WO2023083299A1 - Composé cyclique fusionné utilisé en tant qu'inhibiteur de hpk1 - Google Patents

Composé cyclique fusionné utilisé en tant qu'inhibiteur de hpk1 Download PDF

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WO2023083299A1
WO2023083299A1 PCT/CN2022/131366 CN2022131366W WO2023083299A1 WO 2023083299 A1 WO2023083299 A1 WO 2023083299A1 CN 2022131366 W CN2022131366 W CN 2022131366W WO 2023083299 A1 WO2023083299 A1 WO 2023083299A1
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heterocycloalkyl
cycloalkyl
alkylene
heteroaryl
och
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PCT/CN2022/131366
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Chinese (zh)
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谢雨礼
刘文中
钱立晖
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微境生物医药科技(上海)有限公司
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    • 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
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more specifically relates to a class of fused ring compounds with HPK1 kinase inhibitory effect, a preparation method thereof and the use of such compounds in the preparation of medicines for treating or preventing related diseases mediated by HPK1 use.
  • T cell receptor (TCR)-mediated T cell activation plays a crucial role in the development of thymic T cells, the differentiation of T cell subsets, and the function of effector T cells.
  • TCR can specifically recognize antigenic peptides presented by MHC on the surface of antigen-presenting cells, and convert extracellular antigenic peptides into signals that can be transmitted to the inside of cells through MHC (major histocompatibility complex) recognition.
  • MHC molecules on the surface of antigen-presenting cells include MHC class I molecules and MHC class II molecules, which can be specifically recognized by the corresponding co-receptors CD8 and CD4 molecules on the surface of CD8+ and CD4+ cells, respectively, and can subsequently cause the activation of downstream signaling pathways.
  • Typical intracellular signals activated by TCR include MAPK (mitogen-activated protein kinase), PKC (protein kinase C, protein kinase C) and Calcium (calcium ion) and other signaling pathways. Activation of these signals ultimately activates specific gene expression of T cells, causes cell proliferation, and allows T cells to differentiate into effector T cells.
  • MAPK mitogen-activated protein kinase
  • PKC protein kinase C, protein kinase C
  • Calcium calcium ion
  • HPK1 also known as MAP4K1
  • MAP4K1 is a serine/threonine kinase as a member of the MAP4K family.
  • MAP3K2 MAP4K4, MAP4K5, MAK4K6
  • HPK1 can bind to many adapter proteins, such as SLP-76 family, HIS, HIP-55, GRC2 family, LAT, CRK, etc. Interact and activate the JNK/SAPK signaling pathway of hematopoietic stem cells, thereby negatively regulating the TCR pathway.
  • MAP4K3 is also known as GLK kinase, and its biological role is just opposite to that of HPK1. GLK can promote the activation of TCR pathway by binding to downstream proteins. Therefore, we need to screen for HPK1 inhibitors that are selective for GLK.
  • HPK1 The main process of HPK1 participating in the regulation of TCR is: (1) TCR binds to extracellular antigens through MHC, thereby activating the TCR pathway to transmit signals to the adapter protein; (2) the adapter protein tyrosine kinase Lck and Zap70 activate SLP-76 , and then phosphorylate HPK1; (3) activated HPK1 will then phosphorylate the receptor protein SLP-76; (4) the phosphorylation reaction of SLP-76 provides multiple (5) The SLP-76 phosphorylated complex participates in the downregulation of the Erk signaling pathway, and is connected to the ubiquitination degradation process of SLP-76, thereby leading to the TCR signaling pathway and T cell proliferation decline.
  • HPK1 can negatively regulate the TCR signaling pathway. Therefore, HPK1 can serve as a new regulatory mechanism of T cell-mediated immune response and become a new immune anti-tumor target.
  • HPK1 inhibitors can be used in malignant solid tumors or hematological tumors (such as acute myeloid leukemia, bladder cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, melanoma, etc.), autoimmune diseases (such as systemic lupus erythematosus, psoriasis, arthritis, etc.) and inflammatory response play an important role.
