoimmune diseases or tumor diseases, wherein the autoimmune diseases are preferably systemic lupus erythematosus or psoriasis; wherein the tumor is preferably a hematological malignancy or a solid malignancy; wherein the neoplasm is more preferably acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer, and multiple myeloma.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"alkyl" when taken as a group or part of a group is meant to include C 1 -C 20 Straight chain or branched aliphatic hydrocarbon groups. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles. Preferably C 3 -C 12 Cycloalkyl, more preferably C 3 -C 8 Cycloalkyl, most preferably C 3 -C 6 Cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be substituted or unsubstituted.
"spirocycloalkyl" refers to a 5 to 18 membered, two or more cyclic structure, and monocyclic polycyclic groups sharing one carbon atom (called spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro group, a double spiro group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably single spiro group and double spirocycloalkyl group, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
"fused ring alkyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl, or tetradecahydrophenanthryl.
"bridged cycloalkyl" means an aromatic system having 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups with one another that are not directly attached to a carbon atom, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron, preferably 6 to 12 members, more preferably 7 to 10 members. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1 s,4 s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1 s,5 s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1 r,5 r) -bicyclo [3.3.2] decyl.
"heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is selected from 0, 1 or 2) heteroatoms including monocyclic, polycyclic, fused, bridged and spiro rings. Preferably having a 5 to 7 membered single ring or a 7 to 10 membered double or triple ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulphur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, azetidinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, piperazinyl, hexahydropyrimidine,The heterocyclic group may be substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5-to 18-membered, two or more cyclic structure, polycyclic group having single rings sharing one atom with each other, containing 1 or more double bonds in the ring, but no ring having a completely conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multiple spiro heterocyclic group according to the number of common spiro atoms between rings, and preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5 ]]Decyl, 2-oxa-7-azaspiro [4.4 ]]Nonyl, 7-oxaspiro [3.5 ]]Nonyl, 5-oxaspiro [2.4 ]]A heptyl group.
"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo [3,4-c ] ]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0 ]]Hexyl, octahydrobenzo [ b ]][1,4]Dioxin (dioxin).
"bridged heterocyclyl" means 5 to 14 membered, 5 to 18 membered, containing two or more ringsA polycyclic group having two atoms not directly connected to each other in common, one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl, 2-azabicyclo [3.3.2]And (3) a decyl group.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C 6 -C 10 Aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. Aryl groups may be substituted or unsubstituted.
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl. Heteroaryl groups may be substituted or unsubstituted.
"fused ring" refers to a polycyclic group having two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but at least one of the rings does not have an aromatic group with a fully conjugated pi electronA fragrance system, at the same time at least one ring having a completely conjugated pi-electron fragrance system, wherein the ring atoms are selected from 0, one or more of nitrogen, oxygen or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. The fused ring is preferably a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of a monocyclic aryl or monocyclic heteroaryl and a monocyclic heterocyclyl or monocyclic cycloalkyl, and the tricyclic fused ring is preferably a fused ring of a monocyclic aryl or monocyclic heteroaryl and a bicyclic heterocyclyl or bicyclic cycloalkyl. The fused ring is preferably a 7 to 14 membered ring. Examples of "fused rings" include, but are not limited to:
"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) 1 -C 6 Is preferably selected. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"hydroxy" refers to an-OH group.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"benzyl" means-CH 2 -phenyl.
"carboxy" means-C (O) OH.
"carboxylate" refers to-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl, cycloalkyl are as defined above.
"DMSO" refers to dimethyl sulfoxide.
"BOC" refers to t-butoxycarbonyl.
"TFA" refers to trifluoroacetic acid.
"Ts" refers to p-toluenesulfonyl.
"Tf" refers to p-trifluoromethylbenzenesulfonyl.
"hydroxyalkyl" refers to hydroxy-substituted alkyl.
"haloalkyl" refers to a halogen substituted alkyl.
"haloalkoxy" refers to a halogen substituted alkoxy group.
