CN115772156A - Compound used as HPK1 kinase inhibitor and preparation method and application thereof - Google Patents
Compound used as HPK1 kinase inhibitor and preparation method and application thereof Download PDFInfo
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- CN115772156A CN115772156A CN202211453649.XA CN202211453649A CN115772156A CN 115772156 A CN115772156 A CN 115772156A CN 202211453649 A CN202211453649 A CN 202211453649A CN 115772156 A CN115772156 A CN 115772156A
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Abstract
Disclosure of the inventionA compound used as HPK1 kinase inhibitor, its preparation method and application are provided. Specifically, the invention provides a compound shown as a formula I, wherein the definition of each group is described in the specification. The compound has excellent HPK1 inhibition activity, so that the compound can be used for treating cancers and other HPK activity related diseases.
Description
Technical Field
The invention relates to a kinase inhibitor and a preparation method and application thereof, in particular to a compound used as an HPK1 kinase inhibitor and a preparation method and application thereof.
Background
Surgical resection, radiation therapy, chemotherapy, small molecule targeted drugs are the primary means for treating cancer, unfortunately, surgical resection is often not a viable option for many forms of cancer or tumors, and radiation therapy and chemotherapy, while killing tumor cells, also can damage healthy cells. In addition, the instability of tumor cell genome promotes the mutation of tumor cells, further resulting in the rapid change of cancer genome, which makes it resistant to drugs specifically targeting tumors, which makes the treatment of cancer difficult. In recent years, the killing of tumor cells by the cancer patient's own immune system and the improvement of the body's anti-tumor immunity have been a new strategy for cancer treatment. One approach is to suppress negative regulators of the immune response that maintain peripheral tolerance, allowing tumors to be recognized as non-self antigens, and thus overcoming the immune escape of tumor cells. Hematopoietic progenitor kinase (HPK 1) is one of the members of the plasminogen-activated protein kinase (MAP 4K) family, which also includes GCK/MAP4K2, GLK/MAP4K3, HGK/MAP4K4, KHS/MAP4K5, MINK/MAP4K6.HPK1 is a negative regulator of B cell, T cell and dendritic cell activation reaction, and the inhibition of the expression of the negative regulator can be used for pertinently improving the anti-tumor immunity of the organism, and is mainly expressed in hematopoietic cells, such as T cells, B cells, dendritic cells, macrophages, mast cells and neutrophils. In T cells, HPK1 regulates a role in T cell activation through the TCR signaling pathway. Following TCR activation, HPK1 interacts with T cell receptor proteins, is phosphorylated by tyrosine kinases Zap70 and Lck, and at the same time phosphorylates SLP-76 receptor protein, negatively regulating TCR signaling, thereby inhibiting T cell activation and proliferation. Research has found that HPK1 can participate in many signaling cascades, including the MAKP signaling pathway, the Fas-induced apoptosis pathway, and the NF- κ B signaling pathway. In addition, HPK1 can also inhibit AP-1 and AP-1 from promoting cell proliferation, inhibiting differentiation, promoting tumor cell invasion and metastasis, etc. during tumor formation and development. HPK1 kinase is not expressed in major organs, suggesting that HPK1 kinase inhibitors may not cause any serious complications.
At present, no medicine on the market exists for the target of hematopoietic progenitor cell kinase (HPK 1).
Disclosure of Invention
The purpose of the invention is as follows: the present invention aims to provide a compound useful as an HPK1 kinase inhibitor having selectivity and high activity; it is another object of the present invention to provide a process for the preparation of a compound useful as an inhibitor of HPK1 kinase; it is another object of the present invention to provide the use of a compound that is useful as an inhibitor of HPK1 kinase for the preparation of a pharmaceutical composition for the prevention or treatment of a disease responsive to inhibition of HPK1 activity in a subject.