  • malignant solid tumors or hematological tumors such as acute myeloid leukemia, bladder cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, melanoma, etc.
  • autoimmune diseases Such as systemic lupus erythematosus, psoriasis, arthritis, etc.
  • inflammatory response play an important role.
  • HPK1 high selective and highly active HPK1 inhibitors.
  • the new structure provided by the invention has good selectivity, physical and chemical properties and druggability sex.
  • the present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • R 1 is selected from -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO 2 R a , -S(O ) p R a , -S(O) p NR a R b , -CONR a R b , -NR a COR b , -NR a CO 2 R b , -NR a S(O) p R b , (C1- C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3- 14 yuan) heterocycloalkyl, (C6-C14) aryl or (5-14 yuan) heteroaryl, where
  • Ring B is (C5-C11) partially unsaturated cycloalkyl or (5-11 membered) partially unsaturated heterocycloalkyl;
  • X 2 is a chemical bond
  • X 3 is NR a or CH-R b ;
  • R 2a and R 2b , R 2b and R 2c or R 2a and R 2c form (3-12 membered) heterocycloalkyl together with one or more atoms they are connected to, wherein the (3-12 membered) Heterocycloalkyl can be optionally substituted by 1, 2, 3 or 4 R ;
  • R 2a , R 2b and R 2c are each independently -H, (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, ( C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-14) heterocycloalkyl, (C6-C14) aryl, (5-14) heteroaryl, -(C1-C8 )alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14)heterocycloalkyl,-(C1-C8)alkylene-(C6-C14) Aryl or -(C1-C8)alkylene-(5-14 member)heteroaryl;
  • R 3a and R 3b , R 3b and R 3c or R 3a and R 3c form (3-12 membered) heterocycloalkyl together with one or more atoms they are connected to, wherein the (3-12 membered) Heterocycloalkyl can be optionally substituted by 1, 2, 3 or 4 R ;
  • R 3a , R 3b and R 3c are each independently -H, (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, ( C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-14) heterocycloalkyl, (C6-C14) aryl, (5-14) heteroaryl, -(C1-C8 )alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14)heterocycloalkyl,-(C1-C8)alkylene-(C6-C14) Aryl or -(C1-C8)alkylene-(5-14 member)heteroaryl;
  • R 2 adjacent R 2 and the atoms they are connected to can jointly form a (5-7 member) heterocycloalkyl or (C3-C9) cycloalkyl, the (5-7 member) heterocycloalkyl or
  • Each (C3-C9) cycloalkyl group is independently optionally substituted by 1, 2, 3 or 4 R c ;
  • the two R2 on the same carbon atom on the B ring and the carbon atoms they are connected to can jointly form a (4-7 member) heterocycloalkyl or (C3-C6) cycloalkyl, the (4-7 Yuan) heterocycloalkyl or (C3-C6) cycloalkyl can be independently optionally substituted by 1, 2, 3 or 4 R c ;
  • R 2 and an adjacent R 3 and the atoms they are connected to can jointly form a (5-7 member) heterocycloalkyl or (C3-C9) cycloalkyl group, the (5-7 member) heterocycloalkane
  • the group or (C3-C9) cycloalkyl group is each independently optionally substituted by 1, 2, 3 or 4 R c ;
  • R on X 2 and adjacent R 3 and the atoms they are connected to can jointly form a (5-7 member) heterocycloalkyl or (C3-C9) cycloalkyl group, the (5-7 member) Heterocycloalkyl or (C3 - C9 ) cycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R c ; (5-7 membered) heterocycloalkyl or (C3-C9) cycloalkyl, said (5-7 member) heterocycloalkyl or (C3-C9) cycloalkyl each independently optionally by 1,2 , 3 or 4 R c substitutions; or R a and R b connected to the same carbon atom can form an oxo group;
  • R xa , R xb and R xc are each independently -H, (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2- C8) alkynyl, (C3-C14) cycloalkyl, (3-14) heterocycloalkyl, (C6-C14) aryl, (5-14) heteroaryl, -(C1-C8) Alkyl-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14 membered)heterocycloalkyl,-(C1-C8)alkylene-(C6-C14)aryl Or - (C1-C8) alkylene - (5-14 yuan) heteroaryl;
  • R 4a , R 4b and R 4c are each independently -H, (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2- C8) alkynyl, (C3-C14) cycloalkyl, (3-14) heterocycloalkyl, (C6-C14) aryl, (5-14) heteroaryl, -(C1-C8) Alkyl-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14 membered)heterocycloalkyl,-(C1-C8)alkylene-(C6-C14)aryl Or - (C1-C8) alkylene - (5-14 yuan) heteroaryl;
  • R 4a and R 4b , R 4b and R 4c or R 4a and R 4c together with one or more atoms they are connected to form a (3-12 member) heterocycloalkyl group, wherein the (3-12 member ) heterocycloalkyl can be optionally substituted by 1, 2, 3 or 4 R 4e ;
  • R 4f , R 4g , R 4h , R 4i and R 4j are each independently -H, (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) Alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-14) heterocycloalkyl, (C6-C14) aryl or (5-14) heteroaryl;
  • n 0, 1 or 2;
  • q 0, 1, 2, 3 or 4;
  • n and p are 0, 1 or 2 each independently.