The term "leaving group", or "leaving group", is used in the term nucleophilic substitution reaction and elimination reaction as an atom or functional group that is released from a larger molecule in a chemical reaction. In nucleophilic substitution reactions, the reactant that is attacked by a nucleophile is referred to as a substrate (substrate), and the atom or group of atoms that breaks away from a pair of electrons in the substrate molecule is referred to as a leaving group. Groups that accept electrons easily and bear a strong negative charge are good leaving groups. The smaller the pKa of the leaving group conjugate acid, the easier the leaving group will be to disengage from the other molecule. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to be bound to other atoms, and the tendency to exist in anionic (or charge neutral leaving group) form is enhanced. Common leaving groups include, but are not limited to, halogen, methanesulfonyl, -OTs, -OTf, or-OH.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more groups selected from the group consisting of: alkyl, alkoxy, alkylthio, alkylamino, halogen, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester groups;
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by the general formula (I) may be metal salts, amine salts with suitable acids.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
Synthesis method of compound of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
The present invention provides a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which process comprises:
when L is a bond:
the compound of the general formula (I-A) and the compound of the general formula (I-B) are subjected to coupling reaction under the catalysis of metal to obtain the compound of the general formula (I);
wherein:
y is selected from a leaving group selected from halogen or OTf;
ring a, ring B, R 2 And m is as described in formula (I).
Detailed Description
The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.
Examples
The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. 1 The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate adopts a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate adopted by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product adopted by the thin layer chromatography separation and purification product is 0.4mm
0.5mm。
Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and, unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and, unless otherwise indicated, commercially available manufacturers include, but are not limited to, aldrich Chemical Company, ABCR GmbH & co.kg, acros Organics, praise chemical technology limited, and vision chemical technology limited, etc.
CD 3 OD: deuterated methanol.
CDCl 3 : deuterated chloroform.
DMSO-d 6 : deuterated dimethyl sulfoxide.
The argon atmosphere means that the reaction flask is connected to an argon balloon of about 1L volume.
The examples are not particularly described, and the solution in the reaction is an aqueous solution.
Purifying the compound by using a silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: dichloromethane: ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.
Example 1
N 2 - (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -8-phenylquinazoline-2, 5-diamine
First step
8-bromo-5-chloroquinazolin-2-amine
Guanidine 1b (2.05 g,11.37 mmol) was added to N, N-dimethylacetamide (60 mL), potassium carbonate (4.71 g,34.11 mmol) was added with stirring at room temperature, then a solution of 3-bromo-6-chloro-2-fluorobenzaldehyde 1a (2.7 g,11.37 mmol) in N, N-dimethylacetamide (10 mL) was added dropwise, and the mixture was heated to 160℃under nitrogen to react for 8 hours. After cooling, 50mL of water was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with water (200 mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluent: B system) to give 8-bromo-5-chloroquinazolin-2-amine 1c (2.5 g), yield: 85%.
MS m/z(ESI):258.0[M+1].
Second step
5-chloro-8-phenylquinazolin-2-amine
8-bromo-5-chloroquinazolin-2-amine 1c (1.91 g,7.38 mmol) and phenylboronic acid 1d (1.8 g,14.76 mmol) were dissolved in a mixed solvent of 1, 4-dioxane and water (V: v=50 ml:5 ml), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.54 g,0.74 mmol) and potassium carbonate (3.06 g,22.14 mmol) were sequentially added and reacted at 60℃for 8 hours. The mixture was cooled, filtered, the filter cake was washed with ethyl acetate, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: B system) to give 5-chloro-8-phenylquinazolin-2-amine 1e (1.4 g) in 74% yield.
MS m/z(ESI):256.1[M+1].
Third step
5-chloro-N- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -8-phenylquinazolin-2-amine
5-chloro-8-phenylquinazolin-2-amine 1e (0.9 g,3.54 mmol) and 7-bromo-2-methyl-1, 2,3, 4-tetrahydroisoquinoline 1f (0.8 g,3.54 mmol) were dissolved in 1, 4-dioxane (50 mL), tris (dibenzylideneacetone) dipalladium (0.65 g,0.71 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.41 g,0.71 mmol) and cesium carbonate (3.46 g,10.61 mmol) were added in sequence and reacted at 90℃for 7 hours. Cooling, filtering, eluting the filter cake, concentrating the organic phase under reduced pressure, and separating and purifying the obtained residue by column chromatography (eluent: B system) to obtain 1g (1.15 g) of 5-chloro-N- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -8-phenylquinazolin-2-amine with yield: 81%.