The technical scheme is as follows: the invention relates to a compound shown as the following formula (I) or pharmaceutically acceptable salt, isomer or hydrate thereof:
wherein:
X 1 selected from the group consisting of: none, NR, O, S (O) t 、CHR、NRC(O)、C(O)NR、NRC(O)C(O)NR、NRC(O)NR、NRC(S)NR、NRC(O)NRCH 2 、NRC(S)NRCH 2 Wherein R is selected from the group consisting of: H. c 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or a 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S and O;
X 2 or X 3 Are independent of each otherIs selected from the group consisting of a 、O、S(O) t 、C(O)、CR 4 R 5 ；
Y is selected from NR a 、O、S(O) t Or CR 4 R 5 ；
M 1 、M 2 Or M 3 Each independently is CH or N; when said M is 1 、M 2 Or M 3 When is CH, the
Can be located at said M 1 、M 2 Or M 3 Upper (i.e. M) 1 、M 2 Or M 3 Is C);
ring A is selected from the group consisting of: H. c 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring composed of a 6-membered aromatic ring and a 5-7 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring composed of a 6-membered aromatic ring and a 5-7 membered aromatic heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring composed of a 6-membered heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O and a 5-7 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring composed of a 6-membered heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O and a 5-7-membered heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O;
R 1 、R 2 、R 3 and R 5 Each independently selected from the group consisting of: H. deuterium, halogen, OH, CN, NO 2 、C 1-6 Deuterated alkyl, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 6-10 Aryl, P (O) R 6 R 7 、S(O) 2 R 6 、S(O) 2 NR 6 R 7 、NR 6 R 7 、C(O)NR 6 R 7 、C(O)NR 6 S(O) 2 R 7 、NR 6 S(O) 2 R 7 、C(O)R 6 、NR 6 C(O)R 7 Having 1-3 heteroatoms selected from the group consisting of N, S, O, a 5-12 membered heteroaryl group, a 3-12 membered heterocyclyl group having 1-3 heteroatoms selected from the group consisting of N, S, O, wherein R is substituted with R 1 、R 2 、R 3 And R 5 The alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, NR 6 R 7 、C(＝O)NR 6 R 7 、C(＝O)NR 6 S(＝O) 2 R 7 、P(＝O)R 6 R 7 、S(＝O) 2 R 6 、S(＝O) 2 NR 6 R 7 、NR 6 S(＝O) 2 R 7 ；
R 4 Selected from the group consisting of: H. deuterium, C (O) C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl or C having 1-3 heteroatoms selected from the group N, S, O 3-12 Heterocyclyl, wherein R is 4 The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl radical, C 5-10 A heterocyclic radical and NR 6 R 7 ；
R a Selected from the group consisting of H, deuterium, C (O) C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl or 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S, O wherein R is substituted with R b The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 5-10 membered heterocyclic group and NR 6 R 7 ；
R 6 、R 7 Each independently is H or C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C having 1-3 heteroatoms selected from the group consisting of N, S and O 3-12 Heterocyclyl, wherein R is 6 Or R 7 The alkyl, cycloalkyl and heterocyclyl groups represented by the formula (I) may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-12 A heterocyclic group.
R 6 And R 7 Together with the same nitrogen or phosphorus atom to which they are attached may form C 3-12 Heterocyclyl, which may be substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Deuterated alkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 3-12 A heterocyclic group;
n is 1,2 or 3;
m is 1,2 or 3; and n + m is less than or equal to 4;
p and q are each independently 0, 1,2,3,4 or 5;
t is 0, 1 or 2;
further, the compound of formula (I) has any one of the structures shown in the following formulas:
wherein:
X 1 selected from the group consisting of: none, NR, O, S (O) t 、CHR、NRC(O)、C(O)NR、NRC(O)C(O)NR、NRC(O)NR、NRC(S)NR、NRC(O)NRCH 2 、NRC(S)NRCH 2 Wherein R is selected from the group consisting of: H. c 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl radicalsOr a 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S and O;
X 2 or X 3 Each independently selected from the group consisting of none, NR a 、O、S(O) t 、C(O)、CR 4 R 5 ；
M 2 Is CH or N; and when said M is 2 When is CH, the
Can be located at said M 2 Upper (i.e. M) 2 Is C);
ring A is selected from the group consisting of: H. c 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a 6 membered aromatic ring and a 5-7 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered aromatic ring and a 5-7 membered aromatic heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered aromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O and a 5-7 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O and a 5-7 membered heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O;
R 1 、R 2 、R 3 and R 5 Each independently selected from the group consisting of: H. deuterium, halogen, OH, CN, NO 2 、C 1-6 Deuterated alkyl, C 1-6 Alkyl radical, C 3-8 Cycloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 6-10 Aryl, P (O) R 6 R 7 、S(O) 2 R 6 、S(O) 2 NR 6 R 7 、NR 6 R 7 、C(O)NR 6 R 7 、C(O)NR 6 S(O) 2 R 7 、NR 6 S(O) 2 R 7 、C(O)R 6 、NR 6 C(O)R 7 5-12 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S, O, 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S, OWherein is represented by R 1 、R 2 、R 3 And R 5 The alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, NR 6 R 7 、C(＝O)NR 6 R 7 、C(＝O)NR 6 S(＝O) 2 R 7 、P(＝O)R 6 R 7 、S(＝O) 2 R 6 、S(＝O) 2 NR 6 R 7 、NR 6 S(＝O) 2 R 7 ；
R 4 Selected from the group consisting of: H. deuterium, C (O) C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl or C having 1-3 heteroatoms selected from the group N, S, O 3-12 Heterocyclyl, wherein R is 4 The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl radical, C 5-10 A heterocyclic radical and NR 6 R 7 ；
R a Selected from the group consisting of H, deuterium, C (O) C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl or 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S, O wherein R is substituted with R b The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 5-10 membered heterocyclic group and NR 6 R 7 ；
R 6 、R 7 Each independently is H or C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C having 1-3 heteroatoms selected from the group consisting of N, S and O 3-12 Heterocyclyl, wherein R is 6 Or R 7 The alkyl, cycloalkyl and heterocyclyl groups represented by the formula (I) may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-12 A heterocyclic group.
R 6 And R 7 Together with the same nitrogen or phosphorus atom to which they are attached may form C 3-12 Heterocyclyl, which may be substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Deuterated alkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl radical, C 3-12 A heterocyclic group;
n is 1,2 or 3;
m is 1,2 or 3; and n + m is less than or equal to 4;
p and q are each independently 0, 1,2,3,4 or 5;
t is 0, 1 or 2;
further, the compound of formula (I) has any one of the structures shown in the following formulas:
in another aspect, the present invention provides a method for preparing the above compound or a pharmaceutically acceptable salt, isomer or hydrate thereof, the method comprising:
the compound of formula I is obtained by carrying out reactions such as Suzuki coupling, copper catalytic coupling, deprotection and the like on a benzo 1,2,4-triazine compound.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds described above, or a pharmaceutically acceptable salt, isomer, or hydrate thereof, and a pharmaceutically acceptable excipient.