  • R 1 is -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO 2 R a , -S(O) p R a , -S(O) p NR a R b , -CONR a R b , -NR a COR b , -NR a CO 2 R b , -NR a S(O) p R b , (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, ( C2-C6) alkynyl, (C3-C12) cycloalkyl, (3-12 yuan) heterocycloalkyl, (C6-C10) aryl or (5-12
  • R 1 is -H, -D, halogen, -CN, -NH 2 , -NO 2 , -CONR a R b , (C1 -C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C2-C4)alkenyl.
  • R 1 is -H, -D, -F, -Cl, -Br, -I, -CN, -NH 2 , -NO 2 , -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , -CF 3 , -C(O)NH 2 or R 1 is preferably -F, -Cl, -CN, -NO 2 , -CF 3 or -C(O)NH 2 ; R 1 is more preferably -Cl.
  • X 2 is: a chemical bond
  • each R is independently -H, -D, -F, -Cl, -Br, -I, -OH, -NH 2 , -NO 2 , -C(O)R 2a , -OR 2a , -NR 2a R 2b , -CN, -CONR 2a R 2b , -NR 2a COR 2b , -NR 2a S(O) p R 2b , -S(O) p R 2a , -S(O) p NR 2a R 2b , (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C2-C4) Alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, phenyl, (4-8 member) heterocycloalkyl or (5-6 member) heteroaryl, wherein
  • each R 2 is independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 , -CH 2 N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -N(CH 3 ) 2 , -CN, -C(O)CH 3 , -C(O)NH 2 , - C(O)NH(CH 3 ), -C(O)N(CH 3 ) 2 , -NHC(O)CH 3 , -N(CH 3 )-C(O)CH 3 , -NHS(O) 2 CH 3 , -NCH 3 S(O) 2 CH 3 , -SCH 3 , -S(O) 2 CH 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S (O) 2 N(CH 3 ), -S (O) 2 N(
  • R 3 is -H, -D, -CH 3 , -OCH 3 or -CH 2 CH 3 ;
  • R 3 is preferably -H, -D or -CH 3 ;
  • R 3 is more preferably -H or -CH 3 .
  • R 4 is: -H, -D, -F, -Cl, -Br, -I, -OH, -CH 3 , - CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , -CH 2 N(CH 3 ) 2 , -(CH 2 ) 2 N(CH 3 ) 2 , -N(CH 3 ) 2 , or -CN; R 4 is preferably -H, -F or -OCH 3 ; R 4 is more preferably -H or -OCH 3 .
  • R 5 is: -H, -D, -F, -Cl, -Br, -I, -OH, -CH 3 , - CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , -CH 2 N(CH 3 ) 2 , -(CH 2 ) 2 N(CH 3 ) 2 , -N(CH 3 ) 2 , or -CN; R 5 is preferably -H, -F or -OCH 3 ; R 5 is more preferably -H or -OCH 3 ; R 5 is more preferably -H.
  • two R 6 when When it represents a single bond and m is 2, two R 6 can be connected to 2 different carbon atoms or connected to the same carbon atom; 2 R 6 can be the same or different; those connected to the same carbon atom 2 R 6 and the carbon atoms to which they are attached can jointly form (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl, the (4-7 member) heterocycloalkyl or (C3- C6) cycloalkyl can each independently be optionally substituted by 1, 2, 3 or 4 R c .
  • R 6 is -H, -D, -F, -Cl, -Br, -I, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, Or two R 6 connected to the same carbon atom and the carbon atom they are connected to can jointly form R 6 is preferably -H, -F, -Cl, -CH 3 , -CH 2 OH, R 6 is more preferably -H, -CH 3 ,
  • R 7 is -H, -D, -F, -Cl, -Br, -I, -CHF 2 , -CF 3 , - OCH 3 or R 7 is preferably -H, -D, -F, -Cl, -Br, -I, -CHF 2 , -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 or R 7 is more preferably -H, -F, -Cl, -Br, -CHF 2 , -OCH 3 or R 7 is more preferably -H or -F.
  • the compound of general formula (1) has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.
  • Another object of the present invention provides the compound represented by the general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition Use for preparing medicines for treating, regulating or preventing diseases related to HPK1 protein kinase.
  • said disease is preferably cancer, and said cancer is hematological cancer and solid tumor.
  • Another object of the present invention is to provide a method for treating, regulating or preventing related diseases mediated by HPK1 protein kinase, comprising administering a therapeutically effective amount of the compound represented by the general formula (1) of the present invention to the subject, or Its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical compositions.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below.
  • the compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.
  • the present invention also provides a preparation method of the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following general reaction scheme 1 or 2:
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 , X 3 , m, The n, q, B rings are as defined herein above.
  • compound 1-1 reacts with compound 1-2 under basic conditions to obtain compound 1-3
  • compound 1-3 reacts with IntB under appropriate conditions to obtain target compound (1).
  • the embodiment of the compound of general formula (1) can also be prepared according to general reaction scheme 2, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 , X 3 , R a , m, n, q, B rings are as defined herein above.
  • compound 1-1 is reacted with compound IntA under basic conditions to obtain compound 2-4
  • compound 2-4 is reacted with IntB under appropriate conditions to obtain compound 2-5
  • compound 2-5 is further subjected to
  • the target compound (1) can be obtained by transformation of appropriate functional groups.
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.
  • the term "pharmaceutically acceptable salt” refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and that does not abolish the biological activity and properties of the compound.
  • the pharmaceutically acceptable salt is obtained by reacting the compound of general formula (1) with an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and other inorganic acids, formic acid, acetic acid , propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • an acid such as hydrochloric acid, hydrobromic acid, hydro
  • references to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.
  • compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms.
  • the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.
  • the compounds of general formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomeric forms, and cis-trans isomeric forms occur.
  • Each chiral center or axial chirality will independently give rise to two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.
  • alkyl means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 )CH, iPr , nPr , iBu , nBu or tBu .
  • alkylene refers to a divalent alkyl group as defined above.
  • alkylene groups include, but are not limited to, methylene and ethylene.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing carbon-carbon double bonds, including straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl, are preferred.
  • alkenylene means a divalent alkenyl group as defined above.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms.
  • alkynylene means a divalent alkynyl group as defined above.
  • cycloalkyl means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic.
  • cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of cycloalkyl groups can be optionally oxidized to form oxo or sulfide groups. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinenyl, norcarpanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.
  • cycloalkylene refers to a divalent cycloalkyl group as defined above.
  • alkoxy means an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxyl.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.
  • aryl refers to a hydrocarbon aromatic group, aryl is monocyclic or polycyclic, eg a monocyclic aryl ring fused with one or more carbocyclic aromatic groups.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.
  • aryloxy refers to an aryl group bonded to the rest of the molecule through an ether oxygen atom.
  • Examples of aryloxy include, but are not limited to, phenoxy and naphthyloxy.
  • arylene refers to a divalent aryl group as defined above.
  • arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl is monocyclic or polycyclic.
  • a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrole[2,3-c]pyridinyl, 1H-pyrrole[3,2-c]pyridinyl, 1H- Pyrrolo[2,3-b]pyridyl,
  • heteroarylene refers to a divalent heteroaryl group as defined above.
  • heterocycloalkyl means a non-aromatic ring or ring system which may optionally contain as part of the ring structure one or more alkenylene groups having at least one group independently selected from boron, phosphorus, , nitrogen, sulfur, oxygen, and phosphorus heteroatom ring members.
  • a partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl” if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond. may be referred to as a "heterocycloalkynyl".
  • Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (eg, having two fused or bridged rings) ring systems.
  • heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally oxidized to form oxo or sulfide groups or other oxidized linkages (e.g., C(O), S(O), C(S), or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized.
  • a heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom.
  • heterocycloalkyl groups contain 0 to 3 double bonds.
  • heterocycloalkyl groups contain 0 to 2 double bonds.
  • moieties also known as partially unsaturated heterocycles
  • having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring such as piperidine, Benzo derivatives of morpholine, azepine or thienyl, etc.
  • a heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of a fused aromatic ring.
  • heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuryl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5
  • heterocycloalkylene refers to a divalent heterocycloalkyl group as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen substitution
  • appearing before the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Substituted by F or Cl.
  • the substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • membered ring includes any ring structure.
  • member is meant to indicate the number of skeletal atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • acceptable means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
  • treatment includes alleviating, suppressing or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
  • Active ingredient refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound wait.
  • the present invention provides a method of using the compound of general formula (1) or the pharmaceutical composition of the present invention to treat diseases, including but not limited to conditions related to HPK1 protein kinase (such as cancer).
  • a method for treating cancer comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1) to an individual in need thereof.
  • the cancer is associated with HPK1 protein kinase.
  • the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer , head and neck cancer, stomach cancer, mesothelioma or all cancer metastases.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts .
  • safe and effective amount refers to: the amount of the compound is sufficient to obviously improve the condition without producing serious side effects.
  • the safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity .
  • “Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil,
  • the compounds of the present invention When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants , for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, for example paraffin; (f ) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol,
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in ⁇ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
  • Embodiment 2-17 the synthesis of compound 2-17
  • Example 18-19 1-(5-chloro-2-((2-methyl-2,3,7,8,9,9a-hexahydro-1H-benzo[de]isoquinolin-5-yl )amino)pyrimidin-4-yl)-1H-indole-3-carboxylic acid (compound 18) and 1-(5-chloro-2-((2-methyl-2,3,7,8,9, Synthesis of 9a-hexahydro-1H-benzo[de]isoquinolin-5-yl)amino)pyrimidin-4-yl)-1H-indole-3-carboxamide (compound 19)
  • the target compounds 51-109 in Table 3 can be obtained.
  • HPK1 human HPK1
  • MBP MBP
  • ATP Promega HPK1 Kinase Assay
  • HPK1 Kinase Buffer 40mM Tris, 7.5; 20mM MgCl2; 0.1mg/mL BSA; 50 ⁇ M DTT.
  • dose-response-arranged inhibitors (10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, 0 ⁇ m, eight gradients) from the DMSO stock solution. The reaction was allowed to proceed for 2.5 hours at 25°C. Detection was performed using ADP-Glo reagent. Luminescence was measured on a plate reader, the data fitted, and IC50 calculated from the data. The results are shown in Table 4 below.
  • IL-2 produced by Jurkat T cells activated by CD3/CD28 antibody (ImmunoCult TM Human CD3/CD28T Cell Activator 10971) was affected by the added compound, and judged that it inhibited the HPK1 pathway in T cells.
  • CD3/CD28 antibody ImmunoCult TM Human CD3/CD28T Cell Activator 10971
  • Embodiment 111 In vivo pharmacokinetic experiment of the compound of the present invention
  • the animals in the intravenous group were given the corresponding compound through a single injection of the tail vein, and the administration volume was 10 mL/kg; the animals in the oral group were given the corresponding compound through a single intragastric injection, and the administration volume was 10 mL/kg.
  • the animals were weighed before administration, and the administration volume was calculated according to the body weight. Sample collection times were: 0.083, 0.167, 0.5, 1, 2, 4, 8 and 24h.
  • Approximately 200 ⁇ L of whole blood was collected through the orbital venous plexus at each time point and used to prepare plasma for concentration determination by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • the plasma concentration was processed by the non-compartmental model of Winnolin pharmacokinetic software, and the pharmacokinetic parameters were calculated by the linear logarithmic trapezoidal method.
  • mice Select female BALB/c or C57BL6N mice (6 weeks, 18-22g), mouse colon cancer CT26 or MC38 cells were routinely cultured in 1640 containing 10% fetal bovine serum in a 37°C, 5% CO2 incubator, after passage , when the cells reached the desired amount, the cells were collected.
  • 1 ⁇ 106 CT26 or MC38 were subcutaneously injected to form tumors. After the tumors grew to about 100mm3 , the animals were randomly divided into solvent control group, test compound single drug group, test compound + The PD-1 combined group and the PD-1 single drug group were administered afterward. Tumor volume was measured with calipers on days 3, 7, 10, 14, 17 and 21 after administration.
  • TGI tumor growth inhibition

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Abstract

L'invention concerne un composé cyclique fusionné utilisé en tant qu'inhibiteur de HPK1. Spécifiquement, la présente invention concerne un composé représenté par la formule générale (1) et un procédé de préparation associé, et des utilisations du composé de formule générale (1) et d'isomères, de formes cristallines, de sels, d'hydrates ou de solvates pharmaceutiquement acceptables de celui-ci en tant qu'inhibiteur de HPK1. Le composé et les isomères, les formes cristallines, les sels pharmaceutiquement acceptables, les hydrates ou les solvates de ceux-ci peuvent être utilisés pour préparer des médicaments pour le traitement ou la prévention de maladies associées médiées par HPK1.
PCT/CN2022/131366 2021-11-12 2022-11-11 Composé cyclique fusionné utilisé en tant qu'inhibiteur de hpk1 WO2023083299A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110402248A (zh) * 2017-03-15 2019-11-01 豪夫迈·罗氏有限公司 作为hpk1抑制剂的氮杂吲哚类
WO2021000935A1 (fr) * 2019-07-04 2021-01-07 Qilu Regor Therapeutics Inc. Inhibiteurs de hpk1 et leurs utilisations
WO2021013083A1 (fr) * 2019-07-17 2021-01-28 Beigene, Ltd. Composés tricycliques utilisés en tant qu'inhibiteurs de hpk1 et leur utilisation
WO2021213317A1 (fr) * 2020-04-20 2021-10-28 微境生物医药科技(上海)有限公司 Inhibiteur de hpk1, son procédé de préparation et son utilisation
WO2022174765A1 (fr) * 2021-02-19 2022-08-25 微境生物医药科技(上海)有限公司 Composé cyclique fusionné utilisé comme inhibiteur de wee-1

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110402248A (zh) * 2017-03-15 2019-11-01 豪夫迈·罗氏有限公司 作为hpk1抑制剂的氮杂吲哚类
WO2021000935A1 (fr) * 2019-07-04 2021-01-07 Qilu Regor Therapeutics Inc. Inhibiteurs de hpk1 et leurs utilisations
WO2021013083A1 (fr) * 2019-07-17 2021-01-28 Beigene, Ltd. Composés tricycliques utilisés en tant qu'inhibiteurs de hpk1 et leur utilisation
WO2021213317A1 (fr) * 2020-04-20 2021-10-28 微境生物医药科技(上海)有限公司 Inhibiteur de hpk1, son procédé de préparation et son utilisation
WO2022174765A1 (fr) * 2021-02-19 2022-08-25 微境生物医药科技(上海)有限公司 Composé cyclique fusionné utilisé comme inhibiteur de wee-1

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