MS m/z(ESI):401.2[M+1].
Fourth step
(2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -8-phenylquinazolin-5-yl) carbamic acid tert-butyl ester
1g (0.8 g,2.0 mmol) of 5-chloro-N- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -8-phenylquinazolin-2-amine was dissolved in 1, 4-dioxane (40 mL), to which was added tert-butyl carbamate (3.51 g,29.9 mmol), tris (dibenzylideneacetone) dipalladium-chloroform adduct (0.41 g,0.40 mmol), 2- (dicyclohexylphosphine) 3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl (0.21 g,0.40 mmol), cesium carbonate (1.95 g,5.99 mmol) and Molecular sieves (0.88 g) and the mixture was reacted at 90℃for 6 hours. Cooling, filtering, rinsing the filter cake, concentrating the organic phase under reduced pressure, and separating and purifying the obtained residue by column chromatography (eluent: B system) to obtain tert-butyl (2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -8-phenylquinazolin-5-yl) carbamate for 1h (0.6 g), yield: 62%.
MS m/z(ESI):482.3[M+1].
Fifth step
N 2 - (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -8-phenylquinazoline-2, 5-diamine
Tert-butyl (2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -8-phenylquinazolin-5-yl) carbamate (0.55 g,1.14 mmol) was dissolved in dichloromethane (20 mL), solutionTrifluoroacetic acid (0.65 g,5.71 mmol) was added thereto, and the solution was stirred at room temperature for 18 hours. Diluting with water, separating out water phase, alkalizing with 20% sodium hydroxide to pH=10, extracting with dichloromethane/methanol (ratio 10/1), drying with anhydrous sodium sulfate, filtering, concentrating, and separating and purifying the residue by column chromatography (eluent: A system) to obtain N 2 - (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -8-phenylquinazoline-2, 5-diamine 1 (0.11 g), yield: 25%.
MS m/z(ESI):382.2[M+1].
1 HNMR(400MHz,DMSO-d6)δ9.53(s,1H),9.46(s,1H),7.72(s,1H),7.59-7.62(m,2H),7.42-7.48(m,4H),7.30-7.35(m,1H),6.88(d,J＝8.4Hz,1H),6.53(d,J＝8.0Hz,1H),6.38(s,2H),3.27-3.29(m,2H),2.72-2.74(m,2H),2.58-2.62(m,2H),2.37(s,3H).
Example 2
N 2 - (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -8- (8-methyl-2, 3-dihydro-1H-pyrido [2,3-b ] ][1,4]Oxazin-7-yl) quinazoline-2, 5-diamines
First step
7- (2-amino-5-chloroquinazolin-8-yl) -8-methyl-2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1-carboxylic acid tert-butyl ester
8-bromo-5-chloroquinazolin-2-amine 1c (1.0 g,3.87 mmol) and 8-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1-carboxylic acid tert-butyl ester 2a (1.75 g,4.64 mmol) were dissolved in a mixed solution of 1, 4-dioxabicyclo and water (22 mL, V: V=10:1), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.28 g,0.38 mmol) and potassium carbonate (1.60 g,11.61 mmol) were added in this order and heated to 60℃to react for 6.5 hours. After cooling, filtration, washing of the filter cake with a mixed solvent of dichloromethane and methanol (30 ml, v: v=10:1 ml), concentration of the organic phase under reduced pressure, and separation and purification of the resulting residue by column chromatography (eluent: a system) gave tert-butyl 7- (2-amino-5-chloroquinazolin-8-yl) -8-methyl-2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1-carboxylate 2b (1.14 g), yield 68%.
MS m/z(ESI):428.1[M+1].