In another aspect, the present invention provides a use of the above-mentioned compound, or a pharmaceutically acceptable salt, isomer or hydrate thereof for preparing a pharmaceutical composition for preventing or treating a disease responsive to inhibition of HPK1 activity in a subject.
Further, the use includes a combination regimen of the above compound or its pharmaceutically acceptable salt, isomer or hydrate and other tumor immunotherapy agents selected from the group consisting of: small molecule compounds and antibodies (including but not limited to PD-1, PD-L1, CTLA-4, STING agonists, LAG3 antagonists, etc.), tumor targeting drugs, tumor vaccines, and radiation therapy regimens.
In another aspect, the present invention provides the use of a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, prodrug, solvate, ester, and deuterated compound thereof, in conjunction with CAR-T immunotherapy for the immunotherapy of cancer.
Further, the disease is cancer.
In another aspect, the present invention provides a use of the above compound, or a pharmaceutically acceptable salt, isomer, or hydrate thereof, in an HPK1 kinase inhibitor.
Since the compound of the present invention has a very good HPK1 kinase inhibitory activity, the compound of the present invention and various crystalline forms, pharmaceutically acceptable organic or inorganic salts, solvates or hydrates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of diseases and the like (e.g., cancer) associated with the activity or expression level of HPK1 kinase.
The pharmaceutical composition of the present invention comprises the compound of the present invention in a safe and effective amount range and a pharmaceutically acceptable carrier or excipient. Wherein the safe and effective amount refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
By "pharmaceutically acceptable carrier" is meant: one or more compatible liquid or solid fillers or gel substances, which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and between the compounds of the invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium ethylcellulose, sodium carboxymethylcellulose, cellulose acetate, etc.), gelatin, talc, calcium sulfate, solid lubricants (e.g., stearic acid, magnesium stearate), vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), colorants, polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tween R, wetting agents (e.g., sodium lauryl sulfate), flavoring agents, preservatives, stabilizers, antioxidants, pyrogen-free water, etc.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration include capsules, pills, tablets, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as dicalcium phosphate or sodium citrate, or with the following ingredients: (a) fillers or compatibilizers, for example: lactose, sucrose, starch, glucose, mannitol and silicic acid; (b) binders, such as: hydroxymethyl cellulose, gelatin, alginates, polyvinylpyrrolidone, gum arabic, and sucrose; (c) humectants, such as: glycerol; (d) disintegrants, for example: calcium carbonate, agar-agar, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary amine compounds; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example: kaolin; (i) Lubricants, for example, talc, solid polyethylene glycol, calcium stearate, magnesium stearate, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, capsules, dragees, pills and granules can be prepared using shells and coatings such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, suspensions, solutions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art, such as water or other solvents, solubilizing agents and emulsifiers, as known for example: ethanol, isopropanol, propylene glycol, ethyl acetate, ethyl carbonate, 1,3-butanediol, dimethylformamide, and oils, especially peanut oil, cottonseed oil, corn germ oil, olive oil, sesame oil, and castor oil or mixtures of these and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as emulsifying, wetting and suspending agents, flavoring, sweetening and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, for example: polyoxyethylene sorbitol and sorbitan esters, ethoxylated isostearyl alcohols, microcrystalline cellulose, agar and aluminum methoxide or mixtures of these and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or dispersion, anhydrous solutions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and diluents, non-aqueous carriers, solvents or vehicles include water, polyols, ethanol and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When administered in combination, the pharmaceutical composition further comprises one or more other pharmaceutically acceptable compounds. One or more of the other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with a compound of the invention.
When using pharmaceutical compositions, safe and effective amounts of the compounds of the invention are suitable for administration to a mammal (e.g., human) in need of treatment at dosages that are pharmaceutically accepted as effective dosages, for a human of 60kg body weight, the daily dosage will generally be in the range of 1 to 2000mg, preferably 20 to 500mg. Of course, the particular dosage will also take into account factors such as the health of the patient, the route of administration, and the like, which are within the skill of the skilled practitioner.
Has the advantages that: compared with the prior art, the invention has the following remarkable advantages: has excellent HPK1 inhibiting activity and may be used in preparing medicine composition for treating cancer and other HPK activity related diseases.
Detailed Description
The embodiment of the invention provides a compound shown as the following formula I:
wherein:
X 1 selected from the group consisting of: none, NR, O, S (O) t 、CHR、NRC(O)、C(O)NR、NRC(O)C(O)NR、NRC(O)NR、NRC(S)NR、NRC(O)NRCH 2 、NRC(S)NRCH 2 Wherein R is selected from the group consisting of: H. c 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or a 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S and O;
X 2 or X 3 Each independently selected from the group consisting of none, NR a 、O、S(O) t 、C(O)、CR 4 R 5 ；
Y is selected from NR a 、O、S(O) t Or CR 4 R 5 ；
M 1 、M 2 Or M 3 Each independently is CH or N; when said M is 1 、M 2 Or M 3 When is CH, the
Can be located at said M 1 、M 2 Or M 3 Upper (i.e. M) 1 、M 2 Or M 3 Is C);
ring A is selected from the group consisting of: H. c 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a 6 membered aromatic ring and a 5-7 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered aromatic ring and a 5-7 membered aromatic heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered aromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O and a 5-7 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O and a 5-7 membered heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O;
R 1 、R 2 、R 3 and R 5 Each independently selected from the group consisting of: H. deuterium, halogen, OH, CN, NO 2 、C 1-6 Deuterated alkyl, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 6-10 Aryl, P (O) R 6 R 7 、S(O) 2 R 6 、S(O) 2 NR 6 R 7 、NR 6 R 7 、C(O)NR 6 R 7 、C(O)NR 6 S(O) 2 R 7 、NR 6 S(O) 2 R 7 、C(O)R 6 、NR 6 C(O)R 7 5-12 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S, O, 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S, O, wherein R is substituted with one or more substituents selected from the group consisting of 1 、R 2 、R 3 And R 5 The alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, NR 6 R 7 、C(＝O)NR 6 R 7 、C(＝O)NR 6 S(＝O) 2 R 7 、P(＝O)R 6 R 7 、S(＝O) 2 R 6 、S(＝O) 2 NR 6 R 7 、NR 6 S(＝O) 2 R 7 ；
R 4 Selected from the group consisting of: H. deuterium, C (O) C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl or C having 1-3 heteroatoms selected from the group N, S, O 3-12 Heterocyclyl, wherein R is 4 The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl radical, C 5-10 A heterocyclic radical and NR 6 R 7 ；
R a Selected from the group consisting of H, deuterium, C (O) C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 1-6 Alkyl radical, C 3-8 Cycloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl or 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group N, S, O wherein R is substituted with R b The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 5-10 membered heterocyclic group and NR 6 R 7 ；
R 6 、R 7 Each independently is H or C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C having 1-3 heteroatoms selected from the group consisting of N, S and O 3-12 Heterocyclyl, wherein R is 6 Or R 7 The alkyl, cycloalkyl and heterocyclic groups represented by the formula (I) may be substituted by 1 to 3 substituents independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-12 A heterocyclic group.
R 6 And R 7 Together with the same nitrogen or phosphorus atom to which they are attached may form C 3-12 Heterocyclyl, which may be substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Deuterated alkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl radical, C 3-12 A heterocyclic group;
n is 1,2 or 3;
m is 1,2 or 3; and n + m is less than or equal to 4;
p and q are each independently 0, 1,2,3,4 or 5;
t is 0, 1 or 2;
in the compound of the formula I, each chiral center is in an R configuration or an S configuration.
Preferably, said X 1 、X 2 、X 3 、Y、M 1 、M 2 、M 3 、M 4 、M 5 、R、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R a N, m, p, q, t, are each independently the corresponding group in the specific compound in each example.
The compounds of the embodiments of the invention may act as HPK1 kinase inhibitors, and in preferred embodiments are selective inhibitors of HPK1 kinase.
Preparation of Compounds of formula I
The compounds of formula I of the present invention may be prepared by the following exemplary methods:
the compound of formula I is obtained by carrying out reactions such as Suzuki coupling, copper catalytic coupling, deprotection and the like on a benzo 1,2,4-triazine and 1,2,4-triazine compound.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Preparation of key intermediate 1 (3-amino-5-bromobenzo [ e ] [1,2,4] triazin-8-yl) carbamic acid tert-butyl ester
The method comprises the following steps: boc at room temperature 2 O (53.8g, 247mmol) was slowly added to a THF solution (150 ml) of 4-bromo-2-nitroaniline (12.6g, 57.95mmol) and DMAP (10.6g, 86.76mmol) and the temperature was raised to 70 ℃ for reaction for 3h. Cooling to room temperature, decompressing, concentrating, and purifying by column chromatography to obtain a light yellow compound (4-bromo-2-nitrophenyl) di-tert-butyl carbamate. MS (ESI) M/Z =418[ M + H ]] + 。
Step two: a solution of potassium tert-butoxide (5.2g, 46.4 mmol) in tetrahydrofuran (20 ml) was slowly added dropwise to a solution of di-tert-butyl (4-bromo-2-nitrophenyl) carbamate (2.42g, 5.8 mmol) and guanidine hydrochloride (1.11g, 11.6 mmol) in tetrahydrofuran (40 ml) at room temperature, the temperature was raised to 65 ℃ overnight for reaction, after completion of the reaction, the reaction mixture was cooled to room temperature, a saturated ammonium chloride solution was added thereto, ethyl acetate was extracted, and the organic phase was dried and sulfurizedDrying sodium salt, concentrating under reduced pressure, and purifying by column chromatography to obtain brilliant yellow target compound (3-amino-5-bromobenzo [ e ]][1,2,4]Triazin-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z =341[ M + H ]] + . Preparation of key intermediate 2.7-iodo-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline
The method comprises the following steps: adding 7-methoxy-1,2,3,4-tetrahydroisoquinoline (6 g, 33.85mmol) and concentrated nitric acid (3.46 g) in sequence into precooled trifluoroacetic acid (46 ml) at 0 ℃, stirring for 1h at 0 ℃, concentrating under reduced pressure, adjusting the pH to 10-11 by using 4N NaOH aqueous solution, extracting with DCM, drying the organic phase with anhydrous sodium sulfate, performing suction filtration, spin-drying, and purifying by column chromatography to obtain 6-methoxy-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.85g, 24.6%). MS (ESI) M/Z =209[ M + H ]] + 。
Step two: to a solution of 7-methoxy-6-nitro-1,2,3,4-tetrahydroisoquinoline (7.58g, 46.44mmo 1) in methanol (82 mL) at 0 ℃ was added 37% formaldehyde solution (23 mL), followed by stirring at 0 ℃ for 15 minutes, and NaBH was added in portions 4 (6.15 g), the mixture at room temperature stirring for 3h, using ice water (20 mL) quenching, using DCM extraction, organic phase with anhydrous sodium sulfate drying, suction filtration, spin drying, column chromatography purification to obtain 6-methoxy-2-methyl-7-nitro-1,2,3,4-four hydrogen isoquinoline. MS (ESI) M/Z =223[ M + H ]] + 。
Step three: adding Fe powder (13.2g, 237.60mmol) and hydrochloric acid (1 mL) into a solution of water (10 mL) and EtOH (90 mL) containing 7-methoxy-2-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline (8.8g, 39.6mmo 1), stirring at 60 ℃ for 3 hours, cooling to room temperature, filtering, washing the filter cake with methanol, washing the filtrate with saturated sodium bicarbonate, concentrating by organic phase pressure reduction, and purifying by column chromatography to obtain 6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine. MS (ESI) M/Z =193[ M + H ]] + 。
Step four: at room temperature, p-toluenesulfonic acid monohydrate (1.71g, 9 mmol) was added to a solution of 7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-amine (576.8mg, 3 mmol) in acetonitrile (14 ml)After cooling to 0 ℃, KI (1.25g, 7.5 mmmol) and NaNO were slowly added dropwise 2 (414mg, 6 mmol) in water (6 ml), reacted at this temperature for 2h and then slowly warmed to room temperature. Adding saturated sodium bicarbonate water solution, extracting with ethyl acetate, concentrating the organic phase under reduced pressure, and purifying by column chromatography to obtain the target product 7-iodo-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline. MS (ESI) M/Z =304[ M + H ]] + 。
Preparation of key intermediate 3.6-iodo-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline
Step one, step two, step three, step four: the operation process of the key intermediate 2 is the same, and 6-iodine-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline is prepared. MS (ESI) M/Z =193[ M + H ]] + 。
Key intermediate 4.8-iodo-9-methoxy-1, 3,4,6,11, 11a-hexahydro-2H-pyrido [1,2-b ] isoquinoline preparation
The step is the same as the operation process of the key intermediate 2, step four, 8-iodine-9-methoxyl-1, 3,4,6,11, 11a-hexahydro-2H-pyrido [1,2-b ] is prepared]An isoquinoline. MS (ESI) M/Z =344[ M ] +H] + 。
Preparation of key intermediate 5.6-fluoro-7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinoline
The method comprises the following steps: heat was added dropwise to a solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (900mg, 5.45mmol) in H2SO4 (9 mL) at 0 deg.C with potassium nitrate (578.47mg, 5.72mmol), reacted at 0 deg.C for 2H and poured into ice water, the precipitated solid was collected by filtration and dried under vacuum to afford 6-fluoro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (1.04g, 86%). MS (ESI) M/Z =221[ M + H ]] + 。
Step two: to a solution of 6-fluoro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (2.02g, 9.09mmol) in THF (200 mL) was added 1M BH3/THF (45.46mmol, 45.5 mL), stirred under reflux for 20 hours, carefully quenched with methanol (30 mL) under ice bath, the resulting solution was concentrated under vacuum, added 2N HC1 (50 mL), heated at 80 ℃ for 3 hours with ammonia water to adjust pH to 7-8, extracted with DCM, the organic phase was dried over anhydrous sodium sulfate, filtered with suction, and spin-dried to give 6-fluoro-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.89g, 100.00%). MS (ESI) M/Z =197[ M + H ]] + 。
Step three, step four and step five: the same operation process of the key intermediate 2 is adopted to prepare the 6-fluoro-7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinoline. MS (ESI) M/Z =292[ M + H ]] + 。
Key intermediate 6: preparation of 6-methoxy-2-methylisoindole-5-amine
The operation process is the same as that of the key intermediate 5, and 5-methoxyisoindol-1-one is used for replacing 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one. MS (ESI) M/Z =179[ M + H ]] + 。
Preparation of key intermediate 7.8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo [ d ] aza-7-amine
The steps are the same as the operation process of the key intermediate 6, and finally 8-methoxyl-3-methyl-2,3,4,5-tetrahydro-1H-benzo [ d ] aza-7-amine is prepared. MS (ESI) M/Z =207[ M + H ] +.
Preparation of key intermediate 8.3-iodo-2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine
The step is the same as the operation process of the key intermediate 2, step four, and 3-iodine-2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine is prepared. MS (ESI) M/Z =305[ M + H ]] + 。
Preparation of key intermediate 9.5- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -3,4-dihydroisoquinolin-1 (2H) -one
5-chloro-3,4-dihydroisoquinolin-1 (2H) -one (3.4g, 18.83mmol), dipinacolone diboron (23.93g, 94.22mmol), pd (dppf) Cl2 (II) (2.76g, 3.77mmol), and potassium acetate (5.55g, 56.62mmol) were added to 1,4-dioxane (2 mL) and stirred overnight at 100 ℃ under nitrogen. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -3,4-dihydroisoquinolin-1 (2H) -one. MS (ESI) M/Z =274[ M + H ]] + 。
Preparation of key intermediate 10.5- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -3,4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester
The step is the same as the operation process of the key intermediate 9, and the 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -3,4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester is prepared and obtained. MS (ESI) M/Z =360[ M + H ] +.
Example 1.5- (2-bromophenyl) -N 3 - (6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzo [ e][1,2,4]Triazine-3,8-diamine
The method comprises the following steps: dissolving key intermediate 1 (459mg, 1.35mmol) in a mixed solution of dioxane (21 ml) and water (3 ml), and adding 2-bromophenyl boronic acid (542mg, 2.7mm)ol)、Pd(dppf)Cl 2 (197mg, 0.27mmol) and sodium carbonate (429mg, 4.05mmol) under the protection of nitrogen, refluxing at 90 ℃ for 3h, cooling to room temperature, filtering with kieselguhr, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain (3-amino-5- (2-bromophenyl) benzo [ e][1,2,4]Triazin-8-yl) carbamic acid tert-butyl ester. MS (ESI) M/Z =417[ M + H ]] + 。
Step two: the (3-amino-5- (2-bromophenyl) benzo [ e) obtained in the previous step][1,2,4]Dissolving tert-butyl triazin-8-yl) carbamate (291.4 mg,0.7 mmol) in a mixed solution of toluene (4 ml) and tetrahydrofuran (0.8 ml), adding key intermediates 2 (212.1mmol, 0.7 mmol), cuprous iodide (136.5mg, 0.7 mmol), N' -dimethylethylenediamine (61.6 mg,0.7 mmol) and potassium phosphate (446 mg,2.1 mmol), refluxing at 110 ℃ for 24h under the protection of nitrogen, cooling to room temperature, suction-filtering with diatomaceous earth, spin-drying the filtrate under reduced pressure, and purifying by column chromatography to obtain 5- (2-bromophenyl) -N 3 - (6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzo [ e][1,2,4]Triazine-3,8-diamine. MS (ESI) M/Z =592[ M + H ]] + 。
Step three: to (5- (2-bromophenyl) -3- ((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino) benzo [ e][1,2,4]Triazin-8-yl) carboxylic acid tert-butyl ester (59.1mg, 0.1mmol) in dichloromethane (5 ml) trifluoroacetic acid (1 ml) was added and stirred at room temperature for 2h. Adding saturated sodium bicarbonate to adjust pH to neutral, extracting with dichloromethane for three times, mixing organic phases, spin-drying under reduced pressure, and purifying by column chromatography to obtain orange red target compound 5- (2-bromophenyl) -N 3 - (6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzo [ e][1,2,4]Triazine-3,8-diamine. MS (ESI) M/Z =492[ M ] +H] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),7.84(dd,J＝1.4,7.7Hz,1H),7.75(d,J＝8.3Hz,1H),7.66(dd,J＝1.2,7.8 Hz,1H),7.51(td,J＝1.3,7.6 Hz,1H),7.41–7.31(m,2H),7.01(d,J＝8.5 Hz,1H),6.61(t,J＝0.9 Hz,1H),5.71(s,2H),3.86(s,3H),3.68(dd,J＝1.0,13.6 Hz,1H),3.36(dd,J＝1.0,13.6Hz,1H),3.00–2.86(m,3H),2.75–2.63(m,1H),2.43(s,3H).
Biological Activity test example 1HPK1 ADP-Glo enzymatic Activity test
Preparing enzyme activity test buffer containing 40mM Tris, pH7.5;20mM MgC12;0.1mg/ml BSA;50uM DTT. The compounds were dissolved in pure DMSO at a stock concentration of 10mM. The compound DMSO solution is serially diluted in three times of gradient from 100uM to total 11 concentrations, the diluted compound is diluted by enzyme activity test buffer solution in a ratio of 1. Both negative and positive control wells were loaded with 1ul DMSO solution diluted in 1. 2.5 Xsubstrate/ATP working solution was prepared as enzyme activity assay buffer containing 45uM ATP and 0.25ug/ul MBP protein, 2.5 Xsubstrate/ATP working solution 2ul was added to each well. The prepared 2.5 Xenzyme reaction working solution is enzyme activity test buffer solution containing 0.5ng/ul of HPK1 recombinant protein (Signalchem, product number M23-11G-10), 2ul of the 2.5 Xenzyme reaction working solution is added into each working hole, and only 2ul of the enzyme activity test buffer solution is added into a negative control hole. After the reaction is finished, 5ul of ADP-Glo reagent (Promega, product number V1901) is added into each hole, the reaction is continued for 40 minutes at room temperature, 10ul of kinase detection reagent (Promega, product number V1901) is added, the reaction is continued for 20 minutes at room temperature, and then the final luminescence signal is measured.
The positive and negative well mean values were calculated as positive control value (Signalpos) and negative control value (Signalneg), respectively. The Inhibition rate of the working well signal value (Signaltest) was calculated according to the formula Inhibition rate = (Signalpos-Signaltest)/(Signalpos-Signalneg) × 100%. Calculated inhibition concentration-inhibition curves were plotted as a non-linear fit in GraphPad Prism software and IC50 values were calculated.
Biological Activity test example 2GLK ADP-Glo enzymatic Activity test
Preparing enzyme activity test buffer containing 40mM Tris, pH7.5;20mM MgC12;0.1mg/ml BSA;50uM DTT. The compounds were dissolved in pure DMSO at a stock concentration of 10mM. The compound DMSO solution is serially diluted in three times of gradient from 100uM to total 11 concentrations, the diluted compound is diluted by enzyme activity test buffer solution in a ratio of 1. Both negative and positive control wells were loaded with 1ul DMSO solution diluted in 1. 2.5 Xsubstrate/ATP working solution was prepared as enzyme activity assay buffer containing 105uM ATP and 0.5ug/ul PKA substrate polypeptide, 2ul of 2.5 Xsubstrate/ATP working solution was added to each working well. 2.5 Xenzyme reaction working solution containing 2.5ng/ul enzyme activity test buffer solution of GLK recombinant protein (Signalchem, product number M25-11G-10) is prepared, 2ul enzyme reaction working solution is added into each working well, and only 2ul enzyme activity test buffer solution is added into a negative control well. The plate-sealing membrane was attached and centrifuged, and the reaction mixture was reacted at room temperature for 1 hour, 5ul of ADP-Glo reagent (Promega, cat # V1901) was added to each well after the reaction was completed and reacted at room temperature for 40 minutes, followed by addition of 10ul of kinase detection reagent (Promega, cat # V1901) and reaction at room temperature for 20 minutes, and the final luminescence signal was measured.
The positive and negative well mean values were calculated as positive control value (Signalpos) and negative control value (Signalneg), respectively. The Inhibition rate of the working well signal value (Signaltest) was calculated according to the formula Inhibition rate = (Signalpos-Signaltest)/(Signalpos-Signalneg) × 100%. The calculated inhibition was plotted as a non-linear fit concentration-inhibition curve in GraphPad Prism software and the IC50 value was calculated. The results of the experiment are given in the following table:
TABLE 1HPK1, GLK enzyme activity test experiment results
Wherein A represents IC 50 The value is less than or equal to 50nM; b represents 50nM ≦ IC 50 The value is less than or equal to 500nM; c represents 500nM ≦ IC 50 The value is less than or equal to 10uM.
Claims (9)
1. A compound of the following formula (I) or a pharmaceutically acceptable salt, isomer or hydrate thereof:
wherein:
X 1 selected from the group consisting of: none, NR, O, S (O) t 、CHR、NRC(O)、C(O)NR、NRC(O)C(O)NR、NRC(O)NR、NRC(S)NR、NRC(O)NRCH 2 、NRC(S)NRCH 2 Wherein R is selected from the group consisting of: H. c 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or a 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S and O;
X 2 or X 3 Each independently selected from the group consisting of none, NR a 、O、S(O) t 、C(O)、CR 4 R 5 ；
Y is selected from NR a 、O、S(O) t Or CR 4 R 5 ；
M 1 、M 2 Or M 3 Each independently is CH or N; when said M is 1 、M 2 Or M 3 When is CH, the
Can be located at said M 1 、M 2 Or M 3 Upper (i.e. M) 1 、M 2 Or M 3 Is C);
ring A is selected from the group consisting of: H. c 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a 6 membered aromatic ring and a 5-7 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered aromatic ring and a 5-7 membered aromatic heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered aromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O and a 5-7 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O and a 5-7 membered heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O;
R 1 、R 2 、R 3 and R 5 Each independently selected from the group consisting of: H. deuterium, halogen, OH, CN, NO 2 、C 1-6 Deuterated alkyl, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 6-10 Aryl, P (O) R 6 R 7 、S(O) 2 R 6 、S(O) 2 NR 6 R 7 、NR 6 R 7 、C(O)NR 6 R 7 、C(O)NR 6 S(O) 2 R 7 、NR 6 S(O) 2 R 7 、C(O)R 6 、NR 6 C(O)R 7 5-12 membered heteroaryl having 1-3 heteroatoms selected from the group N, S, O, 1-3 heteroatoms selected from the group N, S, O3-12 membered heterocyclic group of (a), wherein R is 1 、R 2 、R 3 And R 5 The alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, NR 6 R 7 、C(＝O)NR 6 R 7 、C(＝O)NR 6 S(＝O) 2 R 7 、P(＝O)R 6 R 7 、S(＝O) 2 R 6 、S(＝O) 2 NR 6 R 7 、NR 6 S(＝O) 2 R 7 ；
R 4 Selected from the group consisting of: H. deuterium, C (O) C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl or C having 1-3 heteroatoms selected from the group N, S, O 3-12 Heterocyclyl, wherein R is 4 The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl radical, C 5-10 Heterocyclic radical and NR 6 R 7 ；
R a Selected from the group consisting of H, deuterium, C (O) C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl or 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S, O wherein R is substituted with R b The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 5-10 membered heterocyclic group and NR 6 R 7 ；
R 6 、R 7 Each independently is H or C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C having 1-3 heteroatoms selected from the group consisting of N, S and O 3-12 Heterocyclyl, wherein R is 6 Or R 7 The alkyl, cycloalkyl and heterocyclyl groups represented by the formula (I) may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-12 A heterocyclic group.
R 6 And R 7 Together with the same nitrogen or phosphorus atom to which they are attached may form C 3-12 Heterocyclyl, which may be substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Deuterated alkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 3-12 A heterocyclic group;
n is 1,2 or 3;
m is 1,2 or 3; and n + m is less than or equal to 4;
p and q are each independently 0, 1,2,3,4 or 5;
t is 0, 1 or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, or hydrate thereof, wherein the compound of formula (I) has any of the following structures:
wherein:
X 1 selected from the group consisting of: none, NR, O, S (O) t 、CHR、NRC(O)、C(O)NR、NRC(O)C(O)NR、NRC(O)NR、NRC(S)NR、NRC(O)NRCH 2 、NRC(S)NRCH 2 Wherein R is selected from the group consisting of: H. c 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S and O;
X 2 or X 3 Each independently selected from none, NR a 、O、S(O) t 、C(O)、CR 4 R 5 ；
M 2 Is CH or N; and when said M is 2 When is CH, the
Can be located at said M 2 Upper (i.e. M) 2 Is C);
ring A is selected from the group consisting of: H. c 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 An aromatic ring, a 5-10 membered aromatic heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a 6 membered aromatic ring and a 5-7 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered aromatic ring and a 5-7 membered aromatic heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered aromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O and a 5-7 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S, O, a fused ring consisting of a 6 membered heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O and a 5-7 membered heteroaromatic ring having 1-3 heteroatoms selected from the group consisting of N, S, O;
R 1 、R 2 、R 3 and R 5 Each independently selected from the group consisting of: H. deuterium, halogen, OH, CN, NO 2 、C 1-6 Deuterated alkyl, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 6-10 Aryl, P (O) R 6 R 7 、S(O) 2 R 6 、S(O) 2 NR 6 R 7 、NR 6 R 7 、C(O)NR 6 R 7 、C(O)NR 6 S(O) 2 R 7 、NR 6 S(O) 2 R 7 、C(O)R 6 、NR 6 C(O)R 7 5-12 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S, O, 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S, O, wherein R is substituted with one or more substituents selected from the group consisting of 1 、R 2 、R 3 And R 5 The alkyl, alkenyl, alkynyl, alkoxy, phenyl, heteroaryl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, NR 6 R 7 、C(＝O)NR 6 R 7 、C(＝O)NR 6 S(＝O) 2 R 7 、P(＝O)R 6 R 7 、S(＝O) 2 R 6 、S(＝O) 2 NR 6 R 7 、NR 6 S(＝O) 2 R 7 ；
R 4 Selected from the group consisting of: H. deuterium, C (O) C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl or C having 1-3 heteroatoms selected from the group N, S, O 3-12 Heterocyclyl, wherein R is 4 The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl radical, C 5-10 A heterocyclic radical and NR 6 R 7 ；
R a Selected from the group consisting of H, deuterium, C (O) C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl or 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S, O wherein R is substituted with R b The alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl group in the group represented may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 5-10 membered heterocyclic group and NR 6 R 7 ；
R 6 、R 7 Each independently is H or C 1-6 Alkyl radical, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, C having 1-3 heteroatoms selected from the group consisting of N, S and O 3-12 Heterocyclyl, wherein R is 6 Or R 7 The alkyl, cycloalkyl and heterocyclyl groups represented by the formula (I) may be substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-12 A heterocyclic group.
R 6 And R 7 Together with the same nitrogen or phosphorus atom to which they are attached may form C 3-12 Heterocyclyl, which may be substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, OH, CN, NO 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Deuterated alkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl radical, C 3-12 A heterocyclic group;
n is 1,2 or 3;
m is 1,2 or 3; and n + m is less than or equal to 4;
p and q are each independently 0, 1,2,3,4 or 5;
t is 0, 1 or 2.
3. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, or hydrate thereof, wherein the compound of formula (I) has any of the following structures:
4. a process for preparing a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isomer or hydrate thereof, which comprises:
the compound of formula I is obtained by carrying out reactions such as Suzuki coupling, copper catalytic coupling, deprotection and the like on a benzo 1,2,4-triazine compound.
5. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of any one of claims 1-3, or a pharmaceutically acceptable salt, isomer, or hydrate thereof, and a pharmaceutically acceptable excipient.
6. Use of a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, isomer, or hydrate thereof, for the manufacture of a medicament for preventing or treating a disease responsive to inhibition of HPK1 activity in a subject.
7. The use according to claim 6, wherein said use comprises a regimen of combined use of said compound or a pharmaceutically acceptable salt, isomer or hydrate thereof with a further tumour immunosuppressive agent selected from the group consisting of: small molecular compound and antibody, tumor targeting medicine, tumor vaccine and radiotherapy scheme.
8. Use of a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, isomer, or hydrate thereof, in combination with CAR-T immunotherapy for the preparation of a medicament for the immunization of cancer.
9. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isomer or hydrate thereof, in an HPK1 kinase inhibitor.
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| CN114853730A (en) * | 2022-05-27 | 2022-08-05 | 中国药科大学 | Compound used as HPK1 kinase inhibitor and preparation method and application thereof |
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