Second step
7- (5-chloro-2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) quinazolin-8-yl) -8-methyl-2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1-carboxylic acid tert-butyl ester
7- (2-amino-5-chloroquinazolin-8-yl) -8-methyl-2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1-carboxylic acid tert-butyl ester 2b (1.14 g,2.65 mmol) and 7-bromo-2-methyl-1, 2,3, 4-tetrahydroisoquinoline 1f (0.6 g,2.65 mmol) were dissolved in 1, 4-dioxane (50 mL), tris (dibenzylideneacetone) dipalladium (0.48 g,0.53 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.31 g,0.53 mmol) and cesium carbonate (2.59 g,7.96 mmol) were added in this order, and the mixture was heated to 90℃to react for 6 hours. The filter cake was cooled, filtered, rinsed, and the organic phase concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: a system) to give 7- (5-chloro-2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) quinazolin-8-yl) -8-methyl-2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1-carboxylic acid tert-butyl ester 2c (0.95 g), yield: 62%.
MS m/z(ESI):573.2[M+1].
Third step
7- (5- ((tert-Butoxycarbonyl) amino) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) quinazolin-8-yl) -8-methyl-2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1-carboxylic acid tert-butyl ester
7- (5-chloro-2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) quinazolin-8-yl) -8-methyl-2, 3-dihydro-1H-pyrido [2,3-b][1,4]Oxazine-1-carboxylic acid tert-butyl ester 2c (0.9 g,1.57 mmol) was dissolved in 1, 4-dioxane (80 mL), to the solution was added tert-butyl carbamate (2.76 g,23.56 mmol), tris (dibenzylideneacetone) dipalladium (0.21 g,0.31 mmol), 2- (dicyclohexylphosphine) 3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl (0.17 g,0.31 mmol), cesium carbonate (1.54 g,4.71 mmol) andmolecular sieves (0.70 g) and the mixture was reacted at 90℃for 5 hours. Cooling, filtering, eluting filter cake, and concentrating the organic phase under reduced pressureThe residue obtained is purified by column chromatography (eluent: B system) to give 7- (5- ((tert-butoxycarbonyl) amino) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) quinazolin-8-yl) -8-methyl-2, 3-dihydro-1H-pyrido [2,3-B ]][1,4]Oxazine-1-carboxylic acid tert-butyl ester 2d (0.65 g), yield: 63%.
MS m/z(ESI):654.4[M+1].
Fourth step
N 2 - (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -8- (8-methyl-2, 3-dihydro-1H-pyrido [2,3-b ] ][1,4]Oxazin-7-yl) quinazoline-2, 5-diamines
7- (5- ((tert-Butoxycarbonyl) amino) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) quinazolin-8-yl) -8-methyl-2, 3-dihydro-1H-pyrido [2,3-b][1,4]Oxazine-1-carboxylic acid tert-butyl ester 2d (0.6 g,0.92 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (0.20 g,1.84 mmol) was added to the solution, and the solution was stirred at room temperature for 16 hours. Diluting the reaction with water, separating out water phase, adding 20% sodium hydroxide aqueous solution to alkalize to pH=10, extracting with mixed solvent of dichloromethane and methanol (30 mL, V: V=10:1 mL), drying with anhydrous sodium sulfate, filtering, concentrating, and separating by column chromatography (dichloromethane) to obtain N 2 - (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -8- (8-methyl-2, 3-dihydro-1H-pyrido [2,3-b ]][1,4]Oxazin-7-yl) quinazoline-2, 5-diamine 2 (0.28 g), yield: 67%.
MS m/z(ESI):454.2[M+1].
1 HNMR(400MHz,DMSO-d6)δ9.65(s,1H),9.47(s,1H),7.76(s,1H),7.27-7.33(m,3H),6.94(d,J＝8.4Hz,1H),6.52(d,J＝8.0Hz,1H),6.38(s,2H),5.52(s,1H),4.27-4.37(m,2H),3.72-3.74(m,2H),3.40-3.43(m,2H),3.07-3.09(m,2H),2.84-2.86(m,2H),2.71(s,3H),1.81(s,3H).
Biological evaluation
Test example 1 test of the Compounds of the invention for HPK1 kinase inhibitory Activity
The following methods were used to determine the extent of inhibition of recombinant human HPK1 kinase activity by the compounds of the invention under in vitro conditions. The method uses ADP-Glo from Promega company TM Kinase Assay kit (cat. V9102). Upper partThe kit is a luminescent kinase detection kit and is used for detecting the content of ADP generated by kinase reaction, the content of ADP is positively correlated with kinase activity, and the inhibition intensity of a compound on HPK1 kinase activity is reflected by measuring the content of ADP. For detailed experimental procedures reference is made to the kit instructions.
The experimental procedure is briefly described as follows: the test compound was first dissolved in DMSO to prepare a stock solution, and then buffer (20mM MgCl2,50uM DTT,0.1mg/ml BSA,40mM Tris,pH7.4) was prepared according to the buffer formulation provided in the reagent instructions, and the final concentration of the test compound in the reaction system was in the range of 1000nM to 0.02nM by using the buffer for gradient dilution. The reaction was performed in 384 well microplates, first compound and recombinant human HPK1 protein (final concentration 1 ng/. Mu.L, available from Signalchem, cat# M23-11G-10) were added to the wells and incubated at room temperature for 5 minutes, then ATP solution (final concentration 10. Mu.M) and substrate MBP (final concentration 0.2. Mu.g/uL, available from Signalchem, cat# M42-51N) were added to the reaction solution and incubated with shaking at room temperature for 60 minutes. Subsequently, 5. Mu.L of ADP-Glo Reagent was added to the reaction system, and incubation was continued at room temperature with shaking for 40 minutes. Then 10 μ L Kinase Detection Reagent was added to the reaction and incubation was continued at room temperature for 30 minutes with shaking. After the incubation, the chemiluminescent intensity value of each well was measured in a luminometer in the luminometer mode. The percent inhibition of the compounds at each concentration was calculated by comparison with the ratio of the luminescence intensity of the control group (0.1% dmso) and nonlinear regression analysis was performed on the number-inhibition at the compound concentration by GraphPad Prism 5 software to obtain the IC of the compounds 50 Values.
The compound has better inhibition activity on HPK1 kinase and IC 50 <200nM。

Claims (17)

1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
wherein:
ring a is selected from the following groups:
x is selected from CR a Or N;
R a 、R b the same or different, each independently selected from hydrogen, halogen, hydroxy, amino, alkyl, alkoxy or cyano; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;
R 3 the same or different are each independently selected from hydrogen, hydroxy, halogen, alkyl, cyano, alkoxy, cycloalkyl, heterocyclyl or-NR c R d Wherein said alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with one or more halo, amino, hydroxy, cyano, alkyl or alkoxy substituents;
R c 、R d identical or different, each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, -C (O) R 4 or-S (O) 2 R 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, cycloalkyl or heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, hydroxy, cyano, alkyl or alkoxy;
L is selected from the group consisting of bond, -C (O) -, -OC (O) -, -SC (O) -, -CH 2 C (O) -or-NR e C(O)-；
R e Selected from hydrogen atoms or alkyl groups;
ring B is selected from fused ring, aryl, heteroaryl, cycloalkyl or heterocyclyl;
R 1 identical or different, each independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or fused ring, wherein said alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or fused ring is optionally further substituted with one or more R A Substituted;
each R A Identical OR different, each independently selected from alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 4 、-C(O)R 4 、-C(O)OR 4 、-NHC(O)R 4 、-NHC(O)OR 4 、-NR 5 R 6 、-C(O)NR 5 R 6 、-CH 2 NHC(O)OR 4 、-CH 2 NR 5 R 6 、-P(O)R 5 R 6 、-S(O) r NR 5 R 6 or-S (O) r R 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR 4 、-C(O)R 4 、-C(O)OR 4 、-NHC(O)R 4 、-NHC(O)OR 4 、-NR 5 R 6 、-C(O)NR 5 R 6 、-CH 2 NHC(O)OR 4 、-CH 2 NR 5 R 6 or-S (O) r R 4 Is substituted by a substituent of (2);
alternatively, two R A Together with the attached carbon atom, form a-C (=o) -;
R 2 identical OR different, each independently selected from the group consisting of hydrogen, alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 4 、-C(O)R 4 、-C(O)OR 4 、-NHC(O)R 4 、-NHC(O)OR 4 、-NR 5 R 6 、-C(O)NR 5 R 6 、-CH 2 NHC(O)OR 4 、-CH 2 NR 5 R 6 or-S (O) r R 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more R B Substituted;
alternatively, two R 2 Together with the attached carbon atom, form a-C (=o) -;
each R B The same or different are each independently selected from alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkylRadicals, heterocycles, aryl, heteroaryl, -OR 4 、-C(O)R 4 、-C(O)OR 4 、-NHC(O)R 4 、-NHC(O)OR 4 、-NR 5 R 6 、-C(O)NR 5 R 6 、-CH 2 NHC(O)OR 4 、-CH 2 NR 5 R 6 or-S (O) r R 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR 4 、-C(O)R 4 、-C(O)OR 4 、-NHC(O)R 4 、-NHC(O)OR 4 、-NR 5 R 6 、-C(O)NR 5 R 6 、-CH 2 NHC(O)OR 4 、-CH 2 NR 5 R 6 or-S (O) r R 4 Is substituted by a substituent of (2);
alternatively, two R B Together with the attached carbon atom, form a-C (=o) -;
R 4 each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl group, heterocyclic group, aryl group, heteroaryl, =o, -C (O) R 7 、-C(O)OR 7 、-OC(O)R 7 、-NR 8 R 9 、-C(O)NR 8 R 9 、-SO 2 NR 8 R 9 or-NR 8 C(O)R 9 Is substituted by a substituent of (2);
R 5 and R is 6 Each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 7 、-C(O)OR 7 、-OC(O)R 7 、-NR 8 R 9 、-C(O)NR 8 R 9 、-SO 2 NR 8 R 9 or-NR 8 C(O)R 9 Is substituted by a substituent of (2);
alternatively, R 5 And R is 6 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 7 、-C(O)OR 7 、-OC(O)R 7 、-NR 8 R 9 、-C(O)NR 8 R 9 、-SO 2 NR 8 R 9 or-NR 8 C(O)R 9 Is substituted by a substituent of (2);
R 7 、R 8 and R is 9 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;
m is selected from 0, 1, 2, 3, 4 or 5; and is also provided with
r is 0, 1 or 2.
2. The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (II), (III), (IV), (V):
wherein: ring B, L, R 1 ～R 3 、R a 、R b And m is as defined in claim 1.
3. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from aryl, heteroaryl, heterocyclyl or fused ring, wherein said aryl, heteroaryl, heterocyclyl or fused ring is optionally further substituted with one or more substituents selected from alkyl, halogen, hydroxy, amino, hydroxyalkyl, =o, -P (O) R 5 R 6 、-S(O) r NR 5 R 6 or-S (O) r R 4 Is substituted by a substituent of (2);
wherein said R 4 、R 5 、R 6 Each independently selected from a hydrogen atom or an alkyl group; r is 0, 1 or 2.
4. A compound according to claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from the following groups:
5. a compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is selected as a bond.
6. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is selected from-C (O) -, -OC (O) -or-NR e C (O) -; wherein said R e Selected from hydrogen atoms or methyl groups.
7. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of:
8. a compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 Identical or different, each independently selected from hydrogen, alkyl, halogen, cyano, alkoxy, cycloalkyl, heterocyclyl or-C (O) NR 5 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with one or more R B Substituted; wherein said R 5 、R 6 Each independently selected from a hydrogen atom or an alkyl group;
alternatively, two R 2 Together with the attached carbon atom, form a-C (=o) -;
R B the same or different are each independently selected from alkyl, halogen, hydroxy, cyano, alkoxy, cycloalkyl or heterocyclyl, wherein said alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with one or more substituents selected from alkyl, halogen, cyano, hydroxy, amino, alkoxy, haloalkyl, hydroxyalkyl or haloalkoxy.
9. A compound according to any one of claims 6 to 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, whereinSelected from the following groups:
。
10. a compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3 Selected from amino or halogen.
11. A compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:
12. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
13. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the preparation of an HPK1 inhibitor.
14. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the treatment of a disease mediated by HPK1, wherein the disease mediated by HPK1 is preferably an inflammation, autoimmune disease or tumor, wherein the autoimmune disease is preferably systemic lupus erythematosus or psoriasis; wherein the tumor is preferably a hematological malignancy or a solid malignancy.
15. The use of claim 14, wherein the tumor is selected from the group consisting of acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer, and multiple myeloma.
16. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the treatment of inflammation, autoimmune diseases or neoplasms, wherein the autoimmune disease is preferably systemic lupus erythematosus or psoriasis; wherein the tumor is preferably a hematological malignancy or a solid malignancy.
17. The use of claim 16, wherein the tumor is selected from the group consisting of acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer, and multiple myeloma.
CN202210454533.1A 2022-04-27 2022-04-27 Pyrimidine ring derivative and preparation method and application thereof Pending CN117003734A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202210454533.1A CN117003734A (en) 2022-04-27 2022-04-27 Pyrimidine ring derivative and preparation method and application thereof
PCT/CN2023/090548 WO2023207960A1 (en) 2022-04-27 2023-04-25 Fused pyrimidine-based derivative, method for preparing same, and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210454533.1A CN117003734A (en) 2022-04-27 2022-04-27 Pyrimidine ring derivative and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN117003734A true CN117003734A (en) 2023-11-07

Family

ID=88517729

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210454533.1A Pending CN117003734A (en) 2022-04-27 2022-04-27 Pyrimidine ring derivative and preparation method and application thereof

Country Status (2)

Country Link
CN (1) CN117003734A (en)
WO (1) WO2023207960A1 (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111440189B (en) * 2015-04-24 2022-08-09 广州再极医药科技有限公司 Fused ring pyrimidine amino derivative, preparation method, intermediate, pharmaceutical composition and application thereof
CN112079830B (en) * 2019-06-14 2023-12-22 上海翰森生物医药科技有限公司 Inhibitor containing fused ring derivative, preparation method and application thereof
CN114555588A (en) * 2019-11-07 2022-05-27 南京正大天晴制药有限公司 Quinazolines as AXL inhibitors
WO2021139775A1 (en) * 2020-01-10 2021-07-15 江苏先声药业有限公司 Pyridone compound and application

Also Published As

Publication number Publication date
WO2023207960A1 (en) 2023-11-02

Similar Documents

Publication Publication Date Title
KR102058366B1 (en) Condensed pyrimidine compounds or salts thereof
CN115448923B (en) Pyrimidine-fused ring compound, preparation method and application thereof
CN114761394B (en) Pyridine or pyrimidine derivative and preparation method and application thereof
AU2009302360B2 (en) Imidazopyridazinecarbonitriles useful as kinase inhibitors
ES2902050T3 (en) 1,2-dihydro-3H-pyrazolo[3,4-D]pyrimidin-3-one derivative as Wee1 inhibitor
EP2464647B1 (en) Azaindazoles as btk kinase modulators and use thereof
AU2006295439B2 (en) Fused heterocyclic compounds useful as kinase modulators
CA3015484A1 (en) Novel condensed pyrimidine compound or salt thereof
CN111704611A (en) Aryl spiro SHP2 inhibitor compound, preparation method and application
EP2552922A1 (en) Substituted pyrrolotriazines as protein kinase inhibitors
EA021504B1 (en) 1-heterocyclyl-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one derivatives and their use as pde9a modulators
CA2693904A1 (en) Heterocyclic compounds useful as mk2 inhibitors
KR20190017959A (en) The α, β-unsaturated amide compound derived from benzotriazole, which is a TGF-βRI inhibitor
CN112292374B (en) Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof
CN112094269B (en) Saturated six-membered ring heterocyclic compound, preparation method and application
ES2962961T3 (en) Preparation procedure of n-(5-((4-(4-(dimethylamino)methyl)-3-phenyl-1h-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl )acrylamide by reacting the corresponding amine with a 3-halo-propionyl chloride
CN116546985A (en) Pyridopyrimidine derivative and preparation method and application thereof
CN114524810B (en) Pyrimidine heterocyclic compounds, preparation method and application
CA3117319A1 (en) Fused bicyclic heterocycles as thereapeutic agents
CN116323622A (en) Bicyclic heteroaryl derivatives, preparation method and application thereof
IL293107A (en) Adenosine receptor antagonist compounds
CN109384785B (en) Pyrrolopyridinone derivatives, preparation method and medical application thereof
JP6900406B2 (en) Dihydropyrazoloazepine compounds as Akt inhibitors
CN117003734A (en) Pyrimidine ring derivative and preparation method and application thereof
CN115960098A (en) Preparation method and application of nitrogen-containing fused ring compounds

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication