WO2023134608A1 - Fused ring compounds serving as hpk1 inhibitors - Google Patents

Fused ring compounds serving as hpk1 inhibitors Download PDF

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WO2023134608A1
WO2023134608A1 PCT/CN2023/071184 CN2023071184W WO2023134608A1 WO 2023134608 A1 WO2023134608 A1 WO 2023134608A1 CN 2023071184 W CN2023071184 W CN 2023071184W WO 2023134608 A1 WO2023134608 A1 WO 2023134608A1
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alkylene
heterocycloalkyl
cycloalkyl
compound
aryl
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PCT/CN2023/071184
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French (fr)
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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to the field of medicinal chemistry, and more specifically relates to a condensed ring compound as an HPK1 inhibitor, a preparation method thereof, and the use of the compound in the preparation of a drug for treating or preventing related diseases mediated by HPK1.
  • 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-receptor 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.
  • the technical problem to be solved by the present invention is that there is currently no drug on the market for the HPK1 target, which cannot meet the clinical needs. Therefore, the present invention provides a condensed ring compound as an HPK1 inhibitor, which has good HPK1 inhibitory activity, selectivity, physicochemical properties and druggability.
  • the present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • L is a chemical bond, -O-, -S-, -C(O)-, -N(R a )-, *-C(O)O-, -C(O)O-*, *-C(O )N(R a )-, -C(O)N(R a )-*, (C1-C8) alkylene, (C1-C8) alkylene-O-*, (C1-C8) alkylene Group-N(R a )-*, (C2-C8) alkenylene or (C2-C8) alkynylene, wherein the (C1-C8) alkylene, (C1-C8) alkylene-O -*, (C1-C8) alkylene-N(R a )-*, (C2-C8) alkenylene or (C2-C8) alkynylene can be independently optionally replaced by 1, 2, 3 or 4 A R c substitution; where * means that it is connected to the benzene ring
  • X 1 is selected from -C(R a R b )-, chemical bond, -O-, -S- or -C(O)-;
  • X 2 is selected from -C(R a R b )- or -C(O);
  • X 3 is selected from -N(R a )- or -C(R a R b )-;
  • R 1 is -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO 2 Ra , -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) heteroaryl, wherein the (C1-C8) alkyl,
  • R 2 is (C3-C14) cycloalkyl, (3-14 member) heterocycloalkyl, (C6-C14) aryl or (5-14 member) heteroaryl, wherein the (C3-C14) ring Alkyl, (3-14 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl can be independently optionally substituted by 1, 2, 3 or 4 R c ;
  • the two R3s can be connected to two different carbon atoms or the same carbon atom; the two R3s connected to the same carbon atom can be the same or different;
  • the 2 R3s connected to the same carbon atom and the carbon atoms to which they are connected can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein the (4-7 Yuan) heterocycloalkyl or (C3-C6) cycloalkyl can be independently optionally substituted by 1, 2, 3 or 4 R c ;
  • 2 R 3 when 2 R 3 are connected on the same carbon atom, 2 R 3 can form an oxo group
  • R a on X 1 and adjacent X 2 and the atoms they are connected to can jointly form a (5-7 member) heterocycloalkyl or (C3-C9) cycloalkyl group, wherein the (5-7 member ) heterocycloalkyl or (C3-C9) cycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R c ;
  • R a and R b connected to the same atom and the atoms they connect together form a (5-7 membered) heterocycloalkyl or (C3-C9) cycloalkyl group, wherein the (5-7 membered) Heterocycloalkyl or (C3-C9) cycloalkyl each independently optionally substituted by 1, 2, 3 or 4 R c ;
  • 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;
  • n is an integer of 0, 1 or 2;
  • q is an integer of 0, 1, 2 or 3;
  • p is an integer of 0, 1 or 2.
  • L is a chemical bond, -O-, -S-, -C(O)-, -NH-, -N(CH 3 )- , *-C(O)O-, -C(O)O-*, *-C(O)NH-, *-C(O)N(CH 3 )-, -C(O)NH-*, -C(O)N(CH 3 )-*, (C1-C3)alkylene, (C1-C3)alkylene-O-*, (C1-C3)alkylene-NH-*, or (C1 -C3)alkylene-N(CH 3 )-*, wherein said (C1-C3)alkylene, (C1-C3)alkylene-O-*, (C1-C3)alkylene-NH -* or (C1-C3)alkylene-N(CH 3 )-*, wherein said (C1-C3)alkylene, (C1-C3)alkylene-O-*
  • L is a chemical bond, -O-, -NH-, -N(CH 3 )-, -CH 2 -, -CH 2 -CH 2 -, L is preferably a chemical bond, -O-, -CH 2 -, L is more preferably a chemical bond, -O- or -CH 2 -; wherein * means to be connected to a benzene ring, and ** means to be connected to R 2 .
  • X1 is preferably
  • X 2 is X2 is preferably
  • R 1 is -H, -D, halogen, hydroxyl, amino, cyano, nitro, (C1-C3) alkyl, ( C1-C3) alkoxy, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C2-C4) alkynyl, wherein said (C1-C3) alkyl, (C1-C3) alkoxy
  • the radical, (C1-C3)haloalkyl, (C2-C4)alkenyl or (C2-C4)alkynyl may each independently be optionally substituted by 1, 2, 3 or 4 R c .
  • R 1 is -H, -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -NHCH 3 , -N(CH 3 ) 2 , -C(O)CH 3.
  • R 1 is preferably -F, -Cl, -Br, -CN, -NO 2 , -CF 3 or -C(O)NH 2 ; R 1 is more preferably -Cl, -Br, -CN, -CF 3 or -C(O)NH 2 ; R 1 is more preferably -Cl or -CF 3 ; R 1 is more preferably -Cl.
  • R is (C3-C10) cycloalkyl, (3-10 membered) heterocycloalkyl, (C6-C10) aryl Or (5-10 yuan) heteroaryl, wherein the (C3-C8) cycloalkyl, (3-8 yuan) heterocycloalkyl, (C6-C10) aryl or (5-10 yuan) heteroaryl
  • the radicals can each independently be optionally substituted with 1, 2, 3 or 4 Rc .
  • R 2 is R2 is preferably R 2 is more preferably
  • the two R 3 when When it represents a single bond and m is 2, the two R 3 can be connected to two different carbon atoms or the same carbon atom; the two R 3 can be the same or different; the two R 3 can be connected to the same carbon atom 2 R 3 and the carbon atoms to which they are connected can jointly form (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl, wherein said (4-7 member) heterocycloalkyl or (C3 -C6)cycloalkyl can each independently be optionally substituted by 1, 2, 3 or 4 R c .
  • each R 3 is independently -H, -D, -F, -Cl, -Br, -I, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, Or two R 3s connected to the same carbon atom and the carbon atom they are connected to can jointly form R 3 is preferably -H, -CH 3 , -CH 2 OH, R 3 is more preferably -H, -CH 3 , R 3 is more preferably -CH 3 or
  • R 4 is -H, -D, -F, -Cl, -Br, -I, -CHF 2 , -CF 3 , - OCH 3 , -OCHF 2 , -OCF 3 or R 4 is preferably -H, -F, -Cl, -Br, -OCH 3 or R 4 is more preferably -H or -F; R 4 is more preferably -H; R 4 is more preferably -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.
  • 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:
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , m, q are as defined above.
  • compound 1-1 reacts with compound IntA under basic conditions to obtain compound 1-3
  • compound 1-3 reacts with IntB under appropriate conditions to obtain the target compound (1).
  • Embodiments of compounds of general formula (1) can also be prepared according to general reaction scheme 2, wherein R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , m, q are as defined above.
  • compound 1-1 reacts with compound IntA under basic conditions to obtain compound 2-4
  • compound 2-4 reacts with IntB under appropriate conditions to obtain compound 2-5
  • compound 2-5 is 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.
  • 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.
  • pharmaceutically acceptable salts are obtained by reacting a compound of formula with an acid or base including, but not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection , and Use 1st Ed., Acids and Bases in (Wiley, 2002).
  • 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 a cycloalkyl group can be optionally oxidized to form oxo or thioxo. 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-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[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.
  • Ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally oxidized to form oxo or thioxo 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, tetrahydrofuryl, 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 may 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 Tween ), 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, sesam
  • 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, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • 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 1-2000 mg, preferably 50-1000 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.
  • the target intermediates IntA-5 to IntA-12 in Table 1 were obtained by using different raw materials and referring to the similar synthesis methods in IntA-1 to IntA-4.
  • Methyl 3-(2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclobutane-1-carboxylate (320 mg, 1.05 mmol, refer to IntB -1) was added to THF (10ml) and MeOH (1ml), NaBH 4 (60mg, 1.58mmol) was added at room temperature, and the mixture was stirred at room temperature for 2h.
  • Methyl (3-(2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclobutyl)acetate (340 mg, crude product), 10% Pd/ C (40 mg) was added into MeOH (10 mL), hydrogen was replaced three times, and the reaction was stirred under normal temperature and pressure for 20 h. After the reaction was detected by LC-MS, the mixture was filtered, the filtrate was concentrated, and the residue was flash-purified and freeze-dried to obtain an off-white product (73 mg, yield: 24.1%).
  • Compound 17 was synthesized according to the method of compound 1.
  • Compound 35 can be synthesized according to the method of compound 26.
  • IntA-1 (2.2g, 10.73mmol), 2,4,5-trichloropyrimidine (1.97g, 10.73mmol) and DIPEA (1.4g, 10.73mmol) were added to n-butanol (20mL) under argon protection After that, react at 100°C for about 3h. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated, and the residue was purified by column chromatography to obtain a pale yellow solid product 49-1 (3.78 g, yield: 100%).
  • the target compounds 51-155 in Table 10 can be obtained.
  • HPK1 human HPK1
  • MBP MBP
  • Kinase assays were performed in white 384-well plates using the Promega HPK1 Kinase Assay (Promega V4099) standardized kit.
  • the reaction system in the HPK1 kinase assay contains the following substances: (1) 10 ng HPK1 kinase, 500 ng MBP substrate, 10 ⁇ M ATP. (2) HPK1 Kinase Buffer: 40mM Tris, 7.5; 20mM MgCl2; 0.1mg/mL BSA; 50 ⁇ M DTT. (3) Add dose-response-arranged inhibitors (10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, 0um, eight gradients) from the DMSO stock solution. The reaction was carried out at 25° C. for 2.5 hours, and detection was performed using ADP-Glo reagent after the reaction. Luminescence was measured on a plate reader, the data fitted, and IC50 calculated from the data. The results are shown in Table 11 below.
  • the detection was performed on a specific 96-well detection plate using the cisbio_IL2-HTRF kit (62HIL02PET). Cultivate Jurkat cells on a common 96-well cell culture plate at a concentration of 1*10 5 /well, add the compound of the present invention, and add CD3/CD28 antibody at a certain concentration to activate the cells. The highest concentration of the compound is 1uM, and the compound is recovered after 72 hours of treatment Cell supernatant, as the experimental sample. In the HTRF assay experiment, 16 ⁇ L of each IL2 standard (Std 0-Std 7) was first dispensed into each standard well. Simultaneously dispense 16 ⁇ L of the recovered sample into each sample well.
  • 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 time 0.083, 0.167, 0.5, 1, 2, 4, 8 and 24h.
  • About 200 uL 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 Female BALB/c or C57BL6N mice (6 weeks, 18–22 g) were provided by China Victoria Lihua Company and used after one week of quarantine and adaptation. All animals were kept in a room at 23 ⁇ 2°C, relative humidity 50 ⁇ 5%, with artificial lighting from 08:00 to 20:00 every day, and 13-18 air changes per hour. They had free access to a standard laboratory diet and water.
  • 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, the cells were collected when the cells reached the required amount.
  • 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

Abstract

Provided is a class of fused ring compounds that serve as HPK1 inhibitors. Specifically, provided are a compound represented by general formula (1), a preparation method therefor, and a use of the compound of general formula (1) and isomers, crystal forms, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof as an HPK1 inhibitor. The compound as well as the isomers, crystal forms, pharmaceutically acceptable salt, hydrate, or solvate thereof can be used for preparing a drug for treating or preventing diseases related to HPK1 mediation.

Description

作为HPK1抑制剂的稠环化合物Fused ring compounds as HPK1 inhibitors
本申请要求申请日为2022年1月11日的中国专利申请202210029059.8的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of the Chinese patent application 202210029059.8 with the filing date of January 11, 2022. This application cites the full text of the above-mentioned Chinese patent application.
技术领域technical field
本发明属涉及药物化学领域，更具体而言，涉及作为HPK1抑制剂的稠环化合物，及其制备方法和该类化合物用于制备治疗或者预防由HPK1介导的相关疾病的药物中的用途。The present invention relates to the field of medicinal chemistry, and more specifically relates to a condensed ring compound as an HPK1 inhibitor, a preparation method thereof, and the use of the compound in the preparation of a drug for treating or preventing related diseases mediated by HPK1.
背景技术Background technique
T细胞受体(TCR)介导的T细胞活化在胸腺T细胞发育、T细胞亚群分化以及效应T细胞功能发挥过程中均起作至关重要的作用。TCR能特异性识别抗原递呈细胞表面MHC递呈的抗原肽，并将胞外抗原肽通过MHC(主要组织相容性复合物)识别转化成可向细胞内部传递的信号。其中，抗原递呈细胞表面的MHC分子包括MHCⅠ类分子和MHCⅡ类分子，可分别被CD8+和CD4+细胞表面相应的辅助受体CD8和CD4分子特异性识别，随后可以引起下游信号通路的活化。TCR活化的典型胞内信号包括MAPK(丝裂原活化蛋白激酶，mitogen-activated protein kinase)、PKC(蛋白激酶C，protein kinase C)以及Calcium(钙离子)等信号通路。这些信号的活化最终激活T细胞的特异性基因表达，引起细胞的增殖，并使得T细胞分化成效应T细胞。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. Among them, 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-receptor 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.
HPK1，又称MAP4K1，是一种丝氨酸/苏氨酸激酶，作为MAP4K家族的成员之一。除此之外，其家族中还有5个成员，包括MAP3K2,MAP4K4,MAP4K5,MAK4K6.HPK1可与许多接头蛋白结合，如SLP-76家族，HIS,HIP-55,GRC2家族，LAT,CRK等相互作用，活化造血干细胞的JNK/SAPK信号途径，从而对TCR通路进行负向调节。MAP4K3又称为GLK激酶，其生物学作用与HPK1的生物学作用正好相反。GLK可以通过与下游蛋白结合，促进TCR通路的激活。因此我们需要筛选到对GLK具有选择性的HPK1抑制剂。HPK1, also known as MAP4K1, is a serine/threonine kinase as a member of the MAP4K family. In addition, there are 5 members in its family, including 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.
HPK1参与调控TCR的主要过程为：(1)TCR与胞外的抗原通过MHC结合，从而激活TCR通路向下接头蛋白传递信号；(2)接头蛋白酪氨酸激酶Lck和Zap70活化的SLP-76，继而磷酸化HPK1；(3)活化的HPK1会继而磷酸化受体蛋白SLP-76；(4)SLP-76的磷酸化反应为14-3-3(TCR通路抑制蛋白)受体蛋白提供多种蛋白结合位点，形成复合体；(5)SLP-76磷酸化的复合体参与Erk信号途径的下调，并接到SLP-76的泛素化降解 过程，从而导致TCR信号通路和T细胞增殖下降。综上，HPK1可负向调节TCR信号途径，因此，HPK1可作为T细胞介导的免疫反应的新的调节机制，成为新的免疫抗肿瘤的靶点。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. In summary, 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.
由于在免疫方面的重要作用，HPK1抑制剂在恶性实体瘤或血液瘤(如急性髓性白血病、膀胱上皮癌、乳腺癌、结肠癌、肺癌、胰腺癌、黑色素瘤等)、自身免疫性疾病(如系统性红斑狼疮、银屑病、关节炎等)和炎症反应中均扮演重要的角色。Due to its important role in immunity, 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.
然而目前针对HPK1靶点尚未有药物上市。However, there are currently no drugs targeting HPK1 on the market.
发明内容Contents of the invention
本发明要解决的技术问题是目前针对HPK1靶点尚未有药物上市，无法满足临床需求。为此，本发明提供了作为HPK1抑制剂的稠环化合物，该化合物具有良好的HPK1抑制活性、选择性、理化性质和成药性。The technical problem to be solved by the present invention is that there is currently no drug on the market for the HPK1 target, which cannot meet the clinical needs. Therefore, the present invention provides a condensed ring compound as an HPK1 inhibitor, which has good HPK1 inhibitory activity, selectivity, physicochemical properties and druggability.
本发明提供了一种通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：The present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
Figure PCTCN2023071184-appb-000001
Figure PCTCN2023071184-appb-000001
通式(1)中：In general formula (1):
L为化学键、-O-、-S-、-C(O)-、-N(R a)-、*-C(O)O-、-C(O)O-*、*-C(O)N(R a)-、-C(O)N(R a)-*、(C1-C8)亚烷基、(C1-C8)亚烷基-O-*、(C1-C8)亚烷基-N(R a)-*、(C2-C8)亚烯基或(C2-C8)亚炔基，其中所述(C1-C8)亚烷基、(C1-C8)亚烷基-O-*、(C1-C8)亚烷基-N(R a)-*、(C2-C8)亚烯基或(C2-C8)亚炔基可各自独立任选被1，2，3或4个R c取代；其中*表示与苯环相连； L is a chemical bond, -O-, -S-, -C(O)-, -N(R a )-, *-C(O)O-, -C(O)O-*, *-C(O )N(R a )-, -C(O)N(R a )-*, (C1-C8) alkylene, (C1-C8) alkylene-O-*, (C1-C8) alkylene Group-N(R a )-*, (C2-C8) alkenylene or (C2-C8) alkynylene, wherein the (C1-C8) alkylene, (C1-C8) alkylene-O -*, (C1-C8) alkylene-N(R a )-*, (C2-C8) alkenylene or (C2-C8) alkynylene can be independently optionally replaced by 1, 2, 3 or 4 A R c substitution; where * means that it is connected to the benzene ring;
X 1选自-C(R aR b)-、化学键、-O-、-S-或-C(O)-； X 1 is selected from -C(R a R b )-, chemical bond, -O-, -S- or -C(O)-;
X 2选自-C(R aR b)-或-C(O)； X 2 is selected from -C(R a R b )- or -C(O);
X 3选自-N(R a)-或-C(R aR b)-； X 3 is selected from -N(R a )- or -C(R a R b )-;
R 1为-H、-D、卤素、羟基、氨基、氰基、硝基、-OR a、-NR aR b、-C(O)R a、-CO 2R a、 -S(O) pR a、-S(O) pNR aR b、-CONR aR b、-NR aCOR b、-NR aCO 2R b、-NR aS(O) pR b、(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基或(5-14元)杂芳基，其中所述(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基或(5-14元)杂芳基可各自独立任选被1，2，3或4个R c取代； R 1 is -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO 2 Ra , -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) heteroaryl, wherein the (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-membered) heteroaryl groups can each independently be optionally substituted by 1, 2, 3 or 4 R ;
R 2为(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基或(5-14元)杂芳基，其中所述(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基或(5-14元)杂芳基可各自独立任选被1，2，3或4个R c取代； R 2 is (C3-C14) cycloalkyl, (3-14 member) heterocycloalkyl, (C6-C14) aryl or (5-14 member) heteroaryl, wherein the (C3-C14) ring Alkyl, (3-14 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl can be independently optionally substituted by 1, 2, 3 or 4 R c ;
各R 3和R 4各自独立为-H、-D、卤素、羟基、氨基、氰基、硝基、-OR a、-NR aR b、-C(O)R a、-CO 2R a、-(CH 2) mR a、-(CH 2) mCO 2R a、-(CH 2) mCONR aR b、-S(O) pR a、-S(O) pNR aR b、-CONR aR b、-C(＝NR a)-NR aR b、-NR aCOR b、-CR aCONR aR b、-NR aCO 2R a、-NR aS(O) pNR aR b、-NR aS(O) pR a、-POR aR b、(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基、-(C1-C8)亚烷基-(5-14元)杂芳基，其中所述(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基、-(C1-C8)亚烷基-(5-14元)杂芳基可各自独立任选被1，2，3或4个R c取代； Each of R3 and R4 is independently -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO 2 R a , -(CH 2 ) m R a , -(CH 2 ) m CO 2 R a , -(CH 2 ) m CONR a R b , -S(O) p R a , -S(O) p NR a R b , -CONR a R b , -C(=NR a )-NR a R b , -NR a COR b , -CR a CONR a R b , -NR a CO 2 R a , -NR a S(O) p NR a R b , -NR a S(O) p R a , -POR a R b , (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 Group, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14 member) heterocycloalkyl, -(C1-C8) alkylene Base-(C6-C14) aryl, -(C1-C8) alkylene-(5-14 yuan) heteroaryl, wherein the (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) Haloalkyl, (C2-C8) Alkenyl, (C2-C8) Alkynyl, (C3-C14) Cycloalkyl, (3-14) Heterocycloalkyl, (C6-C14) Aryl Base, (5-14) heteroaryl, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14) heterocycloalkane Base, -(C1-C8) alkylene-(C6-C14) aryl, -(C1-C8) alkylene-(5-14 yuan) heteroaryl can be independently optionally replaced by 1,2,3 or 4 R c substitutions;
或当
Figure PCTCN2023071184-appb-000002
代表单键和m是2时，2个R 3可以连接在2个不同的碳原子上或连接在同一个碳原子上；连接在同一个碳原子上的2个R 3可以相同也可以不同； or when
Figure PCTCN2023071184-appb-000002
When it represents a single bond and m is 2, the two R3s can be connected to two different carbon atoms or the same carbon atom; the two R3s connected to the same carbon atom can be the same or different;
或者连接在同一个碳原子上的2个R 3与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可各自独立任选被1，2，3或4个R c取代； Or the 2 R3s connected to the same carbon atom and the carbon atoms to which they are connected can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein the (4-7 Yuan) heterocycloalkyl or (C3-C6) cycloalkyl can be independently optionally substituted by 1, 2, 3 or 4 R c ;
或当2个R 3连接在同一个碳原子上时，2个R 3可以形成一个氧代基； Or when 2 R 3 are connected on the same carbon atom, 2 R 3 can form an oxo group;
R a和R b各自独立为-H、-D、卤素、羟基、氨基、氰基、硝基、-OR xa、-NR xaR xb、-(CH 2) mOR xa、-(CH 2) mNR xaR xb、-C(O)R xa、-CO 2R xa、-S(O) pR xa、-S(O) pNR xaR xb、-CONR xaR xb、-C(＝NR xa)-NR xbR xc、-NR xaCOR xb、-NR xaCONR xbR xc、-NR xaCO 2R xb、-NR xaS(O) pNR xbR xc、-NR xaS(O) pR xb、(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基、-(C1-C8)亚烷基-(5-14元)杂芳基，其中所述(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷 基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基、-(C1-C8)亚烷基-(5-14元)杂芳基可各自独立任选被1，2，3或4个R c取代；或当2个R a连接在同一个原子上时，2个R a可以形成一个氧代基；或当2个R b连接在同一个原子上时，2个R b可以形成一个氧代基； R a and R b are each independently -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR xa , -NR xa R xb , -(CH 2 ) m OR xa , -(CH 2 ) m NR xa R xb , -C(O)R xa , -CO 2 R xa , -S(O) p R xa , -S(O) p NR xa R xb , -CONR xa R xb , -C(= NR xa )-NR xb R xc , -NR xa COR xb , -NR xa CONR xb R xc , -NR xa CO 2 R xb , -NR xa S(O) p NR xb R xc , -NR xa S(O ) p R xb , (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14 ) cycloalkyl group, (3-14 member) heterocycloalkyl group, (C6-C14) aryl group, (5-14 member) heteroaryl group, -(C1-C8) alkylene group-(C3-C14) ring Alkyl, -(C1-C8)alkylene-(3-14 membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene Base-(5-14) heteroaryl, wherein said (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 member)heterocycloalkyl,-(C1-C8)alkylene-(C6-C14)aryl Group, -(C1-C8) alkylene-(5-14 yuan) heteroaryl can be independently optionally substituted by 1, 2, 3 or 4 R c ; or when 2 R a are connected to the same atom When on, 2 R a can form an oxo group; or when 2 R b are connected on the same atom, 2 R b can form an oxo group;
或X 1上的R a和相邻的X 2与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C9)环烷基，其中所述(5-7元)杂环烷基或(C3-C9)环烷基各自独立任选被1，2，3或4个R c取代； Or R a on X 1 and adjacent X 2 and the atoms they are connected to can jointly form a (5-7 member) heterocycloalkyl or (C3-C9) cycloalkyl group, wherein the (5-7 member ) heterocycloalkyl or (C3-C9) cycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R c ;
或者连接在同一个原子上的R a和R b与其连接的原子共同构成一个(5-7元)杂环烷基或(C3-C9)环烷基，其中所述的(5-7元)杂环烷基或(C3-C9)环烷基各自独立任选被1，2，3或4个R c取代； Or R a and R b connected to the same atom and the atoms they connect together form a (5-7 membered) heterocycloalkyl or (C3-C9) cycloalkyl group, wherein the (5-7 membered) Heterocycloalkyl or (C3-C9) cycloalkyl each independently optionally substituted by 1, 2, 3 or 4 R c ;
或连接在同一个碳原子上的R a和R b可以形成一个氧代基； Or R a and R b connected to the same carbon atom can form an oxo group;
R c为-H、-D、卤素、羟基、氨基、氰基、硝基、-OR xa、-NR xaR xb、-(CH 2) mOR xa、-(CH 2) mNR xaR xb、-C(O)R xa、-CO 2R xa、-S(O) pR xa、-S(O) pNR xaR xb、-CONR xaR xb、-C(＝NR xa)-NR xbR xc、-NR xaCOR xb、-NR xaCONR xbR xc、-NR xaCO 2R xb、-NR xaS(O) pNR xbR xc、-NR xaS(O) pR xb、(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C1-C8)烷氧基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基或-(C1-C8)亚烷基-(5-14元)杂芳基；或当2个R c连接在同一个原子上时，2个R c可以形成一个氧代基；或者连接在同一个碳原子上的2个R c与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基； R c is -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR xa , -NR xa R xb , -(CH 2 ) m OR xa , -(CH 2 ) m NR xa R xb , -C(O)R xa , -CO 2 R xa , -S(O) p R xa , -S(O) p NR xa R xb , -CONR xa R xb , -C(=NR xa )-NR xb R xc , -NR xa COR xb , -NR xa CONR xb R xc , -NR xa CO 2 R xb , -NR xa S(O) p NR xb R xc , -NR xa S(O) p R xb , (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-(C1-C8) alkoxy, -( C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14) heterocycloalkyl, -(C1-C8) alkylene-(C6 -C14) aryl or -(C1-C8) alkylene-(5-14 yuan) heteroaryl; or when 2 R c are connected to the same atom, 2 R c can form an oxo group ; or 2 R c connected to the same carbon atom and the carbon atom to which they are connected can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl;
R xa、R xb和R xc各自独立为-H、(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基或-(C1-C8)亚烷基-(5-14元)杂芳基； 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;
m为0、1或2的整数；m is an integer of 0, 1 or 2;
q为0、1、2或3的整数；q is an integer of 0, 1, 2 or 3;
p为0、1或2的整数。p is an integer of 0, 1 or 2.
在本发明的另一实施例中，其中所述通式(1)中，L为化学键、-O-、-S-、-C(O)-、-NH-、-N(CH 3)-、*-C(O)O-、-C(O)O-*、*-C(O)NH-、*-C(O)N(CH 3)-、-C(O)NH-*、-C(O)N(CH 3)-*、(C1-C3)亚烷基、(C1-C3)亚烷基-O-*、(C1-C3)亚烷基-NH-*或(C1-C3)亚烷基-N(CH 3)- *，其中所述(C1-C3)亚烷基、(C1-C3)亚烷基-O-*、(C1-C3)亚烷基-NH-*或(C1-C3)亚烷基-N(CH 3)-*可各自独立任选被1，2，3或4个R c取代；其中*表示与苯环相连。 In another embodiment of the present invention, wherein in the general formula (1), L is a chemical bond, -O-, -S-, -C(O)-, -NH-, -N(CH 3 )- , *-C(O)O-, -C(O)O-*, *-C(O)NH-, *-C(O)N(CH 3 )-, -C(O)NH-*, -C(O)N(CH 3 )-*, (C1-C3)alkylene, (C1-C3)alkylene-O-*, (C1-C3)alkylene-NH-*, or (C1 -C3)alkylene-N(CH 3 )-*, wherein said (C1-C3)alkylene, (C1-C3)alkylene-O-*, (C1-C3)alkylene-NH -* or (C1-C3)alkylene-N(CH 3 )-* can be independently and optionally substituted by 1, 2, 3 or 4 R c ; wherein * indicates that it is connected to a benzene ring.
在本发明的另一实施例中，其中所述通式(1)中，L为化学键、-O-、-NH-、-N(CH 3)-、-CH 2-、-CH 2-CH 2-、
Figure PCTCN2023071184-appb-000003
Figure PCTCN2023071184-appb-000004
Figure PCTCN2023071184-appb-000005
L优选为化学键、-O-、-CH 2-、
Figure PCTCN2023071184-appb-000006
L更优选为化学键、-O-或-CH 2-；其中*表示与苯环相连，**表示与R 2相连。 In another embodiment of the present invention, wherein in the general formula (1), L is a chemical bond, -O-, -NH-, -N(CH 3 )-, -CH 2 -, -CH 2 -CH 2 -,
Figure PCTCN2023071184-appb-000003
Figure PCTCN2023071184-appb-000004
Figure PCTCN2023071184-appb-000005
L is preferably a chemical bond, -O-, -CH 2 -,
Figure PCTCN2023071184-appb-000006
L is more preferably a chemical bond, -O- or -CH 2 -; wherein * means to be connected to a benzene ring, and ** means to be connected to R 2 .
在本发明的另一实施例中，其中所述通式(1)中，X 1为化学键、
Figure PCTCN2023071184-appb-000007
Figure PCTCN2023071184-appb-000008
X 1优选为
Figure PCTCN2023071184-appb-000009
In another embodiment of the present invention, wherein in the general formula (1), X is a chemical bond,
Figure PCTCN2023071184-appb-000007
Figure PCTCN2023071184-appb-000008
X1 is preferably
Figure PCTCN2023071184-appb-000009
在本发明的另一实施例中，其中所述通式(1)中，X 2为
Figure PCTCN2023071184-appb-000010
Figure PCTCN2023071184-appb-000011
X 2优选为
Figure PCTCN2023071184-appb-000012
In another embodiment of the present invention, wherein in the general formula (1), X 2 is
Figure PCTCN2023071184-appb-000010
Figure PCTCN2023071184-appb-000011
X2 is preferably
Figure PCTCN2023071184-appb-000012
在本发明的另一实施例中，其中所述通式(1)中，当X 3为N-R a时，其中R a为-H、-(CH 2) 2OR xa、-(CH 2) 2NR xaR xb、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、
Figure PCTCN2023071184-appb-000013
-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。 In another embodiment of the present invention, in the general formula (1), when X 3 is NR a , wherein R a is -H, -(CH 2 ) 2 OR xa , -(CH 2 ) 2 NR xa R xb , (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4-7 member) heterocycloalkyl, wherein the (C1-C3) alkane Base, (C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4-7 membered) heterocycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, - D, -F, -OH, -CH 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ,
Figure PCTCN2023071184-appb-000013
-OCF 3 , -CH 2 N(CH 3 ) 2 , -(CH 2 ) 2 N(CH 3 ) 2 , -N(CH 3 ) 2 and -CN.
在本发明的另一实施例中，其中所述通式(1)中，当X 3为N-R a时，其中R a为-H、- (CH 2) 2OCH 3、-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
Figure PCTCN2023071184-appb-000014
Figure PCTCN2023071184-appb-000015
Figure PCTCN2023071184-appb-000016
优选为
Figure PCTCN2023071184-appb-000017
Figure PCTCN2023071184-appb-000018
更优选为
Figure PCTCN2023071184-appb-000019
更优选为
Figure PCTCN2023071184-appb-000020
更优选为
Figure PCTCN2023071184-appb-000021
In another embodiment of the present invention, in the general formula (1), when X 3 is NR a , wherein R a is -H, -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 OH, -(CH 2 ) 2 N(CH 3 ) 2 ,
Figure PCTCN2023071184-appb-000014
Figure PCTCN2023071184-appb-000015
Figure PCTCN2023071184-appb-000016
preferably
Figure PCTCN2023071184-appb-000017
Figure PCTCN2023071184-appb-000018
more preferably
Figure PCTCN2023071184-appb-000019
more preferably
Figure PCTCN2023071184-appb-000020
more preferably
Figure PCTCN2023071184-appb-000021
在本发明的另一实施例中，其中所述通式(1)中，当X 3为CH-R b时，其中R b为-H、-(CH 2) 2OR xa、-NR xaR xb、-(CH 2) 2NR xaR xb、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、
Figure PCTCN2023071184-appb-000022
-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。 In another embodiment of the present invention, in the general formula (1), when X 3 is CH-R b , wherein R b is -H, -(CH 2 ) 2 OR xa , -NR xa R xb , -(CH 2 ) 2 NR xa R xb , (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4-7 membered) heterocycloalkyl, wherein The (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4-7 member) heterocycloalkyl can be optionally replaced by 1, 2, 3 or 4 of the following Group substitution: -H, -D, -F, -OH, -CH 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ,
Figure PCTCN2023071184-appb-000022
-OCF 3 , -CH 2 N(CH 3 ) 2 , -(CH 2 ) 2 N(CH 3 ) 2 , -N(CH 3 ) 2 and -CN.
在本发明的另一实施例中，其中所述通式(1)中，当X 3为CH-R b时，其中R b为：-H、-N(CH 3) 2、-N(CD 3) 2、-(CH 2) 2OCH 3、-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
Figure PCTCN2023071184-appb-000023
Figure PCTCN2023071184-appb-000024
Figure PCTCN2023071184-appb-000025
优选为-N(CH 3) 2或-N(CD 3) 2；更优选为-N(CH 3) 2。 In another embodiment of the present invention, in the general formula (1), when X 3 is CH-R b , wherein R b is: -H, -N(CH 3 ) 2 , -N(CD 3 ) 2 , -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 OH, -(CH 2 ) 2 N(CH 3 ) 2 ,
Figure PCTCN2023071184-appb-000023
Figure PCTCN2023071184-appb-000024
Figure PCTCN2023071184-appb-000025
Preferred is -N(CH 3 ) 2 or -N(CD 3 ) 2 ; more preferred is -N(CH 3 ) 2 .
在本发明的另一实施例中，其中所述通式(1)中，结构单元
Figure PCTCN2023071184-appb-000026
选自
Figure PCTCN2023071184-appb-000027
Figure PCTCN2023071184-appb-000028
优选为
Figure PCTCN2023071184-appb-000029
更优选为
Figure PCTCN2023071184-appb-000030
In another embodiment of the present invention, wherein in the general formula (1), the structural unit
Figure PCTCN2023071184-appb-000026
selected from
Figure PCTCN2023071184-appb-000027
Figure PCTCN2023071184-appb-000028
preferably
Figure PCTCN2023071184-appb-000029
more preferably
Figure PCTCN2023071184-appb-000030
在本发明的另一实施例中，其中所述通式(1)中，R 1为-H、-D、卤素、羟基、氨基、氰基、硝基、(C1-C3)烷基、(C1-C3)烷氧基、(C1-C3)卤代烷基、(C2-C4)烯基或(C2-C4)炔基，其中所述(C1-C3)烷基、(C1-C3)烷氧基、(C1-C3)卤代烷基、(C2-C4)烯基或(C2-C4)炔基可各自独立任选被1，2，3或4个R c取代。 In another embodiment of the present invention, wherein in the general formula (1), R 1 is -H, -D, halogen, hydroxyl, amino, cyano, nitro, (C1-C3) alkyl, ( C1-C3) alkoxy, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C2-C4) alkynyl, wherein said (C1-C3) alkyl, (C1-C3) alkoxy The radical, (C1-C3)haloalkyl, (C2-C4)alkenyl or (C2-C4)alkynyl may each independently be optionally substituted by 1, 2, 3 or 4 R c .
在本发明的另一实施例中，其中所述通式(1)中，R 1为-H、-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-CH 3、-OCH 3、-OCH 2CH 3、-OCH 2F、-OCHF 2、-OCF 3、-NHCH 3、-N(CH 3) 2、-C(O)CH 3、-CO 2CH 3、-S(O)CH 3、-S(O) 2CH 3、-C(O)NH 2、-C(O)NHCH 3、-CH 2F、-CHF 2或-CF 3；R 1优选为-F、-Cl、-Br、-CN、-NO 2、-CF 3或-C(O)NH 2；R 1更优选为-Cl、-Br、-CN、-CF 3或-C(O)NH 2；R 1更优选为-Cl或-CF 3；R 1更优选为-Cl。 In another embodiment of the present invention, wherein in the general formula (1), R 1 is -H, -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -NHCH 3 , -N(CH 3 ) 2 , -C(O)CH 3. -CO 2 CH 3 , -S(O)CH 3 , -S(O) 2 CH 3 , -C(O)NH 2 , -C(O)NHCH 3 , -CH 2 F, -CHF 2 or -CF 3 ; R 1 is preferably -F, -Cl, -Br, -CN, -NO 2 , -CF 3 or -C(O)NH 2 ; R 1 is more preferably -Cl, -Br, -CN, -CF 3 or -C(O)NH 2 ; R 1 is more preferably -Cl or -CF 3 ; R 1 is more preferably -Cl.
在本发明的另一实施例中，其中所述通式(1)中，R 2为(C3-C10)环烷基、(3-10元)杂环烷基、(C6-C10)芳基或(5-10元)杂芳基，其中所述(C3-C8)环烷基、(3-8元)杂环烷基、(C6-C10)芳基或(5-10元)杂芳基可各自独立任选被1，2，3或4个R c取代。 In another embodiment of the present invention, wherein in the general formula (1), R is (C3-C10) cycloalkyl, (3-10 membered) heterocycloalkyl, (C6-C10) aryl Or (5-10 yuan) heteroaryl, wherein the (C3-C8) cycloalkyl, (3-8 yuan) heterocycloalkyl, (C6-C10) aryl or (5-10 yuan) heteroaryl The radicals can each independently be optionally substituted with 1, 2, 3 or 4 Rc .
在本发明的另一实施例中，其中所述通式(1)中，R 2为
Figure PCTCN2023071184-appb-000031
Figure PCTCN2023071184-appb-000032
Figure PCTCN2023071184-appb-000033
R 2优选为
Figure PCTCN2023071184-appb-000034
Figure PCTCN2023071184-appb-000035
Figure PCTCN2023071184-appb-000036
R 2更优选为
Figure PCTCN2023071184-appb-000037
In another embodiment of the present invention, wherein in the general formula (1), R 2 is
Figure PCTCN2023071184-appb-000031
Figure PCTCN2023071184-appb-000032
Figure PCTCN2023071184-appb-000033
R2 is preferably
Figure PCTCN2023071184-appb-000034
Figure PCTCN2023071184-appb-000035
Figure PCTCN2023071184-appb-000036
R 2 is more preferably
Figure PCTCN2023071184-appb-000037
在本发明的另一实施例中，其中所述通式(1)中，结构单元-L-R 2为
Figure PCTCN2023071184-appb-000038
Figure PCTCN2023071184-appb-000039
Figure PCTCN2023071184-appb-000040
In another embodiment of the present invention, wherein in the general formula (1), the structural unit -LR 2 is
Figure PCTCN2023071184-appb-000038
Figure PCTCN2023071184-appb-000039
Figure PCTCN2023071184-appb-000040
在本发明的另一实施例中，其中所述通式(1)中，R 3和R 4各自独立为-H、-D、卤素、羟基、氨基、氰基、硝基、-OR a、-NR aR b、-C(O)R a、-CO 2R a、-(CH 2) mR a、-(CH 2) mCO 2R a、-(CH 2) mCONR aR b、-S(O) pR a、-S(O) pNR aR b、-CONR aR b、-C(＝NR a)-NR aR b、-NR aCOR b、-CR aCONR aR b、-NR aCO 2R a、-NR aS(O) pNR aR b、-NR aS(O) pR a、-POR aR b、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)卤代烷基、(C2-C6)烯基，(C2-C6)炔基，(C3-C12)环烷基、(3-12元)杂环烷基、(C6-C10)芳基、(5-12元)杂芳基、-(C1-C3)亚烷基-(C3-C12)环烷基、-(C1-C3)亚烷基-(3-12元)杂环烷基、-(C1-C3)亚烷基-(C6-C10)芳基、-(C1-C3)亚烷基-(5-12元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)卤代烷基、(C2-C6)烯基，(C2-C6)炔基，(C3-C12)环烷基、(3-12元)杂环烷基、(C6-C10)芳基、(5-12元)杂芳基、-(C1-C3)亚烷基-(C3-C12)环烷基、-(C1-C3)亚烷基-(3-12元)杂环烷基、-(C1-C3)亚烷基-(C6-C10)芳基、-(C1-C3)亚烷基-(5-12元)杂芳基可各自独立任选被1，2，3或4个R c取代。 In another embodiment of the present invention, wherein in the general formula (1), R 3 and R 4 are each independently -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO 2 R a , -(CH 2 ) m R a , -(CH 2 ) m CO 2 R a , -(CH 2 ) m CONR a R b , -S(O) p R a , -S(O) p NR a R b , -CONR a R b , -C(=NR a )-NR a R b , -NR a COR b , -CR a CONR a R b , -NR a CO 2 R a , -NR a S(O) p NR a R b , -NR a S(O) p R a , -POR a R b , (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C12) cycloalkyl, (3-12 member) heterocycle Alkyl, (C6-C10) aryl, (5-12 members) heteroaryl, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene- (3-12) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-(5-12) heteroaryl, wherein The (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C12) cycloalkane Base, (3-12) heterocycloalkyl, (C6-C10) aryl, (5-12) heteroaryl, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene-(3-12 yuan) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-( 5-12 membered) heteroaryl groups can each independently be optionally substituted with 1, 2, 3 or 4 R c .
在本发明的另一实施例中，其中所述通式(1)中，当
Figure PCTCN2023071184-appb-000041
代表单键和m是2时，2个R 3可以连接在2个不同的碳原子上或连接在同一个碳原子上；2个R 3可以相同也可以不同；连接在同一个碳原子上的2个R 3与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可各自独立任选被1，2，3或4个R c取代。 In another embodiment of the present invention, wherein in the general formula (1), when
Figure PCTCN2023071184-appb-000041
When it represents a single bond and m is 2, the two R 3 can be connected to two different carbon atoms or the same carbon atom; the two R 3 can be the same or different; the two R 3 can be connected to the same carbon atom 2 R 3 and the carbon atoms to which they are connected can jointly form (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl, wherein said (4-7 member) heterocycloalkyl or (C3 -C6)cycloalkyl can each independently be optionally substituted by 1, 2, 3 or 4 R c .
在本发明的另一实施例中，其中所述通式(1)中，R 3各自独立为-H、-D、-F、-Cl、-Br、-I、-CH 3、-CH 2CH 3、-CH 2OH、-CH 2CH 2OH、
Figure PCTCN2023071184-appb-000042
Figure PCTCN2023071184-appb-000043
Figure PCTCN2023071184-appb-000044
或连接在同一 个碳原子上的2个R 3与他们所连接的碳原子能够共同组成
Figure PCTCN2023071184-appb-000045
R 3优选为-H、-CH 3、-CH 2OH、
Figure PCTCN2023071184-appb-000046
Figure PCTCN2023071184-appb-000047
R 3更优选为-H、-CH 3、
Figure PCTCN2023071184-appb-000048
R 3更优选为-CH 3或
Figure PCTCN2023071184-appb-000049
In another embodiment of the present invention, wherein in the general formula (1), each R 3 is independently -H, -D, -F, -Cl, -Br, -I, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH,
Figure PCTCN2023071184-appb-000042
Figure PCTCN2023071184-appb-000043
Figure PCTCN2023071184-appb-000044
Or two R 3s connected to the same carbon atom and the carbon atom they are connected to can jointly form
Figure PCTCN2023071184-appb-000045
R 3 is preferably -H, -CH 3 , -CH 2 OH,
Figure PCTCN2023071184-appb-000046
Figure PCTCN2023071184-appb-000047
R 3 is more preferably -H, -CH 3 ,
Figure PCTCN2023071184-appb-000048
R 3 is more preferably -CH 3 or
Figure PCTCN2023071184-appb-000049
在本发明的另一实施例中，其中所述通式(1)中，R 4为-H、-D、-F、-Cl、-Br、-I、-CHF 2、-CF 3、-OCH 3、-OCHF 2、-OCF 3或
Figure PCTCN2023071184-appb-000050
R 4优选为-H、-F、-Cl、-Br、-OCH 3或
Figure PCTCN2023071184-appb-000051
R 4更优选为-H或-F；R 4更优选为-H；R 4更优选为-F。 In another embodiment of the present invention, wherein in the general formula (1), R 4 is -H, -D, -F, -Cl, -Br, -I, -CHF 2 , -CF 3 , - OCH 3 , -OCHF 2 , -OCF 3 or
Figure PCTCN2023071184-appb-000050
R 4 is preferably -H, -F, -Cl, -Br, -OCH 3 or
Figure PCTCN2023071184-appb-000051
R 4 is more preferably -H or -F; R 4 is more preferably -H; R 4 is more preferably -F.
在本发明的另一具体实施例中，通式(1)化合物具有以下结构之一：In another specific embodiment of the present invention, the compound of general formula (1) has one of the following structures:
Figure PCTCN2023071184-appb-000052
Figure PCTCN2023071184-appb-000052
Figure PCTCN2023071184-appb-000053
Figure PCTCN2023071184-appb-000053
Figure PCTCN2023071184-appb-000054
Figure PCTCN2023071184-appb-000054
Figure PCTCN2023071184-appb-000055
Figure PCTCN2023071184-appb-000055
Figure PCTCN2023071184-appb-000056
Figure PCTCN2023071184-appb-000056
本发明的另一个目的是提供了一种药物组合物，其含有药学上可接受的载体、稀释剂和/或赋形剂，以及本发明通式(1)化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。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.
本发明的再一个目的提供了本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗、调节或预防与HPK1相关疾病的药物中的用途。其中，所述的疾病优选癌症，所述癌症为血液癌和实体瘤。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. Wherein, said disease is preferably cancer, and said cancer is hematological cancer and solid tumor.
本发明的再一个目的还提供治疗、调节或预防与HPK1蛋白激酶介导的相关疾病的方法，包括对受试者给与治疗有效量的本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。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.
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
化合物的合成compound synthesis
下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。The preparation method of the compound of general formula (1) of the present invention is specifically described below, but these specific methods do not constitute any limitation to the present invention.
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。 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.
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、 溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其中通式(1)化合物可采用下列一般反应流程1或2制备：In one aspect, the compounds described herein are according to methods well known in the art. However, 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. On the one hand, 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:
一般反应流程1General reaction scheme 1
Figure PCTCN2023071184-appb-000057
Figure PCTCN2023071184-appb-000057
通式(1)化合物的实施方式可根据一般反应流程1制备，其中R 1、R 2、R 3、R 4、X 1、X 2、X 3、m、q如上述文中定义。如一般反应流程1所示,化合物1-1在碱性条件下与化合物IntA反应得到化合物1-3，化合物1-3再在适当条件下与IntB反应得到目标化合物(1)。 Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , m, q are as defined above. As shown in general reaction scheme 1, compound 1-1 reacts with compound IntA under basic conditions to obtain compound 1-3, and compound 1-3 reacts with IntB under appropriate conditions to obtain the target compound (1).
一般反应流程2General reaction scheme 2
Figure PCTCN2023071184-appb-000058
Figure PCTCN2023071184-appb-000058
通式(1)化合物的实施方式也可根据一般反应流程2制备，其中R 1、R 2、R 3、R 4、X 1、X 2、X 3、m、q如上述文中定义。如一般反应流程1所示,化合物1-1在碱性条件下与化 合物IntA反应得到化合物2-4，化合物2-4在适当条件下与IntB反应得到化合物2-5，化合物2-5再经适当官能团转化得到目标化合物(1)。 Embodiments of compounds of general formula (1) can also be prepared according to general reaction scheme 2, wherein R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , m, q are as defined above. As shown in the general reaction scheme 1, compound 1-1 reacts with compound IntA under basic conditions to obtain compound 2-4, compound 2-4 reacts with IntB under appropriate conditions to obtain compound 2-5, and compound 2-5 is subjected to The target compound (1) can be obtained by transformation of appropriate functional groups.
化合物的进一步形式Further forms of compounds
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。"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.
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式化合物与酸或碱反应获得，其中所述的酸或碱包括，但不限于发现于Stahl和Wermuth，Handbook of Pharmaceutical Salts:Properties,Selection,and Use 1 st Ed.，(Wiley,2002)中的酸和碱。 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. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of formula with an acid or base including, but not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection , and Use 1st Ed., Acids and Bases in (Wiley, 2002).
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。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. For example, 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. Furthermore, 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.
在其他具体实施例中，通式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。In other embodiments, compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms. In addition, 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.
在另一个方面，通式(1)化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。In another aspect, 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.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)、碘-125( 125I)和C-14( 14C)。又例 如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C). For another example, 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.
术语the term
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。Unless otherwise stated, the terms used in the present application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, the singular form "a" and "an" includes plural references unless the context clearly dictates otherwise. If not stated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In this application, the use of "or" or "and" means "and/or" if not stated otherwise.
除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH 3、CH 3CH 2、CF 3、CHF 2、CF 3CH 2、CF 3(CH 3)CH、 iPr、 nPr、 iBu、 nBu或 tBu。 Unless otherwise specified, "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 .
除非另有规定，“亚烷基”指二价的如上所定义的烷基。亚烷基的例子包括但不限于，亚甲基和亚乙基。Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.
除非另有规定，“烯基”指含有碳-碳双键的不饱和脂肪烃基团，包括1至14个碳原子的直链或支链基团。优选含有1至4个碳原子的低级烯基，例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。Unless otherwise specified, "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.
除非另有规定，“亚烯基”指二价的如上所定义的烯基。Unless otherwise specified, "alkenylene" means a divalent alkenyl group as defined above.
除非另有规定，“炔基”指含有碳-碳叁键的不饱和脂肪烃基团，包括1至14个碳原子的直链和支链基团。优选含有1至4个碳原子的低级炔基，例如乙炔基、1-丙炔基或1-丁炔基。Unless otherwise specified, "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. A lower alkynyl group having 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, is preferred.
除非另有规定，“亚炔基”指二价的如上所定义的炔基。Unless otherwise specified, "alkynylene" means a divalent alkynyl group as defined above.
除非另有规定，“环烷基”是指非芳香族烃环系统(单环、双环或多环)，如果碳环含有至少一个双键，那么部分不饱和环烷基可被称为“环烯基”，或如果碳环含有至少一个三键，那么部分不饱和环烷基可被称为“环炔基”。环烷基可以包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。在一些实施方案中，环烷基为单环的。在一些实施方案中，环烷基为单环的或双环的。环烷基的成环碳原子可以任选地被氧化以形成氧代或硫代基。环烷基还包括亚环烷基。在一些实施方案中，环烷基含有0、1或2个双键。在一些实施方案中，环烷基含有1或2个双键(部分不饱和环烷基)。在一些实施方案中，环 烷基可以与芳基、杂芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基和杂环烷基稠合。一些实施方案中，环烷基可以与芳基和环烷基稠合。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环已二烯基、环庚三烯基、降莰基、降蒎基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。Unless otherwise specified, "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. In some embodiments, cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form oxo or thioxo. 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. In some embodiments, 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. Examples of 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.
除非另有规定，“亚环烷基”指二价的如上所定义的环烷基。Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.
除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH 3、OCF 3、CHF 2O、CF 3CH 2O、 i-PrO、 n-PrO、 i-BuO、 n-BuO或 t-BuO。 Unless otherwise specified, "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. As used herein, "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.
除非另有规定，“芳基”指碳氢芳香基团，芳基是单环或多环的，例如单环芳基环与一个或多个碳环芳香基团稠和。芳基的例子包括但不限于，苯基、萘基和菲基。Unless otherwise specified, "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. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.
除非另有规定，“芳氧基”指通过醚氧原子键合到分子其余部分的芳基。芳氧基的例子包括但不限于苯氧基和萘氧基。Unless otherwise specified, "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.
除非另有规定，“亚芳基”指二价的如上所定义的芳基。亚芳基的例子包括但不限于，亚苯基、亚萘基和亚菲基。Unless otherwise specified, "arylene" refers to a divalent aryl group as defined above. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.
除非另有规定，“杂芳基”指含有一个或多个杂原子(O、S或N)的芳香基团，杂芳基是单环或多环的。例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环烷基基团稠和。杂芳基的例子包括但不限于，吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、喹啉基、异喹啉基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基、吡咯并嘧啶基、1H-吡咯[3,2-b]吡啶基、1H-吡咯[2,3-c]吡啶基、1H-吡咯[3,2-c]吡啶基、1H-吡咯[2,3-b]吡啶基、
Figure PCTCN2023071184-appb-000059
Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl is monocyclic or polycyclic. For example a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of 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-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H- Pyrrolo[2,3-b]pyridyl,
Figure PCTCN2023071184-appb-000059
除非另有规定，“亚杂芳基”指二价的如上所定义的杂芳基。Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.
除非另有规定，“杂环烷基”指非芳香族环或环系统，其可以任选地含有一个或多个亚烯基作为环结构的一部分，其具有至少一个独立地选自硼、磷、氮、硫、氧和磷的杂原子环成员。如果杂环烷基含有至少一个双键，那么部分不饱和杂环烷基可被称为“杂环烯基”，或如果杂环烷基含有至少一个三键，那么部分不饱和杂环烷基可被称为“杂环炔基”。杂环烷基可以包括单环、双环、螺环或多环(例如具有两个稠合或桥接环)环系统。在一些 实施例中，杂环烷基为具有1、2或3个独立地选自氮、硫和氧的杂原子的单环基团。杂环烷基的成环碳原子和杂原子可以任选地氧化以形成氧代或硫代基或其他氧化键(例如C(O)、S(O)、C(S)或S(O)2、N-氧化物等)，或氮原子可以季铵化。杂环烷基可以经由成环碳原子或成环杂原子而连接。在一些实施例中，杂环烷基含有0至3个双键。在一些实施例中，杂环烷基含有0至2个双键。杂环烷基的定义中还包括具有一个或多个与杂环烷基环稠合(即，与其共用键)的芳香族环的部分(也称为部分不饱和杂环)，例如哌啶、吗啉、氮杂环庚三烯或噻吩基等的苯并衍生物。含有稠合芳香族环的杂环烷基可以经由任何成环原子，包括稠合芳香族环的成环原子而连接。杂环烷基的实例包括但不限于氮杂环丁基、氮杂环庚基、二氢苯并呋喃基、二氢呋喃基、二氢吡喃基、N-吗啉基、3-氧杂-9-氮杂螺[5.5]十一烷基、1-氧杂-8-氮杂螺[4.5]癸烷基、哌啶基、哌嗪基、氧代哌嗪基、吡喃基、吡咯烷基、奎宁基、四氢呋喃基、四氢吡喃基、1,2,3,4-四氢喹啉基、莨菪烷基、4,5,6,7-四氢噻唑并[5,4-c]吡啶基、4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶、N-甲基哌啶基、四氢咪唑基、吡唑烷基、丁内酰胺基、戊内酰胺基、咪唑啉酮基、乙内酰脲基、二氧戊环基、邻苯二甲酰亚胺基、嘧啶-2,4(1H,3H)-二酮基、1,4-二氧六环基、吗啉基、硫代吗啉基、硫代吗啉-S-氧化物基、硫代吗啉-S,S-氧化物基、哌嗪基、吡喃基、吡啶酮基、3-吡咯啉基、噻喃基、吡喃酮基、四氢噻吩基、2-氮杂螺[3.3]庚烷基、吲哚啉基、
Figure PCTCN2023071184-appb-000060
Figure PCTCN2023071184-appb-000061
Unless otherwise specified, "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. In some embodiments, heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally oxidized to form oxo or thioxo 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. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are 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. Examples of 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, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butane Amide group, valerolactam group, imidazolinone group, hydantoin group, dioxolanyl group, phthalimide group, pyrimidine-2,4(1H,3H)-dione group, 1 ,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl , pyridonyl, 3-pyrrolinyl, thiopyranyl, pyroneyl, tetrahydrothiophenyl, 2-azaspiro[3.3]heptanyl, indolinyl,
Figure PCTCN2023071184-appb-000060
Figure PCTCN2023071184-appb-000061
除非另有规定，“亚杂环烷基”指二价的如上所定义的杂环烷基。Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.
除非另有规定，“氧代基”指＝O；例如，碳经一个氧代基取代形成的基团为“羰基
Figure PCTCN2023071184-appb-000062
”；硫经一个氧代基取代形成的基团为“亚硫酰基
Figure PCTCN2023071184-appb-000063
”，硫经二个氧代基取代形成的基团为“磺酰基
Figure PCTCN2023071184-appb-000064
”。 Unless otherwise specified, "oxo" means =O; for example, a group formed by replacing a carbon with an oxo group is "carbonyl
Figure PCTCN2023071184-appb-000062
"; The group formed by the substitution of sulfur by an oxo group is "sulfinyl
Figure PCTCN2023071184-appb-000063
", the group formed by the substitution of sulfur by two oxo groups is "sulfonyl
Figure PCTCN2023071184-appb-000064
".
除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "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.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
除非另有规定，可以理解词语“包含”，或其变体如“包括”或“含有”是指包括所述的元素或整数，或者元素或整数的组，但不排除任意其他的元素或整数，或者元素或整数的组。Unless otherwise specified, it is to be understood that the word "comprising", or variations thereof such as "includes" or "containing", means the inclusion of a stated element or integer, or group of elements or integers, but not the exclusion of any other element or integer , or a group of elements or integers.
取代基“-O-CH 2-O-”指该取代基中二个氧原子和杂环烷基、芳基或杂芳基二个相邻的碳原子连接，比如：
Figure PCTCN2023071184-appb-000065
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:
Figure PCTCN2023071184-appb-000065
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。When one of the variables is selected from a chemical bond, it means that the two groups connected are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.
术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。例如，环己基、吡啶基、吡喃基、噻喃基是六元环，环戊基、吡咯基、呋喃基和噻吩基是五元环。The term "membered ring" includes any ring structure. The term "member" is meant to indicate the number of skeletal atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings, and cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
术语“片断”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。The term "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.
除非另有说明，用楔形实线键
Figure PCTCN2023071184-appb-000066
和楔形虚线键
Figure PCTCN2023071184-appb-000067
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2023071184-appb-000068
和直形虚线键
Figure PCTCN2023071184-appb-000069
表示立体中心的相对构型，用波浪线
Figure PCTCN2023071184-appb-000070
表示楔形实线键
Figure PCTCN2023071184-appb-000071
或楔形虚线键
Figure PCTCN2023071184-appb-000072
或用波浪线
Figure PCTCN2023071184-appb-000073
表示直形实线键
Figure PCTCN2023071184-appb-000074
或直形虚线键
Figure PCTCN2023071184-appb-000075
Unless otherwise noted, keys with wedge-shaped solid lines
Figure PCTCN2023071184-appb-000066
and dotted wedge keys
Figure PCTCN2023071184-appb-000067
Indicates the absolute configuration of a stereocenter, with a straight solid-line bond
Figure PCTCN2023071184-appb-000068
and straight dashed keys
Figure PCTCN2023071184-appb-000069
Indicates the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2023071184-appb-000070
Indicates wedge-shaped solid-line bond
Figure PCTCN2023071184-appb-000071
or dotted wedge key
Figure PCTCN2023071184-appb-000072
or with tilde
Figure PCTCN2023071184-appb-000073
Indicates a straight solid line key
Figure PCTCN2023071184-appb-000074
or straight dotted key
Figure PCTCN2023071184-appb-000075
除非另有说明，用
Figure PCTCN2023071184-appb-000076
表示单键或双键。 Unless otherwise specified, use
Figure PCTCN2023071184-appb-000076
Indicates a single or double bond.
特定药学及医学术语Certain pharmaceutical and medical terms
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。The term "acceptable", as used herein, means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。The term "treatment", "course of treatment" or "therapy" as used herein 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. As used herein, 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.
“活性成分”指通式(1)所示化合物，以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以 存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。"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 may 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.
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。The terms "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to In animals), a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。The term "administered, administering, or administration" as used herein means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound wait.
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the relative numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently inherently contain standard deviations resulting from their individual testing methodology. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as considered by those skilled in the art. Except for the experimental examples, or unless otherwise expressly stated, all ranges, quantities, numerical values and percentages used herein should be understood (for example, to describe the amount of material used, the length of time, temperature, operating conditions, quantitative ratios and other similar Those) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in the specification and the appended claims are approximate values and may be changed as required. At a minimum, these numerical parameters should be understood as the number of significant digits indicated plus the usual rounding method.
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as the usual meanings understood by those skilled in the art. In addition, the singular nouns used in this specification include the plural forms of the nouns, and the plural nouns used also include the singular forms of the nouns, unless the context conflicts with the context.
治疗用途therapeutic use
本发明提供了使用本发明通式(1)化合物或药物组合物治疗疾病的方法，包括但不限于涉及HPK1蛋白激酶相关的病况(例如癌症)。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).
在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的包括结构通式(1)化合物的药物组合物。在一些实施例中，癌症与HPK1蛋白激酶相关。在其它实施例中，该癌症是血液癌和实体瘤，包括但不限于白血病、乳腺癌、肺癌、胰腺癌、结肠癌、膀胱癌、脑癌、尿路上皮癌、前列腺癌、肝癌、卵巢癌、头颈癌、胃癌、间皮瘤或所有癌症转移。In some embodiments, there is provided a method for treating cancer, the method 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. In some embodiments, the cancer is associated with HPK1 protein kinase. In other embodiments, 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.
给药途径Route of administration
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。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 . Wherein "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.
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2023071184-appb-000077
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "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 Tween
Figure PCTCN2023071184-appb-000077
), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, 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, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。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. 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.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, 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.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。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.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。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.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。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.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, 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 1-2000 mg, preferably 50-1000 mg. Of course, 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.
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.
具体实施方式Detailed ways
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。In the following description, various specific aspects, characteristics and advantages of the above-mentioned compounds, methods and pharmaceutical compositions will be described in detail, so that the content of the present invention becomes very clear. It is to be understood that the following detailed description and examples describe specific embodiments and are given by reference only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined in the present application.
所有实施例中， 1H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。 In all the examples, 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in δ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
本发明采用下述缩略词：(Coc) 2O代表二碳酸二叔丁酯；CDCl 3代表氘代氯仿；EtOAc代表乙酸乙酯；Hexane代表正己烷；HPLC代表高效液相色谱；MeCN代表乙腈；DCM代表二氯甲烷；DIPEA代表二异丙基乙基胺；Dioxane代表1,4-二氧六环；DMF代表N,N-二甲基甲酰胺；DMAP代表4-(二甲氨基)吡啶；DMSO代表二甲亚砜；hr代表小时；HOBt 代表1-羟基苯并三氮唑；IPA代表异丙醇；K 2CO 3代表碳酸钾；KOAc代表醋酸钾；K 3PO 4代表磷酸钾；LiOH代表氢氧化锂；min代表分钟；MeOH代表甲醇；mL代表毫升；MS代表质谱；MsOH代表甲磺酸；m-CPCA代表间氯过氧苯甲酸；n-BuLi代表正丁基锂；NaBH 4代表硼氢化钠；n-BuOH代表正丁醇；NH 3/THF代表氨的四氢呋喃溶液；NMP代表N-甲基吡咯烷酮；NMR代表核磁共振；Pd/C代表钯碳；Pd(PPh 3) 4代表四三苯基膦钯；Pd 2(dca) 3代表三(二亚苄基丙酮)二钯(0)；PE代表石油醚；TFA代表三氟乙酸；T 3P代表1-丙基磷酸酐；XantPhos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；TLC代表薄层色谱；XPhos代表2-二环己基磷-2′,4′,6′-三异丙基联苯。 The present invention adopts the following abbreviations: (Coc) 2 O represents di-tert-butyl dicarbonate; CDCl 3 represents deuterated chloroform; EtOAc represents ethyl acetate; Hexane represents n-hexane; HPLC represents high performance liquid chromatography; MeCN represents acetonitrile ; DCM stands for dichloromethane; DIPEA stands for diisopropylethylamine; Dioxane stands for 1,4-dioxane; DMF stands for N,N-dimethylformamide; DMAP stands for 4-(dimethylamino)pyridine ; DMSO represents dimethylsulfoxide; hr represents hour; HOBt represents 1-hydroxybenzotriazole; IPA represents isopropanol; K 2 CO 3 represents potassium carbonate; KOAc represents potassium acetate; K 3 PO 4 represents potassium phosphate; LiOH stands for lithium hydroxide; min stands for minute; MeOH stands for methanol; mL stands for milliliter; MS stands for mass spectrum; MsOH stands for methanesulfonic acid; m-CPCA stands for m-chloroperoxybenzoic acid ; n-BuLi stands for n-butyl lithium; Represents sodium borohydride; n-BuOH represents n-butanol; NH 3 /THF represents ammonia in tetrahydrofuran; NMP represents N-methylpyrrolidone; NMR represents nuclear magnetic resonance; Pd/C represents palladium carbon; Pd(PPh 3 ) 4 represents Tetrakistriphenylphosphine palladium; Pd 2 (dca) 3 represents tris(dibenzylideneacetone) dipalladium (0); PE represents petroleum ether; TFA represents trifluoroacetic acid; T 3 P represents 1-propyl phosphoric anhydride; XantPhos stands for 4,5-bisdiphenylphosphine-9,9-dimethylxanthene; TLC stands for thin layer chromatography; XPhos stands for 2-dicyclohexylphosphine-2′,4′,6′-triisopropyl base biphenyl.
制备例1 IntA-1的合成Synthesis of Preparation Example 1 IntA-1
Figure PCTCN2023071184-appb-000078
Figure PCTCN2023071184-appb-000078
3-甲基二氢吲哚-2-酮3-Methylindolin-2-one
将吲哚-2-酮(13.3g，0.10mol)加入到无水THF(260ml)中，氩气保护下降温至-78℃，后缓慢滴加n-BuLi(88ml，2.5M的正己烷溶液，0.22mol)。滴毕，混合液保温在-80～-70℃搅拌反应30min，然后保温在-80～-70℃下滴加MeI(15.6g，0.11mol)的THF(50ml)溶液。滴毕，混合液继续保温搅拌15min，后自然升至室温搅拌反应15min。混合液加入饱和氯化铵溶液(200ml)淬灭。EA(100ml*2)萃取，合并有机相，用饱和氯化钠溶液洗涤。有机相浓缩至干，残留物柱层析纯化得淡黄色液体产物(10.6g，收率：72.1％)。Add indol-2-one (13.3g, 0.10mol) to anhydrous THF (260ml), lower the temperature to -78°C under the protection of argon, and then slowly add n-BuLi (88ml, 2.5M n-hexane solution , 0.22mol). After dropping, the mixture was kept at -80~-70°C and stirred for 30 minutes, then MeI (15.6g, 0.11mol) in THF (50ml) was added dropwise at -80~-70°C. After dropping, the mixture was kept warm and stirred for 15 minutes, then naturally rose to room temperature and stirred for 15 minutes. The mixture was quenched by adding saturated ammonium chloride solution (200ml). EA (100ml*2) was extracted, and the combined organic phases were washed with saturated sodium chloride solution. The organic phase was concentrated to dryness, and the residue was purified by column chromatography to obtain a pale yellow liquid product (10.6 g, yield: 72.1%).
ESI-MS m/z:148.1[M+H] +。 ESI-MS m/z: 148.1 [M+H] + .
叔丁基3-甲基-2-羰基二氢吲哚-1-羧酸酯tert-Butyl 3-methyl-2-carbonylindoline-1-carboxylate
将3-甲基二氢吲哚-2-酮(10g,67.95mmol)加入无水THF(100mL)中，氩气保护下冷却至0℃，分批加入NaH(3.26g,81.54mmol)，加毕，0-5℃搅拌反应0.5h；滴加Boc 2O(14.83g,67.95mmol)的THF(25mL)溶液，继续冰浴下反应1h。LC-MS检测 反应完成后，体系加入饱和氯化铵溶液(25mL)淬灭，加入水(50mL)，EA萃取两遍，合并有机相浓缩，残留物柱层析纯化得淡黄色液体产物(12.64g，收率：75％)。 Add 3-methylindolin-2-one (10g, 67.95mmol) into anhydrous THF (100mL), cool to 0°C under argon protection, add NaH (3.26g, 81.54mmol) in batches, add After completion, the reaction was stirred at 0-5°C for 0.5h; a solution of Boc 2 O (14.83g, 67.95mmol) in THF (25mL) was added dropwise, and the reaction was continued for 1h under ice-cooling. After the LC-MS detection reaction was completed, the system was quenched by adding saturated ammonium chloride solution (25mL), adding water (50mL), extracting twice with EA, merging the organic phases and concentrating, and purifying the residue by column chromatography to obtain a light yellow liquid product (12.64 g, yield: 75%).
叔丁基3-(2-甲氧基-2-羰基乙基)-3-甲基-2-羰基二氢吲哚-1-羧酸酯tert-Butyl 3-(2-methoxy-2-carbonylethyl)-3-methyl-2-carbonylindoline-1-carboxylate
将叔丁基3-甲基-2-羰基二氢吲哚-1-羧酸酯(12.14g,49.09mmol)加入无水THF(100mL)中，氩气保护下冷却至0℃，分批加入NaH(2.36g,58.91mmol)，加毕，冰浴下反应0.5h；滴加溴乙酸甲酯(9g,58.91mmol)的THF(20mL)溶液，继续冰浴下反应1h。LC-MS检测反应完全后，体系加入饱和氯化铵溶液(25mL)淬灭，加入水(50mL)，EA萃取两遍，合并有机相浓缩，残留物柱层析纯化得白色固体产物(13.93g，收率：88％)。Add tert-butyl 3-methyl-2-carbonylindoline-1-carboxylate (12.14g, 49.09mmol) into anhydrous THF (100mL), cool to 0°C under argon protection, and add in batches NaH (2.36g, 58.91mmol) was added and reacted under ice bath for 0.5h; a solution of methyl bromoacetate (9g, 58.91mmol) in THF (20mL) was added dropwise and continued to react under ice bath for 1h. After the LC-MS detection reaction was complete, the system was quenched by adding saturated ammonium chloride solution (25mL), adding water (50mL), extracting with EA twice, combining the organic phases and concentrating, and purifying the residue by column chromatography to obtain a white solid product (13.93g , yield: 88%).
ESI-MS m/z:320.1[M+H] +/265.1[M-C 4H 8+H] +。 ESI-MS m/z: 320.1 [M+H] + /265.1 [MC 4 H 8 +H] + .
甲基2-(3-甲基-2-羰基二氢吲哚-3-基)乙酸酯Methyl 2-(3-methyl-2-carbonylindolin-3-yl)acetate
将叔丁基3-(2-甲氧基-2-羰基乙基)-3-甲基-2-羰基二氢吲哚-1-羧酸酯(13.93g,43.62mmol)加入DCM(50mL)中，然后加入4M HCl的1,4-二氧六环(21.8mL)，室温反应2h。LC-MS检测反应完全后，将反应液浓缩，用饱和碳酸氢钠溶液调PH至7-8，DCM萃取两遍，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得白色固体产物(9.6g，收率：100％)。tert-Butyl 3-(2-methoxy-2-carbonylethyl)-3-methyl-2-carbonylindoline-1-carboxylate (13.93 g, 43.62 mmol) was added to DCM (50 mL) , then added 4M HCl in 1,4-dioxane (21.8 mL), and reacted at room temperature for 2 h. After the reaction was detected by LC-MS, concentrate the reaction solution, adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract twice with DCM, combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and filter. Concentration afforded a white solid product (9.6 g, yield: 100%).
ESI-MS m/z:220.1[M+H] +。 ESI-MS m/z: 220.1 [M+H] + .
甲基2-(3-甲基-2-硫代二氢吲哚-3-基)乙酸酯Methyl 2-(3-methyl-2-thioindolin-3-yl)acetate
将甲基2-(3-甲基-2-羰基二氢吲哚-3-基)乙酸酯(9.6g,43.62mmol)和劳森试剂(8.82g,21.81mmol)加入Tol(100mL)中，加热至130℃反应1.5h。LC-MS检测反应完全后，将反应液浓缩，残留物柱层析纯化得白色固体产物(10.8g，收率：>100％)。Methyl 2-(3-methyl-2-carbonylindolin-3-yl)acetate (9.6 g, 43.62 mmol) and Lawson's reagent (8.82 g, 21.81 mmol) were added to Tol (100 mL) , heated to 130°C for 1.5h. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated, and the residue was purified by column chromatography to obtain a white solid product (10.8 g, yield: >100%).
IntA-1(甲基2-(3-甲基二氢吲哚-3-基)乙酸酯)IntA-1 (methyl 2-(3-methylindolin-3-yl) acetate)
将甲基2-(3-甲基-2-硫代二氢吲哚-3-基)乙酸酯(10.26g,43.62mmol)和NiCl(11.31g,87.24mmol)加入THF/MeOH(70mL/70mL)中，氩气保护后，冷却至0℃，缓慢分批加入NaBH 4(9.9g,261.72mmol)，加毕，冰浴反应0.5h。LC-MS检测反应完全后，将反应液通过硅藻土过滤，滤饼用甲醇洗涤，取滤液，浓缩；残留物中加入EA(200mL)，依次用水、饱和氯化钠洗涤，有机相浓缩，残留物柱层析纯化得黄棕色液体产物(5.37g，收率：60％)。 To THF/MeOH (70 mL/ 70 mL), under argon protection, cooled to 0°C, slowly added NaBH 4 (9.9 g, 261.72 mmol) in batches, and reacted in ice bath for 0.5 h. After LC-MS detects that the reaction is complete, the reaction solution is filtered through diatomaceous earth, the filter cake is washed with methanol, the filtrate is taken, and concentrated; EA (200 mL) is added to the residue, washed with water and saturated sodium chloride successively, and the organic phase is concentrated. The residue was purified by column chromatography to obtain a yellow-brown liquid product (5.37 g, yield: 60%).
ESI-MS m/z:206.1[M+H] +。 ESI-MS m/z: 206.1 [M+H] + .
制备例2和3IntA-2和IntA-3的合成Synthesis of Preparation Examples 2 and 3IntA-2 and IntA-3
Figure PCTCN2023071184-appb-000079
Figure PCTCN2023071184-appb-000079
1-(叔丁基)3-甲基1H-吲哚-1,3-二羧酸酯1-(tert-butyl)3-methyl 1H-indole-1,3-dicarboxylate
将1H-吲哚-3-羧酸甲酯(7g,40.0mmol)加入无水THF(140mL)中，氩气保护下冷却至0℃，分批加入60％的NaH(1.92g,48.0mmol)，加毕，0-5℃搅拌反应0.5h；滴加Boc 2O(10.5g,48mmol)的THF(50mL)溶液，继续冰浴下反应1h。LC-MS检测反应完成后，体系加入饱和氯化铵溶液(100mL)淬灭，加入水(100mL)，EA萃取两遍，合并有机相浓缩，残留物柱层析纯化得淡黄色液体产物(8.1g，收率：73.6％)。 Add methyl 1H-indole-3-carboxylate (7g, 40.0mmol) into anhydrous THF (140mL), cool to 0°C under argon protection, and add 60% NaH (1.92g, 48.0mmol) in batches After the addition, the reaction was stirred at 0-5°C for 0.5h; a solution of Boc 2 O (10.5g, 48mmol) in THF (50mL) was added dropwise, and the reaction was continued for 1h under ice-cooling. After the LC-MS detection reaction was completed, the system was quenched by adding saturated ammonium chloride solution (100mL), adding water (100mL), and extracting EA twice, merging the organic phase and concentrating, and purifying the residue by column chromatography to obtain a light yellow liquid product (8.1 g, yield: 73.6%).
1-(叔丁基)3-甲基二氢吲哚-1,3-二羧酸酯(IntA-2)1-(tert-butyl)3-methylindoline-1,3-dicarboxylate (IntA-2)
将1-(叔丁基)3-甲基1H-吲哚-1,3-二羧酸酯(8.1g，29.45mmol)、10％Pd/C(100mg)加入到MeOH(200ml)中，混合液氢气置换3次，后常温常压下搅拌反应20h。LC-MS检测反应完成后，混合液过滤，滤饼用甲醇淋洗，滤液浓缩至干，残留物柱层析纯化得微黄色产物(7.1g，收率：87％)1-(tert-butyl) 3-methyl 1H-indole-1,3-dicarboxylate (8.1 g, 29.45 mmol), 10% Pd/C (100 mg) was added to MeOH (200 ml), mixed Liquid hydrogen was replaced 3 times, and then stirred and reacted for 20 h at normal temperature and pressure. After the reaction was detected by LC-MS, the mixture was filtered, the filter cake was rinsed with methanol, the filtrate was concentrated to dryness, and the residue was purified by column chromatography to obtain a slightly yellow product (7.1 g, yield: 87%)
ESI-MS m/z:278.2[M+H] +。 ESI-MS m/z: 278.2 [M+H] + .
1-(叔丁基)3-甲基3-甲基二氢吲哚-1,3-二羧酸酯1-(tert-butyl) 3-methyl 3-methylindoline-1,3-dicarboxylate
将IntA-2(4g,14.44mmol)加入无水THF(80mL)中，氩气保护下冷却至0℃，分批加入NaH(693mg,17.33mmol)，加毕，冰浴下反应0.5h；滴加MeI(2.26g,15.92mmol)的THF(20mL)溶液，继续冰浴下反应1h。LC-MS检测反应完全后，体系加入饱和氯化铵溶液(50mL)淬灭，加入水(50mL)，EA萃取两遍，合并有机相浓缩，残留物柱层析纯化得白色固体产物(3.36g，收率：80％)。Add IntA-2 (4g, 14.44mmol) into anhydrous THF (80mL), cool to 0°C under the protection of argon, add NaH (693mg, 17.33mmol) in batches, and react under ice bath for 0.5h; drop A solution of MeI (2.26 g, 15.92 mmol) in THF (20 mL) was added, and the reaction was continued for 1 h under ice-cooling. After the LC-MS detection reaction was complete, the system was quenched by adding saturated ammonium chloride solution (50mL), adding water (50mL), extracting twice with EA, combining the organic phases for concentration, and purifying the residue by column chromatography to obtain a white solid product (3.36g , yield: 80%).
ESI-MS m/z:292.2[M+H] +/237.2[M-C 4H 8+H] +。 ESI-MS m/z: 292.2[M+H] + / 237.2 [ MC4H8 +H] + .
3-甲基二氢吲哚-3-羧酸甲酯(IntA-3)：Methyl 3-methylindoline-3-carboxylate (IntA-3):
将1-(叔丁基)3-甲基3-甲基二氢吲哚-1,3-二羧酸酯(3.36g,11.55mmol)加入DCM(50mL)中，然后加入4M HCl的1,4-二氧六环(30mL)，室温反应2h。LC-MS检测 反应完全后，将反应液浓缩，残留物用饱和碳酸氢钠溶液调pH至7-8，DCM萃取两遍，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得白色固体产物(2.03g，收率：92％)。1-(tert-Butyl) 3-methyl 3-methylindoline-1,3-dicarboxylate (3.36 g, 11.55 mmol) was added to DCM (50 mL), followed by 4M HCl in 1, 4-Dioxane (30mL), react at room temperature for 2h. After the completion of the reaction detected by LC-MS, the reaction solution was concentrated, the residue was adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted twice with DCM, the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration and concentration gave a white solid product (2.03 g, yield: 92%).
ESI-MS m/z:192.1[M+H] +。 ESI-MS m/z: 192.1 [M+H] + .
制备例4 IntA-4的合成Synthesis of Preparation Example 4 IntA-4
Figure PCTCN2023071184-appb-000080
Figure PCTCN2023071184-appb-000080
3-(1-甲氧基-1-氧代丙-2-基)-1H-吲哚-1-羧酸叔丁酯tert-butyl 3-(1-methoxy-1-oxopropan-2-yl)-1H-indole-1-carboxylate
将3-(2-甲氧基-2-氧乙基)-1H-吲哚-1-羧酸叔丁酯(200mg,0.691mmol)加入无水THF(5mL)中，氩气保护下冷却至0℃，加入NaH(33mg,0.83mmol)，加毕，冰浴下反应0.5h；滴加MeI(118mg,0.83mmol)的THF(2mL)溶液，继续冰浴下反应1h。LC-MS检测反应完全后，体系加入饱和氯化铵溶液(5mL)淬灭，加入水(5mL)，EA萃取两遍，合并有机相浓缩，得白色固体粗品(210mg，收率：100％)。Add tert-butyl 3-(2-methoxy-2-oxyethyl)-1H-indole-1-carboxylate (200 mg, 0.691 mmol) into anhydrous THF (5 mL), and cool to 0°C, NaH (33mg, 0.83mmol) was added, and the reaction was carried out under ice bath for 0.5h; a solution of MeI (118mg, 0.83mmol) in THF (2mL) was added dropwise, and the reaction was continued for 1h under ice bath. After LC-MS detected that the reaction was complete, the system was quenched by adding saturated ammonium chloride solution (5mL), adding water (5mL), extracting twice with EA, combining the organic phases and concentrating to obtain a white solid crude product (210mg, yield: 100%) .
2-(1H-吲哚-3-基)丙酸甲酯(IntA-4)Methyl 2-(1H-indol-3-yl)propionate (IntA-4)
将3-(1-甲氧基-1-氧代丙-2-基)-1H-吲哚-1-羧酸叔丁酯(210mg,0.691mmol)加入DCM(3mL)中，然后加入4M HCl的1,4-二氧六环(2mL)，室温反应2h。LC-MS检测反应完全后，将反应液浓缩，残留物Flash纯化，冻干得白色固体产物(76mg，收率：54.1％)。tert-Butyl 3-(1-methoxy-1-oxopropan-2-yl)-1H-indole-1-carboxylate (210 mg, 0.691 mmol) was added to DCM (3 mL) followed by 4M HCl 1,4-dioxane (2mL), react at room temperature for 2h. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated, and the residue was flash-purified and freeze-dried to obtain a white solid product (76 mg, yield: 54.1%).
ESI-MS m/z:204.1[M+H] +。 ESI-MS m/z: 204.1 [M+H] + .
采用不同的原料，参考IntA-1至IntA-4中类似的合成方法，得到表1中的目标中间体IntA-5至IntA-12。The target intermediates IntA-5 to IntA-12 in Table 1 were obtained by using different raw materials and referring to the similar synthesis methods in IntA-1 to IntA-4.
表1Table 1
Figure PCTCN2023071184-appb-000081
Figure PCTCN2023071184-appb-000081
Figure PCTCN2023071184-appb-000082
Figure PCTCN2023071184-appb-000082
Figure PCTCN2023071184-appb-000083
Figure PCTCN2023071184-appb-000083
制备例5 IntB-1的合成Preparation Example 5 Synthesis of IntB-1
Figure PCTCN2023071184-appb-000084
Figure PCTCN2023071184-appb-000084
5-碘-7-硝基-1,2,3,4-四氢异喹啉5-iodo-7-nitro-1,2,3,4-tetrahydroisoquinoline
将7-硝基-1,2,3,4-四氢异喹啉盐酸盐(50.0g,230.5mmol)溶于TfOH(250.0mL)，在0℃氮气保护下加入NIS(78.5g,350mmol)。反应液在室温下搅拌16小时。LC-MS监测显示反应结束。反应液冷却至室温，将反应液倒入冰水中，用稀NaOH溶液调pH值至8-9，过滤得到黑色固体产物(70g,粗产物)，粗产物可直接用于下一步反应。Dissolve 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (50.0g, 230.5mmol) in TfOH (250.0mL), add NIS (78.5g, 350mmol ). The reaction was stirred at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, poured into ice water, adjusted to pH 8-9 with dilute NaOH solution, and filtered to obtain a black solid product (70 g, crude product), which was directly used in the next reaction.
ESI-MS m/z:305[M+H] +。 ESI-MS m/z: 305 [M+H] + .
5-碘-7-硝基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯tert-butyl 5-iodo-7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate
将5-碘-7-硝基-1,2,3,4-四氢异喹啉(14.0g,46.0mmol)，(Boc) 2O(25.1g,115mmol,26.4mL)溶于DCM(200mL)，室温下加入TEA(14.0g,138mmol,19.2mL)。反应液在室温下搅拌16小时。LC-MS监测显示反应结束。向反应液中加入水(100mL)，水相用二氯甲烷萃取(150mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(1.1mg,粗产物)。粗产物经过柱层析制备纯化(SiO 2,EtOAc/PE＝0/1-1/9)得白色固体(10g,产率：53.7％)。 Dissolve 5-iodo-7-nitro-1,2,3,4-tetrahydroisoquinoline (14.0 g, 46.0 mmol), (Boc) 2 O (25.1 g, 115 mmol, 26.4 mL) in DCM (200 mL ), TEA (14.0 g, 138 mmol, 19.2 mL) was added at room temperature. The reaction was stirred at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Water (100 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (150 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain crude product (1.1 mg, crude product). The crude product was preparatively purified by column chromatography (SiO 2 , EtOAc/PE=0/1-1/9) to obtain a white solid (10 g, yield: 53.7%).
ESI-MS m/z:349[M+H] +。 ESI-MS m/z: 349 [M+H] + .
5-环丙基-7-硝基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯tert-butyl 5-cyclopropyl-7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate
将5-碘-7-硝基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(6.00g,14.5mmol)，环丙基硼酸 (6.4g,74.2mmol)，碳酸铯(9.7g,29.7mmol)和Pd(dppf)Cl 2.CH 2Cl 2(1.2mg,1.5mmol)溶解在1,4-二氧六环(80ml)和水(8ml)中，氩气保护下，加热到100℃搅拌反应5小时。LC-MS监测显示反应结束。将反应液旋干，粗产物经过柱层析制备纯化(SiO 2,EtOAc/PE＝0/1-1/9)得白色固体(3.3g，收率：70％)。 5-iodo-7-nitro-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate (6.00g, 14.5mmol), cyclopropylboronic acid (6.4g, 74.2mmol), Cesium carbonate (9.7g, 29.7mmol) and Pd (dppf) Cl2.CH2Cl2 ( 1.2mg , 1.5mmol) were dissolved in 1,4-dioxane (80ml) and water (8ml), argon Under protection, the mixture was heated to 100°C and stirred for 5 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was spin-dried, and the crude product was prepared and purified by column chromatography (SiO 2 , EtOAc/PE=0/1-1/9) to obtain a white solid (3.3 g, yield: 70%).
1H NMR(400MHz,DMSO-d 6)δ7.95(d,J＝2.0Hz,1H),7.62(d,J＝2.3Hz,1H),4.62(br s,2H),3.63(br t,J＝5.9Hz,2H),2.98(t,J＝5.9Hz,2H),2.04-1.94(m,1H),1.47-1.35(m,9H),1.05-0.93(m,2H),0.74-0.62(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ7.95(d, J=2.0Hz, 1H), 7.62(d, J=2.3Hz, 1H), 4.62(br s, 2H), 3.63(br t, J＝5.9Hz, 2H), 2.98(t, J＝5.9Hz, 2H), 2.04-1.94(m, 1H), 1.47-1.35(m, 9H), 1.05-0.93(m, 2H), 0.74-0.62 (m,2H).
5-环丙基-7-硝基-1,2,3,4-四氢异喹啉5-cyclopropyl-7-nitro-1,2,3,4-tetrahydroisoquinoline
将5-环丙基-7-硝基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(3.3g，10.36mmol)加入到DCM(100ml)中，后室温下加入TFA(5ml)，混合液室温搅拌反应5h。LC-MS检测反应完成后，混合物浓缩，残留物加入DCM(100ml)，饱和碳酸氢钠(50ml)，搅拌，分液，水相再用DCM(50ml*2)萃取两次，合并有机相用饱和氯化钠溶液洗涤两次，无水硫酸钠干燥，过滤，浓缩至干，得类白色固体产物(2.3g，收率：100％)。5-Cyclopropyl-7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (3.3g, 10.36mmol) was added to DCM (100ml), and then TFA (5ml) was added, and the mixture was stirred at room temperature for 5h. After the LC-MS detection reaction was completed, the mixture was concentrated, the residue was added with DCM (100ml), saturated sodium bicarbonate (50ml), stirred, separated, the aqueous phase was extracted twice with DCM (50ml*2), and the organic phase was combined for Washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain an off-white solid product (2.3 g, yield: 100%).
ESI-MS m/z:219.2[M+H] +。 ESI-MS m/z: 219.2 [M+H] + .
5-环丙基-2-甲基-7-硝基-1,2,3,4-四氢异喹啉5-cyclopropyl-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline
将5-环丙基-7-硝基-1,2,3,4-四氢异喹啉(2.0g，9.16mmol)和AcOH(824mg，13.7mmol)加入到DCM(50ml)/MeOH(10ml)混合液中，后室温下加入30％甲醛水溶液(2ml)，混合液室温搅拌反应0.5h，后加入三乙酰基硼氢化钠(3.88g，18.32mmol)，混合液室温搅拌反应5h。LC-MS检测反应完成后，混合物浓缩，残留物加入DCM(100ml)，饱和氯化钠溶液你(50ml)，搅拌，分液，水相再用DCM(50ml*2)萃取两次，浓缩至干，残留物Flash纯化，冻干，得白色固体产物(1.86g，收率：87.4％)。5-Cyclopropyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (2.0 g, 9.16 mmol) and AcOH (824 mg, 13.7 mmol) were added to DCM (50 ml)/MeOH (10 ml ) mixed solution, then added 30% formaldehyde aqueous solution (2ml) at room temperature, stirred the mixed solution at room temperature for 0.5h, then added sodium triacetylborohydride (3.88g, 18.32mmol), stirred the mixed solution at room temperature for 5h. After the LC-MS detection reaction was completed, the mixture was concentrated, and the residue was added with DCM (100ml), saturated sodium chloride solution (50ml), stirred, separated, and the aqueous phase was extracted twice with DCM (50ml*2), concentrated to After drying, the residue was flash-purified and lyophilized to obtain a white solid product (1.86 g, yield: 87.4%).
ESI-MS m/z:233.2[M+H] +。 ESI-MS m/z: 233.2 [M+H] + .
5-环丙基-2-甲基-1,2,3,4-四氢异喹啉-7-胺(IntB-1):5-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (IntB-1):
将5-环丙基-2-甲基-7-硝基-1,2,3,4-四氢异喹啉(1.8g,7.75mmol)溶于甲醇(20.0mL)和水(20.0mL)，加入NH 4Cl(4.15g,77.5mmol)和Fe粉(4.32g,77.5mmol)。反应液加热到80℃反应5小时。LC-MS监测显示反应结束。反应液过滤得到滤液，滤液减压浓缩，残留物Flash纯化，冻干，得到白色固体产物(1.06g,收率：67.6％)。 Dissolve 5-cyclopropyl-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.8 g, 7.75 mmol) in methanol (20.0 mL) and water (20.0 mL) , NH 4 Cl (4.15 g, 77.5 mmol) and Fe powder (4.32 g, 77.5 mmol) were added. The reaction solution was heated to 80° C. for 5 hours. LC-MS monitoring showed the reaction was complete. The reaction liquid was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure. The residue was flash-purified and lyophilized to obtain a white solid product (1.06 g, yield: 67.6%).
ESI-MS m/z:203.2[M+H] +。 ESI-MS m/z: 203.2 [M+H] + .
采用不同的原料，参考IntB-1中类似的合成方法，得到表2中的目标中间体IntB-2至IntB-24。Using different raw materials and referring to the similar synthesis method in IntB-1, the target intermediates IntB-2 to IntB-24 in Table 2 were obtained.
表2Table 2
Figure PCTCN2023071184-appb-000085
Figure PCTCN2023071184-appb-000085
Figure PCTCN2023071184-appb-000086
Figure PCTCN2023071184-appb-000086
制备例6 IntB-25的合成Synthesis of Preparation Example 6 IntB-25
Figure PCTCN2023071184-appb-000087
Figure PCTCN2023071184-appb-000087
将5-(2,5-二氢呋喃-3-基)-2-甲基-7-硝基-1,2,3,4-四氢异喹啉(100mg，0.385mol，参照IntB-1的方法制备)、10％Pd/C(10mg)加入到MeOH(10mL)中，氢气置换三次后常温常压下搅拌反应48h。LC-MS检测反应完成后，混合液过滤，滤液浓缩至干，得类白色固体产物(92mg，收率：100％)。5-(2,5-dihydrofuran-3-yl)-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (100mg, 0.385mol, refer to IntB-1 prepared by the method), 10% Pd/C (10mg) was added into MeOH (10mL), hydrogen was replaced three times, and the reaction was stirred under normal temperature and pressure for 48h. After the reaction was detected by LC-MS, the mixture was filtered, and the filtrate was concentrated to dryness to obtain an off-white solid product (92 mg, yield: 100%).
ESI-MS m/z:233.2[M+H] +。 ESI-MS m/z: 233.2 [M+H] + .
采用不同的原料，参考IntB-25中类似的合成方法，得到表3中的目标中间体IntB-26至IntB-28。Using different raw materials and referring to the similar synthesis method in IntB-25, the target intermediates IntB-26 to IntB-28 in Table 3 were obtained.
表3table 3
Figure PCTCN2023071184-appb-000088
Figure PCTCN2023071184-appb-000088
制备例7 IntB-29的合成Preparation Example 7 Synthesis of IntB-29
Figure PCTCN2023071184-appb-000089
Figure PCTCN2023071184-appb-000089
5-(氮杂环丁烷-3-基)-7-硝基-1,2,3,4-四氢异喹啉5-(azetidin-3-yl)-7-nitro-1,2,3,4-tetrahydroisoquinoline
将5-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-7-硝基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(200mg，0.461mmol，参考IntB-1合成)加入到DCM(10ml)中，后加入TFA(1ml)，混合液室温搅拌反应5h。LC-MS检测反应完成后，混合物浓缩至干，后加入无水碳酸钾、THF(10ml)室温搅拌1h，过滤，滤液浓缩至干得粗品(180mg)。5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester ( 200mg, 0.461mmol, refer to IntB-1 synthesis) was added to DCM (10ml), then TFA (1ml) was added, and the mixture was stirred at room temperature for 5h. After the reaction was detected by LC-MS, the mixture was concentrated to dryness, then anhydrous potassium carbonate and THF (10 ml) were added and stirred at room temperature for 1 h, filtered, and the filtrate was concentrated to dryness to obtain a crude product (180 mg).
2-甲基-5-(1-甲基氮杂环丁烷-3-基)-7-硝基-1,2,3,4-四氢异喹啉2-Methyl-5-(1-methylazetidin-3-yl)-7-nitro-1,2,3,4-tetrahydroisoquinoline
将5-(氮杂环丁烷-3-基)-7-硝基-1,2,3,4-四氢异喹啉(180mg，0.461mmol)和AcOH(41mg，0.69mmol)加入到DCM(5ml)/MeOH(2ml)混合液中，后室温下加入30％甲醛水溶液(0.1ml)，混合液室温搅拌反应0.5h，后加入三乙酰基硼氢化钠(194mg，0.92mmol)，混合液室温搅拌反应5h。LC-MS检测反应完成后，混合物浓缩，残留物加入 DCM(10ml)，饱和氯化钠溶液你(10ml)，搅拌，分液，水相再用DCM(10ml*2)萃取两次，浓缩至干，残留物Flash纯化，冻干，得白色固体产物(73mg，收率：60.6％)。5-(azetidin-3-yl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (180 mg, 0.461 mmol) and AcOH (41 mg, 0.69 mmol) were added to DCM (5ml)/MeOH (2ml) mixed solution, then add 30% formaldehyde aqueous solution (0.1ml) at room temperature, stir the mixed solution at room temperature for 0.5h, then add triacetyl sodium borohydride (194mg, 0.92mmol), the mixed solution The reaction was stirred at room temperature for 5h. After the LC-MS detection reaction was completed, the mixture was concentrated, and the residue was added with DCM (10ml), saturated sodium chloride solution (10ml), stirred, separated, and the aqueous phase was extracted twice with DCM (10ml*2) and concentrated to After drying, the residue was purified by Flash and lyophilized to give the product as a white solid (73 mg, yield: 60.6%).
ESI-MS m/z:262.2[M+H] +。 ESI-MS m/z: 262.2 [M+H] + .
2-甲基-5-(1-甲基氮杂环丁烷-3-基)-1,2,3,4-四氢异喹啉-7-胺(IntB-29):2-Methyl-5-(1-methylazetidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-amine (IntB-29):
将2-甲基-5-(1-甲基氮杂环丁烷-3-基)-7-硝基-1,2,3,4-四氢异喹啉(73mg,0.28mmol)溶于甲醇(5.0mL)和水(5.0mL)，加入NH 4Cl(150mg,2.8mmol)和Fe粉(156mg,2.8mmol)。反应液加热到80℃反应5小时。LC-MS监测显示反应结束。反应液过滤得到滤液，滤液减压浓缩，残留物Flash纯化，冻干，得到白色固体产物(42mg,收率：65％)。 Dissolve 2-methyl-5-(1-methylazetidin-3-yl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (73mg, 0.28mmol) in Methanol (5.0 mL) and water (5.0 mL), NH 4 Cl (150 mg, 2.8 mmol) and Fe powder (156 mg, 2.8 mmol) were added. The reaction solution was heated to 80° C. for 5 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure. The residue was flash-purified and lyophilized to obtain a white solid product (42 mg, yield: 65%).
ESI-MS m/z:232.2[M+H] +。 ESI-MS m/z: 232.2 [M+H] + .
制备例8 IntB-30的合成Preparation Example 8 Synthesis of IntB-30
Figure PCTCN2023071184-appb-000090
Figure PCTCN2023071184-appb-000090
7-氨基-6-溴-2-甲基-3,4-二氢异喹啉-1(2H)-酮7-Amino-6-bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one
将7-氨基-2-甲基-3，4-二氢异喹啉-1(2H)-酮(10g，56.8mmol)加入到冰乙酸(100ml)中，后室温下分批加入NBS(10.62g，59.64mmol)，加完后混合物室温搅拌反应2h。LC-MS检测反应完成后，混合物减压浓缩，残留物加入EA(200ml)，饱和碳酸氢钠溶液(200ml)，搅拌，分液，水相再用EA(100ml)萃取，合并有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩至干，得粗品产(12.7g，收率：87％)。7-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (10g, 56.8mmol) was added to glacial acetic acid (100ml), and NBS (10.62 g, 59.64mmol), after the addition, the mixture was stirred at room temperature for 2h. After the LC-MS detection reaction was completed, the mixture was concentrated under reduced pressure, the residue was added with EA (200ml), saturated sodium bicarbonate solution (200ml), stirred, separated, the aqueous phase was extracted with EA (100ml), and the combined organic phases were washed with saturated Washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude product (12.7 g, yield: 87%).
ESI-MS m/z:255.0/257.0[M+H] +。 ESI-MS m/z: 255.0/257.0 [M+H] + .
6-溴-2-甲基-1,2,3,4-四氢异喹啉-7-胺6-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine
将7-氨基-6-溴-2-甲基-3,4-二氢异喹啉-1(2H)-酮(12.7g，49.8mmol)加入到THF(150ml)中，氩气保护下室温分批加入LiAlH 4(2.84g，74.7mmol)，加完后混合液氩气保护下升至50℃搅拌反应5h。LC-MS检测反应完成后，混合液冰浴下滴加饱和氯化铵溶液(100ml)淬灭，EA(100ml)萃取，水相再用DCM(100ml*2)萃取两次，合并有机相浓缩至干，残留物Flash纯化，冻干，得类白色固体产物(6.7g，收率：55.8％)。 7-Amino-6-bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (12.7g, 49.8mmol) was added to THF (150ml), at room temperature under the protection of argon LiAlH 4 (2.84g, 74.7mmol) was added in batches, and after the addition, the mixture was raised to 50°C under the protection of argon and stirred for 5h. After the reaction was detected by LC-MS, the mixture was quenched by adding saturated ammonium chloride solution (100ml) dropwise in an ice bath, extracted with EA (100ml), and the aqueous phase was extracted twice with DCM (100ml*2), and the combined organic phase was concentrated To dryness, the residue was flash-purified and lyophilized to obtain an off-white solid product (6.7 g, yield: 55.8%).
ESI-MS m/z:242.1[M+H] +。 ESI-MS m/z: 242.1 [M+H] + .
6-(2,5-二氢呋喃-3-基)-2-甲基-1,2,3,4-四氢异喹啉-7-胺(IntB-30)6-(2,5-Dihydrofuran-3-yl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (IntB-30)
将6-溴-2-甲基-1,2,3,4-四氢异喹啉-7-胺(351mg,1.45mmol)，2,5-二氢呋喃-3-硼酸(330mg,2.9mmol)，碳酸铯(945mg,2.9mmol)和Pd(dppf)Cl 2.CH 2Cl 2(120mg,0.15mmol)溶解在1,4-二氧六环(10ml)和水(2ml)中，氩气保护下，加热到100℃搅拌反应5小时。LC-MS监测显示反应结束。将反应液旋干，残留物Flash纯化得白色固体(180mg，收率：54％)。 6-bromo-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (351mg, 1.45mmol), 2,5-dihydrofuran-3-boronic acid (330mg, 2.9mmol ), cesium carbonate (945mg, 2.9mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (120mg, 0.15mmol) dissolved in 1,4-dioxane (10ml) and water (2ml), argon Under protection, the mixture was heated to 100°C and stirred for 5 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was spin-dried, and the residue was flash-purified to obtain a white solid (180 mg, yield: 54%).
ESI-MS m/z:231.2[M+H] +。 ESI-MS m/z: 231.2 [M+H] + .
制备例9 IntB-31的合成Preparation Example 9 Synthesis of IntB-31
Figure PCTCN2023071184-appb-000091
Figure PCTCN2023071184-appb-000091
2-甲基-6-(四氢呋喃-3-基)-1,2,3,4-四氢异喹啉-7-胺(IntB-31)2-Methyl-6-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-amine (IntB-31)
将IntB-30(100mg，0.434mol)、10％Pd/C(20mg)加入到MeOH(10mL)中，氢气置换三次后常温常压下搅拌反应20h。LC-MS检测反应完成后，混合液过滤，滤液浓缩至干，得类白色固体产物(106mg，收率：100％)。IntB-30 (100 mg, 0.434 mol) and 10% Pd/C (20 mg) were added to MeOH (10 mL), replaced by hydrogen three times, and stirred at room temperature and pressure for 20 h. After the reaction was detected by LC-MS, the mixture was filtered, and the filtrate was concentrated to dryness to obtain an off-white solid product (106 mg, yield: 100%).
ESI-MS m/z:233.2[M+H] +。 ESI-MS m/z: 233.2 [M+H] + .
采用不同的原料，参考IntB-30中类似的合成方法，得到表4中的目标中间体IntB-32至IntB-37。Using different raw materials and referring to the similar synthesis method in IntB-30, the target intermediates IntB-32 to IntB-37 in Table 4 were obtained.
表4Table 4
Figure PCTCN2023071184-appb-000092
Figure PCTCN2023071184-appb-000092
Figure PCTCN2023071184-appb-000093
Figure PCTCN2023071184-appb-000093
制备例10 IntB-38的合成Preparation Example 10 Synthesis of IntB-38
Figure PCTCN2023071184-appb-000094
Figure PCTCN2023071184-appb-000094
5-环丙氧基-2-甲基-7-硝基-1,2,3,4-四氢异喹啉5-cyclopropoxy-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline
将2-甲基-7-硝基-5-羟基-1,2,3,4-四氢异喹啉(100mg，0.481mmol)、PPh 3(189mg，0.721mmol)加入到THF(5ml)中，后室温下缓慢滴加DIAD(146mg，0.721mmol)的THF(5ml)溶液，滴毕，混合液升至50℃搅拌反应5小时。LC-MS检测反应完全后，混合液浓缩，柱层析纯化得产物(32mg，收率：26.8％)。 2-Methyl-7-nitro-5-hydroxy-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.481 mmol), PPh (189 mg, 0.721 mmol) were added to THF (5 ml) , and then slowly added a solution of DIAD (146 mg, 0.721 mmol) in THF (5 ml) dropwise at room temperature. After the drop was completed, the mixture was raised to 50° C. and stirred for 5 hours. After the completion of the reaction detected by LC-MS, the mixture was concentrated and purified by column chromatography to obtain the product (32 mg, yield: 26.8%).
ESI-MS m/z:249.2[M+H] +。 ESI-MS m/z: 249.2 [M+H] + .
5-环丙氧基-2-甲基-1,2,3,4-四氢异喹啉-7-胺(IntB-38)5-cyclopropoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (IntB-38)
将5-环丙氧基-2-甲基-7-硝基-1,2,3,4-四氢异喹啉(32mg，0.129mol)、10％Pd/C(10mg)加入到MeOH(5mL)中，氢气置换三次后常温常压下搅拌反应20h。LC-MS检测反应完成后，混合液过滤，滤液浓缩至干，得类白色产物(34mg，收率：100％)。5-Cyclopropoxy-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (32 mg, 0.129 mol), 10% Pd/C (10 mg) were added to MeOH ( 5mL), the hydrogen was replaced three times, and the reaction was stirred at room temperature and pressure for 20h. After the reaction was detected by LC-MS, the mixture was filtered, and the filtrate was concentrated to dryness to obtain an off-white product (34 mg, yield: 100%).
ESI-MS m/z:219.2[M+H] +。 ESI-MS m/z: 219.2 [M+H] + .
采用不同的原料，参考IntB-38中类似的合成方法，得到表5中的目标中间体IntB-39至IntB-41。Using different raw materials and referring to the similar synthesis method in IntB-38, the target intermediates IntB-39 to IntB-41 in Table 5 were obtained.
表5table 5
Figure PCTCN2023071184-appb-000095
Figure PCTCN2023071184-appb-000095
Figure PCTCN2023071184-appb-000096
Figure PCTCN2023071184-appb-000096
制备例11 IntB-42的合成Preparation Example 11 Synthesis of IntB-42
Figure PCTCN2023071184-appb-000097
Figure PCTCN2023071184-appb-000097
6-环丙氧基-2-甲基-7-硝基-1,2,3,4-四氢异喹啉6-cyclopropoxy-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline
将环丙醇(200mg，3.45mmol)、碳酸铯(1.12g，3.45mmol)和6-氟-2-甲基-7-硝基-1,2,3,4-四氢异喹啉(105mg，0.5mmol)加入到NMP(5ml)中，混合液氩气保护下升温至100℃搅拌反应20小时。LC-MS检测反应完成后，混合液中加入EA(20ml)，水(20ml)，搅拌，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩至干得粗品(230mg，粗品)。Cyclopropanol (200mg, 3.45mmol), cesium carbonate (1.12g, 3.45mmol) and 6-fluoro-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (105mg , 0.5mmol) was added into NMP (5ml), and the mixture was heated to 100°C under the protection of argon and stirred for 20 hours. After the reaction was detected by LC-MS, EA (20ml) and water (20ml) were added to the mixture, stirred, separated, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude product (230 mg, crude).
6-环丙氧基-2-甲基-1,2,3,4-四氢异喹啉-7-胺(IntB-42)6-cyclopropoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (IntB-42)
将6-环丙氧基-2-甲基-7-硝基-1,2,3,4-四氢异喹啉(230mg，粗品)、10％Pd/C(20mg)加入到MeOH(10mL)中，氢气置换三次后常温常压下搅拌反应20h。LC-MS检测反应完成后，混合液过滤，滤液浓缩，残留物Flash纯化，冻干，得类白色产物(42mg，收率：38.5％)。6-Cyclopropoxy-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (230 mg, crude product), 10% Pd/C (20 mg) were added to MeOH (10 mL ), hydrogen was replaced three times and then stirred and reacted for 20 h at room temperature and pressure. After the reaction was detected by LC-MS, the mixture was filtered, the filtrate was concentrated, and the residue was flash-purified and lyophilized to obtain an off-white product (42 mg, yield: 38.5%).
ESI-MS m/z:219.2[M+H] +。 ESI-MS m/z: 219.2 [M+H] + .
采用不同的原料，参考IntB-42中类似的合成方法，得到表6中的目标中间体IntB-43至IntB-45。Using different raw materials and referring to the similar synthesis method in IntB-42, the target intermediates IntB-43 to IntB-45 in Table 6 were obtained.
表6Table 6
Figure PCTCN2023071184-appb-000098
Figure PCTCN2023071184-appb-000098
Figure PCTCN2023071184-appb-000099
Figure PCTCN2023071184-appb-000099
制备例12 IntB-46的合成Preparation Example 12 Synthesis of IntB-46
Figure PCTCN2023071184-appb-000100
Figure PCTCN2023071184-appb-000100
参考IntB-1和IntB-42的合成方法制备。Refer to the synthesis method of IntB-1 and IntB-42 for preparation.
制备例13 IntB-47的合成Preparation Example 13 Synthesis of IntB-47
Figure PCTCN2023071184-appb-000101
Figure PCTCN2023071184-appb-000101
(3-(2-甲基-7-硝基-1,2,3,4-四氢异喹啉-5-基)环丁基)甲醇(3-(2-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclobutyl)methanol
将3-(2-甲基-7-硝基-1,2,3,4-四氢异喹啉-5-基)环丁烷-1-羧酸甲酯(320mg，1.05mmol，参考IntB-1的方法制备)加入到THF(10ml)、MeOH(1ml)中，室温下加入NaBH 4(60mg，1.58mmol)，混合液室温搅拌反应2h。LC-MS检测反应完成后，混合液浓缩，残留物加入EA(20ml)，水(20ml)，搅拌，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩至干得粗品(315mg，粗品)。 Methyl 3-(2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclobutane-1-carboxylate (320 mg, 1.05 mmol, refer to IntB -1) was added to THF (10ml) and MeOH (1ml), NaBH 4 (60mg, 1.58mmol) was added at room temperature, and the mixture was stirred at room temperature for 2h. After the LC-MS detection reaction was completed, the mixed solution was concentrated, and the residue was added with EA (20ml), water (20ml), stirred, separated, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to Crude product (315 mg, crude) was obtained by drying.
ESI-MS m/z:277.3[M+H] +。 ESI-MS m/z: 277.3 [M+H] + .
(3-(2-甲基-7-硝基-1,2,3,4-四氢异喹啉-5-基)环丁基)乙酸甲酯Methyl (3-(2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclobutyl)acetate
将(3-(2-甲基-7-硝基-1,2,3,4-四氢异喹啉-5-基)环丁基)甲醇(315mg，1.05mmol，粗品)加入到DCM(10ml)、TEA(318mg，3.15mmol)中，室温下滴加乙酰氯(124mg，1.58mmol)的DCM(2ml)溶液，滴毕，混合液室温搅拌反应2h。LC-MS检测反应完成 后，混合液加入水(20ml)，搅拌，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩至干得粗品(340mg，粗品)。(3-(2-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclobutyl)methanol (315 mg, 1.05 mmol, crude) was added to DCM ( 10ml), TEA (318mg, 3.15mmol), a solution of acetyl chloride (124mg, 1.58mmol) in DCM (2ml) was added dropwise at room temperature, and the mixture was stirred at room temperature for 2h. After the reaction was detected by LC-MS, water (20ml) was added to the mixture, stirred, and separated. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude product (340mg, crude product).
(3-(7-氨基-2-甲基-1,2,3,4-四氢异喹啉-5-基)环丁基)醋酸甲酯(IntB-47)Methyl (3-(7-amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclobutyl)acetate (IntB-47)
将(3-(2-甲基-7-硝基-1,2,3,4-四氢异喹啉-5-基)环丁基)乙酸甲酯(340mg，粗品)、10％Pd/C(40mg)加入到MeOH(10mL)中，氢气置换三次后常温常压下搅拌反应20h。LC-MS检测反应完成后，混合液过滤，滤液浓缩，残留物Flash纯化，冻干，得类白色产物(73mg，收率：24.1％)。Methyl (3-(2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclobutyl)acetate (340 mg, crude product), 10% Pd/ C (40 mg) was added into MeOH (10 mL), hydrogen was replaced three times, and the reaction was stirred under normal temperature and pressure for 20 h. After the reaction was detected by LC-MS, the mixture was filtered, the filtrate was concentrated, and the residue was flash-purified and freeze-dried to obtain an off-white product (73 mg, yield: 24.1%).
ESI-MS m/z:289.3[M+H] +。 ESI-MS m/z: 289.3 [M+H] + .
制备例14 IntB-48的合成Preparation Example 14 Synthesis of IntB-48
Figure PCTCN2023071184-appb-000102
Figure PCTCN2023071184-appb-000102
(2-甲基-5-(3-氧代环己基)-1,2,3,4-四氢异喹啉-7-基)氨基甲酸叔丁酯(2-Methyl-5-(3-oxocyclohexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)carbamate tert-butyl ester
将3-(2-甲基-7-硝基-1,2,3,4-四氢异喹啉-5-基)环己基-2-烯-1-酮(550mg，1.923mmol，参考IntB-1的方法合成)、Boc 2O(630mg，2.885mmol)、10％Pd/C(100mg)加入到MeOH(40mL)中，氢气置换三次后常温常压下搅拌反应48h。LC-MS检测反应完成后，混合液过滤，滤液浓缩得类白色产物(572mg，收率：83％)。 3-(2-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclohexyl-2-en-1-one (550 mg, 1.923 mmol, refer to IntB Synthesized by the method of -1), Boc 2 O (630mg, 2.885mmol), 10% Pd/C (100mg) were added into MeOH (40mL), replaced by hydrogen three times, and stirred at normal temperature and pressure for 48h. After the reaction was detected by LC-MS, the mixture was filtered, and the filtrate was concentrated to obtain an off-white product (572 mg, yield: 83%).
ESI-MS m/z:359.3[M+H] +。 ESI-MS m/z: 359.3 [M+H] + .
(5-(3-羟基环己基)-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基甲酸叔丁酯(5-(3-Hydroxycyclohexyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)carbamate tert-butyl ester
将(2-甲基-5-(3-氧代环己基)-1,2,3,4-四氢异喹啉-7-基)氨基甲酸叔丁酯(180mg，0.5mmol)加入到THF(10ml)中，室温下加入NaBH 4(9.4mg，0.25mmol)，混合液室温搅拌反应2h。LC-MS检测反应完成后，混合液浓缩，残留物加入EA(20ml)，水(20ml)，搅拌，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩至干得粗品(210mg，粗品)。 (2-Methyl-5-(3-oxocyclohexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)carbamate (180 mg, 0.5 mmol) was added to THF (10ml), NaBH 4 (9.4mg, 0.25mmol) was added at room temperature, and the mixture was stirred at room temperature for 2h. After the LC-MS detection reaction was completed, the mixed solution was concentrated, and the residue was added with EA (20ml), water (20ml), stirred, separated, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to Crude product (210 mg, crude product) was obtained by drying.
ESI-MS m/z:361.3[M+H] +。 ESI-MS m/z: 361.3 [M+H] + .
3-(7-((叔丁氧基羰基)氨基)-2-甲基-1,2,3,4-四氢异喹啉-5-基)环己基乙酸酯3-(7-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclohexyl acetate
将(5-(3-羟基环己基)-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基甲酸叔丁酯(210mg，0.5 mmol，粗品)加入到DCM(10ml)、TEA(202mg，2mmol)中，室温下滴加乙酰氯(59mg，0.75mmol)的DCM(2ml)溶液，滴毕，混合液室温搅拌反应2h。LC-MS检测反应完成后，混合液加入水(20ml)，搅拌，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩至干得粗品(230mg，粗品)。(5-(3-Hydroxycyclohexyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)carbamate (210 mg, 0.5 mmol, crude) was added to To DCM (10ml) and TEA (202mg, 2mmol), a solution of acetyl chloride (59mg, 0.75mmol) in DCM (2ml) was added dropwise at room temperature, and the mixture was stirred at room temperature for 2h. After the reaction was detected by LC-MS, water (20ml) was added to the mixture, stirred, and separated. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude product (230mg, crude product).
3-(7-氨基-2-甲基-1,2,3,4-四氢异喹啉-5-基)环己基乙酸酯(IntB-48)3-(7-Amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclohexyl acetate (IntB-48)
将3-(7-((叔丁氧基羰基)氨基)-2-甲基-1,2,3,4-四氢异喹啉-5-基)环己基乙酸酯(230mg，0.5mmol，粗品)加入到DCM(10ml)中，室温下加入4M的HCl/Diox(1ml，4mmol)，混合液室温搅拌反应2h。LC-MS检测反应完成后，混合液低温浓缩，残留物Flash纯化，冻干，得类白色固体产物(31mg，收率：20.5％)。3-(7-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)cyclohexyl acetate (230mg, 0.5mmol , crude product) was added to DCM (10ml), 4M HCl/Diox (1ml, 4mmol) was added at room temperature, and the mixture was stirred at room temperature for 2h. After the reaction was detected by LC-MS, the mixture was concentrated at low temperature, and the residue was flash-purified and lyophilized to obtain an off-white solid product (31 mg, yield: 20.5%).
ESI-MS m/z:303.3[M+H] +。 ESI-MS m/z: 303.3 [M+H] + .
采用不同的原料，参考IntB-48中类似的合成方法，得到表7中的目标中间体IntB-49。Using different raw materials, referring to the similar synthesis method in IntB-48, the target intermediate IntB-49 in Table 7 was obtained.
表7Table 7
Figure PCTCN2023071184-appb-000103
Figure PCTCN2023071184-appb-000103
制备例15 IntB-50的合成Preparation Example 15 Synthesis of IntB-50
Figure PCTCN2023071184-appb-000104
Figure PCTCN2023071184-appb-000104
(5-(3,3-二氟环己基)-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基甲酸叔丁酯(5-(3,3-Difluorocyclohexyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)carbamate tert-butyl ester
将(2-甲基-5-(3-氧代环己基)-1,2,3,4-四氢异喹啉-7-基)氨基甲酸叔丁酯(180mg，0.5mmol)加入到甲苯(5ml)中，后加入双(2-甲氧基乙基)氨基三氟化硫(221mg，1.0mmol)，混合液氩气保护下加热至80℃搅拌反应20小时。LC-MS检测反应完成后，混合液柱层 析纯化，得类白色固体产物(92mg，收率：48.4％)。(2-Methyl-5-(3-oxocyclohexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)carbamate tert-butyl ester (180 mg, 0.5 mmol) was added to toluene (5ml), then added bis(2-methoxyethyl)aminosulfur trifluoride (221mg, 1.0mmol), and the mixture was heated to 80°C under the protection of argon and stirred for 20 hours. After the reaction was detected by LC-MS, it was purified by mixed liquid column chromatography to obtain an off-white solid product (92 mg, yield: 48.4%).
ESI-MS m/z:381.3[M+H] +。 ESI-MS m/z: 381.3 [M+H] + .
5-(3,3-二氟环己基)-2-甲基-1,2,3,4-四氢异喹啉-7-胺(IntB-50)5-(3,3-Difluorocyclohexyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (IntB-50)
将(5-(3,3-二氟环己基)-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基甲酸叔丁酯(92mg，0.242mmol)加入到DCM(10ml)中，室温下加入4M的HCl/Diox(1ml，4mmol)，混合液室温搅拌反应2h。LC-MS检测反应完成后，混合液浓缩，残留物Flash纯化，冻干，得类白色固体产物(47mg，收率：69.3％)。(5-(3,3-Difluorocyclohexyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)carbamate tert-butyl ester (92 mg, 0.242 mmol) was added To DCM (10ml), 4M HCl/Diox (1ml, 4mmol) was added at room temperature, and the mixture was stirred at room temperature for 2h. After the reaction was detected by LC-MS, the mixture was concentrated, and the residue was flash-purified and lyophilized to obtain an off-white solid product (47 mg, yield: 69.3%).
ESI-MS m/z:281.3[M+H] +。 ESI-MS m/z: 281.3 [M+H] + .
实施例1 N-(5-氯-4-(吲哚-1-基)嘧啶-2-基)-5-环丙基-2-甲基-1,2,3,4-四氢异喹啉-7-胺(化合物1)的合成Example 1 N-(5-chloro-4-(indol-1-yl)pyrimidin-2-yl)-5-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinone Synthesis of Lin-7-amine (Compound 1)
Figure PCTCN2023071184-appb-000105
Figure PCTCN2023071184-appb-000105
1-1的合成：Synthesis of 1-1:
将二氢吲哚(119mg,1.0mmol)，2,4,5-三氯嘧啶(183mg，1.0mmol)和DIPEA(258mg，2.0mmol)加入到NMP(5mL)中，氩气保护后，100℃反应约3h。LC-MS检测反应完全后，将反应液浓缩，残留物柱层析纯化得淡黄色固体产物1-1(176mg，收率：66.2％)。Add indoline (119mg, 1.0mmol), 2,4,5-trichloropyrimidine (183mg, 1.0mmol) and DIPEA (258mg, 2.0mmol) into NMP (5mL), under argon protection, 100°C The reaction is about 3h. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated, and the residue was purified by column chromatography to obtain a pale yellow solid product 1-1 (176 mg, yield: 66.2%).
ESI-MS m/z:266.0[M+H] +。 ESI-MS m/z: 266.0 [M+H] + .
化合物1的合成Synthesis of compound 1
将1-1(100mg，0.376mmol)，IntB-1(76mg，0.376mmol)和MsOH(72mg，0.752mmol)加入异丙醇(5mL)中，氩气保护后，100℃反应过夜。LC-MS检测反应完全后，将反应液浓缩，残留物Flash纯化，得目标化合物1(121mg，收率：74.5％)。1-1 (100mg, 0.376mmol), IntB-1 (76mg, 0.376mmol) and MsOH (72mg, 0.752mmol) were added into isopropanol (5mL) and reacted overnight at 100°C under argon protection. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated, and the residue was flash-purified to obtain the target compound 1 (121 mg, yield: 74.5%).
ESI-MS m/z:432.2[M+H] +。 ESI-MS m/z: 432.2 [M+H] + .
采用不同的原料，参考实施例1中类似的合成方法，得到表8中的目标化合物2-17。Using different raw materials and referring to the similar synthesis method in Example 1, the target compounds 2-17 in Table 8 were obtained.
表8Table 8
Figure PCTCN2023071184-appb-000106
Figure PCTCN2023071184-appb-000106
Figure PCTCN2023071184-appb-000107
Figure PCTCN2023071184-appb-000107
实施例2 1-(5-氯-2-((5-环丙基-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)嘧啶-4-基)-1H-吲哚-3-羧酸(化合物18)的合成Example 2 1-(5-chloro-2-((5-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl )-1H-indole-3-carboxylic acid (compound 18) synthesis
Figure PCTCN2023071184-appb-000108
Figure PCTCN2023071184-appb-000108
化合物17参照化合物1的方法合成得到。Compound 17 was synthesized according to the method of compound 1.
化合物18的合成：Synthesis of Compound 18:
将化合物17(62mg，0.128mmol)溶于CH 3OH/THF/H 2O(2mL/2mL/1mL)中，加入LiOH.H 2O(42mg，1.0mmol)，室温反应约3h。LC-MS检测反应完全后，将反应液浓缩，残留物Flash纯化，冻干，得类白色固体化合物18(33mg，收率：54.4％)。 Compound 17 (62 mg, 0.128 mmol) was dissolved in CH 3 OH/THF/H 2 O (2 mL/2 mL/1 mL), LiOH.H 2 O (42 mg, 1.0 mmol) was added, and reacted at room temperature for about 3 h. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated, and the residue was flash-purified and lyophilized to obtain compound 18 as an off-white solid (33 mg, yield: 54.4%).
ESI-MS m/z:474.1[M+H] +。 ESI-MS m/z: 474.1 [M+H] + .
实施例3 1-(5-氯-2-((5-环丙基-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)嘧啶-4-基)-1H-吲哚-3-甲酰胺(化合物19)的合成Example 3 1-(5-chloro-2-((5-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl )-1H-indole-3-carboxamide (Compound 19) Synthesis
Figure PCTCN2023071184-appb-000109
Figure PCTCN2023071184-appb-000109
Figure PCTCN2023071184-appb-000110
Figure PCTCN2023071184-appb-000110
将化合物18(15mg，0.032mmol)、EDCI(9mg，0.048mmol)、HOBt(7mg，0.052mmol)、DIPEA(8mg，0.062mmol)加入到DMF(2mL)中，混合液氩气保护下室温搅拌30min，后加入1M的氨/THF溶液(0.1mL，0.1mmol)，混合液室温搅拌反应20h。LC-MS检测反应完成后，混合液Flash纯化，冻干，得类白色固体化合物19(7mg，收率：46.7％)。Compound 18 (15 mg, 0.032 mmol), EDCI (9 mg, 0.048 mmol), HOBt (7 mg, 0.052 mmol), DIPEA (8 mg, 0.062 mmol) were added to DMF (2 mL), and the mixture was stirred at room temperature for 30 min under the protection of argon , and then added 1M ammonia/THF solution (0.1 mL, 0.1 mmol), and the mixture was stirred at room temperature for 20 h. After the reaction was detected by LC-MS, the mixture was flash-purified and freeze-dried to obtain compound 19 (7 mg, yield: 46.7%) as an off-white solid.
ESI-MS m/z:473.1[M+H] +。 ESI-MS m/z: 473.1 [M+H] + .
类似于上述化合物18、化合物19的合成，采用不同中间体为原料，可以得到表9中目标化合物20-25、27-34、36-48。Similar to the synthesis of compound 18 and compound 19 above, using different intermediates as raw materials, the target compounds 20-25, 27-34, and 36-48 in Table 9 can be obtained.
表9Table 9
Figure PCTCN2023071184-appb-000111
Figure PCTCN2023071184-appb-000111
Figure PCTCN2023071184-appb-000112
Figure PCTCN2023071184-appb-000112
Figure PCTCN2023071184-appb-000113
Figure PCTCN2023071184-appb-000113
Figure PCTCN2023071184-appb-000114
Figure PCTCN2023071184-appb-000114
实施例4(1-(5-氯-2-((5-环丙基-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)嘧啶-4-基)吲哚-3-基)甲醇(化合物26)的合成Example 4 (1-(5-chloro-2-((5-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidine-4- yl)indol-3-yl)methanol (compound 26) synthesis
Figure PCTCN2023071184-appb-000115
Figure PCTCN2023071184-appb-000115
化合物26的合成Synthesis of compound 26
将化合物21(48mg，0.099mmol)加入到THF(5mL)、MeOH(0.5mL)的混合液中，后室温下加入NaBH 4(8mg，0.212mmol)，室温搅拌反应3h。LC-MS检测反应完成，混合物浓缩，残留物Flash纯化，冻干，得类白色固体化合物26(22mg，收率：48.6％) Compound 21 (48 mg, 0.099 mmol) was added to a mixture of THF (5 mL) and MeOH (0.5 mL), then NaBH 4 (8 mg, 0.212 mmol) was added at room temperature, and the reaction was stirred at room temperature for 3 h. LC-MS detected that the reaction was complete, the mixture was concentrated, and the residue was flash-purified and lyophilized to obtain off-white solid compound 26 (22 mg, yield: 48.6%)
ESI-MS m/z:462.2[M+H] +。 ESI-MS m/z: 462.2 [M+H] + .
实施例5(1-(5-氯-2-((5-环丙基-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)嘧啶-4-基)-3-甲基吲哚-3-基)甲醇(化合物35)的合成Example 5 (1-(5-chloro-2-((5-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidine-4- Synthesis of -3-methylindol-3-yl)methanol (compound 35)
化合物35可参照化合物26的方法合成得到。Compound 35 can be synthesized according to the method of compound 26.
实施例6甲基2-(1-(5-氯-2-((5-环丙基-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)嘧啶-4-基)- 3-甲基吲哚-3-基)乙酸酯(化合物49)的合成Example 6 Methyl 2-(1-(5-chloro-2-((5-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino) Synthesis of pyrimidin-4-yl)-3-methylindol-3-yl)acetate (compound 49)
Figure PCTCN2023071184-appb-000116
Figure PCTCN2023071184-appb-000116
49-1的合成:Synthesis of 49-1:
将IntA-1(2.2g,10.73mmol)，2,4,5-三氯嘧啶(1.97g，10.73mmol)和DIPEA(1.4g，10.73mmol)加入到正丁醇(20mL)中，氩气保护后，100℃反应约3h。LC-MS检测反应完全后，将反应液浓缩，残留物柱层析纯化得淡黄色固体产物49-1(3.78g，收率：100％)。IntA-1 (2.2g, 10.73mmol), 2,4,5-trichloropyrimidine (1.97g, 10.73mmol) and DIPEA (1.4g, 10.73mmol) were added to n-butanol (20mL) under argon protection After that, react at 100°C for about 3h. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated, and the residue was purified by column chromatography to obtain a pale yellow solid product 49-1 (3.78 g, yield: 100%).
化合物49合成:Synthesis of compound 49:
将49-1(100mg，0.284mmol)，IntB-1(63mg，0.312mmol)和MsOH(27mg，0.284mmol)加入异丙醇(5mL)中，氩气保护后，100℃反应48h。LC-MS检测反应完全后，将反应液浓缩得粗品，取少量粗品pre-TLC纯化，得目标化合物49。剩余粗品直接用于下一步。Add 49-1 (100mg, 0.284mmol), IntB-1 (63mg, 0.312mmol) and MsOH (27mg, 0.284mmol) into isopropanol (5mL), and react at 100°C for 48h under argon protection. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated to obtain a crude product, and a small amount of the crude product was purified by pre-TLC to obtain the target compound 49. The remaining crude product was used directly in the next step.
ESI-MS m/z:518.2[M+H] +。 ESI-MS m/z: 518.2 [M+H] + .
实施例7 2-(1-(5-氯-2-((5-环丙基-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)嘧啶-4-基)-3-甲基吲哚-3-基)乙酸(化合物50)的合成Example 7 2-(1-(5-chloro-2-((5-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidine- Synthesis of 4-yl)-3-methylindol-3-yl)acetic acid (compound 50)
Figure PCTCN2023071184-appb-000117
Figure PCTCN2023071184-appb-000117
将上述化合物49的粗品(0.284mmol)溶于CH 3OH/THF/H 2O(3mL/3mL/1mL)中，加入LiOH.H 2O(179mg，4.26mmol)，室温反应约2h。LC-MS检测反应完全后，将反应液浓缩，残留物HPLC制备纯化，得类白色固体目标化合物50(70mg，收率：48.9％)。 The above crude compound 49 (0.284mmol) was dissolved in CH 3 OH/THF/H 2 O (3mL/3mL/1mL), LiOH.H 2 O (179mg, 4.26mmol) was added and reacted at room temperature for about 2h. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated, and the residue was prepared and purified by HPLC to obtain the target compound 50 (70 mg, yield: 48.9%) as an off-white solid.
ESI-MS m/z:504.3[M+H] +。 ESI-MS m/z: 504.3 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ9.26(s,1H),8.25(s,1H),7.26(d,J＝8.9Hz,3H),7.11(t,J＝7.5Hz,1H),7.01(s,1H),6.94(t,J＝7.4Hz,1H),4.38(d,J＝10.7Hz,1H),3.98(d,J＝10.9Hz,1H),3.31(s,2H),2.77(s,2H),2.70–2.52(m,4H),2.28(s,3H),1.75(s,1H),1.34(s,3H),0.79(s,2H),0.41(s,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ9.26(s,1H),8.25(s,1H),7.26(d,J=8.9Hz,3H),7.11(t,J=7.5Hz,1H) ,7.01(s,1H),6.94(t,J=7.4Hz,1H),4.38(d,J=10.7Hz,1H),3.98(d,J=10.9Hz,1H),3.31(s,2H) ,2.77(s,2H),2.70–2.52(m,4H),2.28(s,3H),1.75(s,1H),1.34(s,3H),0.79(s,2H),0.41(s,2H ).
类似于上述化合物49及50的合成，采用不同中间体为原料，可以得到表10中目标化合物51-155。Similar to the synthesis of the above-mentioned compounds 49 and 50, using different intermediates as raw materials, the target compounds 51-155 in Table 10 can be obtained.
表10Table 10
Figure PCTCN2023071184-appb-000118
Figure PCTCN2023071184-appb-000118
Figure PCTCN2023071184-appb-000119
Figure PCTCN2023071184-appb-000119
Figure PCTCN2023071184-appb-000120
Figure PCTCN2023071184-appb-000120
Figure PCTCN2023071184-appb-000121
Figure PCTCN2023071184-appb-000121
Figure PCTCN2023071184-appb-000122
Figure PCTCN2023071184-appb-000122
Figure PCTCN2023071184-appb-000123
Figure PCTCN2023071184-appb-000123
Figure PCTCN2023071184-appb-000124
Figure PCTCN2023071184-appb-000124
Figure PCTCN2023071184-appb-000125
Figure PCTCN2023071184-appb-000125
Figure PCTCN2023071184-appb-000126
Figure PCTCN2023071184-appb-000126
Figure PCTCN2023071184-appb-000127
Figure PCTCN2023071184-appb-000127
Figure PCTCN2023071184-appb-000128
Figure PCTCN2023071184-appb-000128
生物实施例1 HPK1激酶抑制活性测定Biological Example 1 Determination of HPK1 Kinase Inhibitory Activity
采用以MBP为底物的生化测定检测人HPK1(MAP4K1)的酶活性。HPK1对底物的磷酸化的影响表明其激酶活性，激酶测定均在白色384孔板中进行，该检测利用Promega HPK1 Kinase Assay(Promega V4099)标准化试剂盒。The enzymatic activity of human HPK1 (MAP4K1) was detected using a biochemical assay with MBP as substrate. The effect of HPK1 on the phosphorylation of substrates indicates its kinase activity. Kinase assays were performed in white 384-well plates using the Promega HPK1 Kinase Assay (Promega V4099) standardized kit.
HPK1激酶分析中反应体系包含以下物质：(1)10ng HPK1激酶，500ng MBP底物，10μM ATP。(2)HPK1 Kinase Buffer:40mM Tris,7.5；20mM MgCl2；0.1mg/mL BSA；50μM DTT。(3)从DMSO储备液中添加按剂量反应排列的抑制剂(10，2，0.4，0.08，0.016，0.0032，0.00064，0um，八个梯度)。在25℃下使反应进行2.5小时，反应后使用ADP-Glo试剂进行检测。在读板仪上测量发光，拟合数据，并根据数据计算IC 50。结果见下表11。 The reaction system in the HPK1 kinase assay contains the following substances: (1) 10 ng HPK1 kinase, 500 ng MBP substrate, 10 μM ATP. (2) HPK1 Kinase Buffer: 40mM Tris, 7.5; 20mM MgCl2; 0.1mg/mL BSA; 50μM DTT. (3) Add dose-response-arranged inhibitors (10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, 0um, eight gradients) from the DMSO stock solution. The reaction was carried out at 25° C. for 2.5 hours, and detection was performed using ADP-Glo reagent after the reaction. Luminescence was measured on a plate reader, the data fitted, and IC50 calculated from the data. The results are shown in Table 11 below.
表11本发明化合物对HPK1激酶抑制活性(IC 50,nM) Table 11 Compounds of the present invention have inhibitory activity on HPK1 kinase (IC 50 , nM)
化合物compound IC 50 IC50 化合物compound IC 50 IC50 化合物compound IC 50 IC50 化合物compound IC 50 IC50 化合物compound IC 50 IC50
11 BB 3232 AA 6363 AA 9494 BB 125125 AA
22 BB 3333 AA 6464 AA 9595 BB 126126 AA
33 AA 3434 AA 6565 AA 9696 AA 127127 AA
44 AA 3535 AA 6666 AA 9797 AA 128128 AA
55 AA 3636 AA 6767 AA 9898 AA 129129 AA
66 AA 3737 AA 6868 AA 9999 AA 130130 AA
77 AA 3838 AA 6969 AA 100100 AA 131131 AA
88 AA 3939 AA 7070 BB 101101 AA 132132 AA
99 AA 4040 AA 7171 BB 102102 AA 133133 AA
1010 AA 4141 AA 7272 AA 103103 AA 134134 AA
1111 AA 4242 AA 7373 BB 104104 AA 135135 AA
1212 BB 4343 AA 7474 AA 105105 AA 136136 AA
1313 AA 4444 AA 7575 BB 106106 AA 137137 AA
1414 AA 4545 AA 7676 AA 107107 AA 138138 AA
1515 AA 4646 AA 7777 AA 108108 AA 139139 AA
1616 AA 4747 AA 7878 AA 109109 AA 140140 AA
1717 AA 4848 AA 7979 AA 110110 AA 141141 AA
1818 AA 4949 AA 8080 AA 111111 AA 142142 AA
1919 AA 5050 AA 8181 AA 112112 AA 143143 AA
2020 BB 5151 AA 8282 AA 113113 AA 144144 AA
21twenty one AA 5252 AA 8383 AA 114114 AA 145145 AA
22twenty two AA 5353 AA 8484 AA 115115 AA 146146 AA
23twenty three AA 5454 AA 8585 AA 116116 AA 147147 AA
24twenty four AA 5555 AA 8686 BB 117117 AA 148148 AA
2525 AA 5656 AA 8787 AA 118118 AA 149149 AA
2626 AA 5757 AA 8888 AA 119119 AA 150150 AA
2727 AA 5858 AA 8989 AA 120120 AA 151151 AA
2828 AA 5959 AA 9090 AA 121121 AA 152152 AA
2929 AA 6060 AA 9191 AA 122122 AA 153153 AA
3030 AA 6161 AA 9292 AA 123123 AA 154154 AA
3131 AA 6262 AA 9393 AA 124124 AA 155155 AA
A表示IC 50<50nM A means IC 50 <50nM
B表示50nM≤IC 50≤200nM B means 50nM≤IC 50 ≤200nM
C表示IC 50>200nM C means IC 50 >200nM
生物实施例2 Jurkat细胞IL-2诱导分泌活性测定Biological Example 2 Determination of IL-2 Induced Secretion Activity of Jurkat Cells
通过测定在CD3/CD28抗体(ImmunoCult TM Human CD3/CD28 T Cell Activator 10971)激活的Jurkat T细胞产生的IL-2，是否受添加后的化合物的影响，判断在T细胞中HPK1通路上起到的抑制作用。 By determining whether the IL-2 produced by Jurkat T cells activated by the CD3/CD28 antibody (ImmunoCult TM Human CD3/CD28 T Cell Activator 10971) is affected by the added compound, it can be judged that the role played by the HPK1 pathway in T cells inhibition.
检测利用cisbio_IL2-HTRF试剂盒(62HIL02PET)，在特定96孔检测板进行。在普通96孔细胞培养板上以1*10 5/well浓度培养Jurkat细胞，并添加本发明化合物，并按照一定浓度添加CD3/CD28抗体激活细胞，化合物最高浓度为1uM，化合物处理72小时后回收细胞上清液，作为实验样本。HTRF测定实验中首先分配16μL的每种IL2标准品(Std 0-Std 7)放入每个标准孔中。同时将16μL的回收样品分配到每个样品孔中。之后将4μL预混合的IL2 Eu Cryptate antibody，IL2-d2 antibody抗体分配到所有孔中，密封孔 板并在室温下孵育。室温孵育3h后，拆下平板封口机并在兼容
Figure PCTCN2023071184-appb-000129
的机器上阅读。通过计算标准曲线得出样本中具体的IL2浓度。结果见下表12。 The detection was performed on a specific 96-well detection plate using the cisbio_IL2-HTRF kit (62HIL02PET). Cultivate Jurkat cells on a common 96-well cell culture plate at a concentration of 1*10 5 /well, add the compound of the present invention, and add CD3/CD28 antibody at a certain concentration to activate the cells. The highest concentration of the compound is 1uM, and the compound is recovered after 72 hours of treatment Cell supernatant, as the experimental sample. In the HTRF assay experiment, 16 μL of each IL2 standard (Std 0-Std 7) was first dispensed into each standard well. Simultaneously dispense 16 µL of the recovered sample into each sample well. Afterwards, 4 μL of pre-mixed IL2 Eu Cryptate antibody and IL2-d2 antibody were dispensed into all wells, the wells were sealed and incubated at room temperature. After incubating at room temperature for 3 h, remove the plate sealer and place in a compatible
Figure PCTCN2023071184-appb-000129
read on the machine. The specific IL2 concentration in the sample was obtained by calculating the standard curve. The results are shown in Table 12 below.
表12本发明化合物对Jurkat细胞IL-2诱导分泌活性Table 12 Compounds of the present invention induce secretion activity of Jurkat cells IL-2
Figure PCTCN2023071184-appb-000130
Figure PCTCN2023071184-appb-000130
Figure PCTCN2023071184-appb-000131
Figure PCTCN2023071184-appb-000131
Figure PCTCN2023071184-appb-000132
Figure PCTCN2023071184-appb-000132
生物实施例3本发明化合物的体内药代动力学实验The in vivo pharmacokinetic experiment of biological embodiment 3 compounds of the present invention
选取7至10周龄的CD-1雌性小鼠，静脉和口服给药的剂量分别为2mg/kg和10mg/kg。小鼠在给药前禁食至少12小时，给药4小时后恢复供食，整个实验期间自由饮水。CD-1 female mice aged 7 to 10 weeks were selected, and the doses of intravenous and oral administration were 2 mg/kg and 10 mg/kg, respectively. Mice were fasted for at least 12 hours before administration, fed again 4 hours after administration, and had free access to water throughout the experiment.
实验当天静脉组动物通过尾静脉单次注射给予相应化合物，给药体积为10mL/kg；口服组动物通过灌胃单次注射给予相应化合物，给药体积为10mL/kg。在给药前称量动物体重，根据体重计算给药体积。样品采集时间为:0.083、0.167、0.5、1、2、4、8和24h。每个时间点通过眼眶静脉丛采集大约200uL全血以及用于制备血浆，供高效液相色谱-串联质谱(LC-MS/MS)进行浓度测定。采用Winnolin药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法计算药动学参数。On the day of the experiment, 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 time: 0.083, 0.167, 0.5, 1, 2, 4, 8 and 24h. About 200 uL 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.
生物实施例4本发明化合物的体内药效实验Biological Example 4 In vivo drug efficacy test of the compound of the present invention
雌性BALB/c或C57BL6N小鼠(6周，18-22g)由中国维通利华公司提供，并在检疫和适应一周后使用。所有动物饲养在23±2℃，相对湿度50±5％的房间里，每天08:00-20:00人工照明，每小时换气13-18次。他们可以自由地获得标准的实验室饮食和水。Female BALB/c or C57BL6N mice (6 weeks, 18–22 g) were provided by China Victoria Lihua Company and used after one week of quarantine and adaptation. All animals were kept in a room at 23±2°C, relative humidity 50±5%, with artificial lighting from 08:00 to 20:00 every day, and 13-18 air changes per hour. They had free access to a standard laboratory diet and water.
小鼠结肠癌CT26或MC38细胞用含10％胎牛血清的1640于37℃、5％CO2培养箱中常规培养，传代后，待细胞达到所需量时，收集细胞。在BALB/c小鼠右侧皮下注射1×10 6个CT26或MC38成瘤，待肿瘤生长至100mm 3左右后，将动物随机分为溶剂对照组、受试化合物单药组、受试化合物+PD-1连用组、PD-1单药组后开始给药。在给药后第3，7，10，14，17和21天用卡尺测量肿瘤体积。按照肿瘤生长抑制率(TGI)＝1-(给药组第28天肿瘤体积-给药组第一天肿瘤体积)/(对照组第28天给药体积-对照组第一天肿瘤体积)，评 价化合物抑制肿瘤生长能力。根据小鼠体重和状态评价化合物的毒性。 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, the cells were collected when the cells reached the required amount. On the right side of BALB/c mice, 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. According to the rate of tumor growth inhibition (TGI)=1-(the tumor volume on the 28th day of the administration group-the tumor volume on the first day of the administration group)/(the administration volume on the 28th day of the control group-the tumor volume on the first day of the control group), Compounds were evaluated for their ability to inhibit tumor growth. Compound toxicity was assessed based on mouse body weight and state.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific implementations of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these implementations without departing from the principle and essence of the present invention. Revise. Accordingly, the protection scope of the present invention is defined by the appended claims.

Claims (22)

  1. 一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：A compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
    Figure PCTCN2023071184-appb-100001
    Figure PCTCN2023071184-appb-100001
    通式(1)中：In general formula (1):
    L为化学键、-O-、-S-、-C(O)-、-N(R a)-、*-C(O)O-、-C(O)O-*、*-C(O)N(R a)-、-C(O)N(R a)-*、(C1-C8)亚烷基、(C1-C8)亚烷基-O-*、(C1-C8)亚烷基-N(R a)-*、(C2-C8)亚烯基或(C2-C8)亚炔基，其中所述(C1-C8)亚烷基、(C1-C8)亚烷基-O-*、(C1-C8)亚烷基-N(R a)-*、(C2-C8)亚烯基或(C2-C8)亚炔基可各自独立任选被1，2，3或4个R c取代；其中*表示与苯环相连； L is a chemical bond, -O-, -S-, -C(O)-, -N(R a )-, *-C(O)O-, -C(O)O-*, *-C(O )N(R a )-, -C(O)N(R a )-*, (C1-C8) alkylene, (C1-C8) alkylene-O-*, (C1-C8) alkylene Group-N(R a )-*, (C2-C8) alkenylene or (C2-C8) alkynylene, wherein the (C1-C8) alkylene, (C1-C8) alkylene-O -*, (C1-C8) alkylene-N(R a )-*, (C2-C8) alkenylene or (C2-C8) alkynylene can be independently optionally replaced by 1, 2, 3 or 4 A R c substitution; where * means that it is connected to the benzene ring;
    X 1选自-C(R aR b)-、化学键、-O-、-S-或-C(O)-； X 1 is selected from -C(R a R b )-, chemical bond, -O-, -S- or -C(O)-;
    X 2选自-C(R aR b)-或-C(O)； X 2 is selected from -C(R a R b )- or -C(O);
    X 3选自-N(R a)-或-C(R aR b)-； X 3 is selected from -N(R a )- or -C(R a R b )-;
    R 1为-H、-D、卤素、羟基、氨基、氰基、硝基、-OR a、-NR aR b、-C(O)R a、-CO 2R a、-S(O) pR a、-S(O) pNR aR b、-CONR aR b、-NR aCOR b、-NR aCO 2R b、-NR aS(O) pR b、(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基或(5-14元)杂芳基，其中所述(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基或(5-14元)杂芳基可各自独立任选被1，2，3或4个R c取代； R 1 is -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO 2 Ra , -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) heteroaryl, wherein the (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-membered) heteroaryl groups can each independently be optionally substituted by 1, 2, 3 or 4 R ;
    R 2为(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基或(5-14元)杂芳基，其中所述(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基或(5-14元)杂芳基可各自独立任选被1，2，3或4个R c取代； R 2 is (C3-C14) cycloalkyl, (3-14 member) heterocycloalkyl, (C6-C14) aryl or (5-14 member) heteroaryl, wherein the (C3-C14) ring Alkyl, (3-14 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl can be independently optionally substituted by 1, 2, 3 or 4 R c ;
    各R 3和R 4各自独立为-H、-D、卤素、羟基、氨基、氰基、硝基、-OR a、-NR aR b、-C(O)R a、-CO 2R a、-(CH 2) mR a、-(CH 2) mCO 2R a、-(CH 2) mCONR aR b、-S(O) pR a、-S(O) pNR aR b、 -CONR aR b、-C(＝NR a)-NR aR b、-NR aCOR b、-CR aCONR aR b、-NR aCO 2R a、-NR aS(O) pNR aR b、-NR aS(O) pR a、-POR aR b、(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基、-(C1-C8)亚烷基-(5-14元)杂芳基，其中所述(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基、-(C1-C8)亚烷基-(5-14元)杂芳基可各自独立任选被1，2，3或4个R c取代； Each of R3 and R4 is independently -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO 2 R a , -(CH 2 ) m R a , -(CH 2 ) m CO 2 R a , -(CH 2 ) m CONR a R b , -S(O) p R a , -S(O) p NR a R b , -CONR a R b , -C(=NR a )-NR a R b , -NR a COR b , -CR a CONR a R b , -NR a CO 2 R a , -NR a S(O) p NR a R b , -NR a S(O) p R a , -POR a R b , (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 Group, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14 member) heterocycloalkyl, -(C1-C8) alkylene Base-(C6-C14) aryl, -(C1-C8) alkylene-(5-14 yuan) heteroaryl, wherein the (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) Haloalkyl, (C2-C8) Alkenyl, (C2-C8) Alkynyl, (C3-C14) Cycloalkyl, (3-14) Heterocycloalkyl, (C6-C14) Aryl Base, (5-14) heteroaryl, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14) heterocycloalkane Base, -(C1-C8) alkylene-(C6-C14) aryl, -(C1-C8) alkylene-(5-14 yuan) heteroaryl can be independently optionally replaced by 1,2,3 or 4 R c substitutions;
    或当
    Figure PCTCN2023071184-appb-100002
    代表单键和m是2时，2个R 3可以连接在2个不同的碳原子上或连接在同一个碳原子上；连接在同一个碳原子上的2个R 3可以相同也可以不同；     or when
    Figure PCTCN2023071184-appb-100002
    When it represents a single bond and m is 2, the two R3s can be connected to two different carbon atoms or the same carbon atom; the two R3s connected to the same carbon atom can be the same or different;
    或者连接在同一个碳原子上的2个R 3与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可各自独立任选被1，2，3或4个R c取代； Or the 2 R3s connected to the same carbon atom and the carbon atoms to which they are connected can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein the (4-7 Yuan) heterocycloalkyl or (C3-C6) cycloalkyl can be independently optionally substituted by 1, 2, 3 or 4 R c ;
    或当2个R 3连接在同一个碳原子上时，2个R 3可以形成一个氧代基； Or when 2 R 3 are connected on the same carbon atom, 2 R 3 can form an oxo group;
    R a和R b各自独立为-H、-D、卤素、羟基、氨基、氰基、硝基、-OR xa、-NR xaR xb、-(CH 2) mOR xa、-(CH 2) mNR xaR xb、-C(O)R xa、-CO 2R xa、-S(O) pR xa、-S(O) pNR xaR xb、-CONR xaR xb、-C(＝NR xa)-NR xbR xc、-NR xaCOR xb、-NR xaCONR xbR xc、-NR xaCO 2R xb、-NR xaS(O) pNR xbR xc、-NR xaS(O) pR xb、(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基、-(C1-C8)亚烷基-(5-14元)杂芳基，其中所述(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基、-(C1-C8)亚烷基-(5-14元)杂芳基可各自独立任选被1，2，3或4个R c取代；或当2个R a连接在同一个原子上时，2个R a可以形成一个氧代基；或当2个R b连接在同一个原子上时，2个R b可以形成一个氧代基； R a and R b are each independently -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR xa , -NR xa R xb , -(CH 2 ) m OR xa , -(CH 2 ) m NR xa R xb , -C(O)R xa , -CO 2 R xa , -S(O) p R xa , -S(O) p NR xa R xb , -CONR xa R xb , -C(= NR xa )-NR xb R xc , -NR xa COR xb , -NR xa CONR xb R xc , -NR xa CO 2 R xb , -NR xa S(O) p NR xb R xc , -NR xa S(O ) p R xb , (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14 ) cycloalkyl group, (3-14 member) heterocycloalkyl group, (C6-C14) aryl group, (5-14 member) heteroaryl group, -(C1-C8) alkylene group-(C3-C14) ring Alkyl, -(C1-C8)alkylene-(3-14 membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene Base-(5-14) heteroaryl, wherein said (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 member)heterocycloalkyl,-(C1-C8)alkylene-(C6-C14)aryl Group, -(C1-C8) alkylene-(5-14 yuan) heteroaryl can be independently optionally substituted by 1, 2, 3 or 4 R c ; or when 2 R a are connected to the same atom When on, 2 R a can form an oxo group; or when 2 R b are connected on the same atom, 2 R b can form an oxo group;
    或X 1上的R a和相邻的X 2与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C9)环烷基，其中所述(5-7元)杂环烷基或(C3-C9)环烷基各自独立任选被1，2，3或4个R c取代； Or R a on X 1 and adjacent X 2 and the atoms they are connected to can jointly form a (5-7 member) heterocycloalkyl or (C3-C9) cycloalkyl group, wherein the (5-7 member ) heterocycloalkyl or (C3-C9) cycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R c ;
    或者连接在同一个原子上的R a和R b与其连接的原子共同构成一个(5-7元)杂环烷基或(C3-C9)环烷基，其中所述的(5-7元)杂环烷基或(C3-C9)环烷基各自独立任选被1，2， 3或4个R c取代； Or R a and R b connected to the same atom and the atoms they connect together form a (5-7 membered) heterocycloalkyl or (C3-C9) cycloalkyl group, wherein the (5-7 membered) Heterocycloalkyl or (C3-C9) cycloalkyl each independently optionally substituted by 1, 2, 3 or 4 R c ;
    或连接在同一个碳原子上的R a和R b可以形成一个氧代基； Or R a and R b connected to the same carbon atom can form an oxo group;
    R c为-H、-D、卤素、羟基、氨基、氰基、硝基、-OR xa、-NR xaR xb、-(CH 2) mOR xa、-(CH 2) mNR xaR xb、-C(O)R xa、-CO 2R xa、-S(O) pR xa、-S(O) pNR xaR xb、-CONR xaR xb、-C(＝NR xa)-NR xbR xc、-NR xaCOR xb、-NR xaCONR xbR xc、-NR xaCO 2R xb、-NR xaS(O) pNR xbR xc、-NR xaS(O) pR xb、(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C1-C8)烷氧基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基或-(C1-C8)亚烷基-(5-14元)杂芳基；或当2个R c连接在同一个原子上时，2个R c可以形成一个氧代基；或者连接在同一个碳原子上的2个R c与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基； R c is -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR xa , -NR xa R xb , -(CH 2 ) m OR xa , -(CH 2 ) m NR xa R xb , -C(O)R xa , -CO 2 R xa , -S(O) p R xa , -S(O) p NR xa R xb , -CONR xa R xb , -C(=NR xa )-NR xb R xc , -NR xa COR xb , -NR xa CONR xb R xc , -NR xa CO 2 R xb , -NR xa S(O) p NR xb R xc , -NR xa S(O) p R xb , (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-(C1-C8) alkoxy, -( C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14) heterocycloalkyl, -(C1-C8) alkylene-(C6 -C14) aryl or -(C1-C8) alkylene-(5-14 yuan) heteroaryl; or when 2 R c are connected to the same atom, 2 R c can form an oxo group ; or 2 R c connected to the same carbon atom and the carbon atom to which they are connected can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl;
    R xa、R xb和R xc各自独立为-H、(C1-C8)烷基、(C1-C8)烷氧基、(C1-C8)卤代烷基、(C2-C8)烯基，(C2-C8)炔基，(C3-C14)环烷基、(3-14元)杂环烷基、(C6-C14)芳基、(5-14元)杂芳基、-(C1-C8)亚烷基-(C3-C14)环烷基、-(C1-C8)亚烷基-(3-14元)杂环烷基、-(C1-C8)亚烷基-(C6-C14)芳基或-(C1-C8)亚烷基-(5-14元)杂芳基； 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;
    m为0、1或2的整数；m is an integer of 0, 1 or 2;
    q为0、1、2或3的整数；q is an integer of 0, 1, 2 or 3;
    p为0、1或2的整数。p is an integer of 0, 1 or 2.
  2. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，L为化学键、-O-、-S-、-C(O)-、-NH-、-N(CH 3)-、*-C(O)O-、-C(O)O-*、*-C(O)NH-、*-C(O)N(CH 3)-、-C(O)NH-*、-C(O)N(CH 3)-*、(C1-C3)亚烷基、(C1-C3)亚烷基-O-*、(C1-C3)亚烷基-NH-*或(C1-C3)亚烷基-N(CH 3)-*，其中所述(C1-C3)亚烷基、(C1-C3)亚烷基-O-*、(C1-C3)亚烷基-NH-*或(C1-C3)亚烷基-N(CH 3)-*可各自独立任选被1，2，3或4个R c取代；其中*表示与苯环相连。 The compound as claimed in claim 1 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), L is a chemical bond, -O- , -S-, -C(O)-, -NH-, -N(CH 3 )-, *-C(O)O-, -C(O)O-*, *-C(O)NH- , *-C(O)N(CH 3 )-, -C(O)NH-*, -C(O)N(CH 3 )-*, (C1-C3)alkylene, (C1-C3) Alkylene-O-*, (C1-C3) alkylene-NH-* or (C1-C3) alkylene-N(CH 3 )-*, wherein said (C1-C3) alkylene, (C1-C3)alkylene-O-*, (C1-C3)alkylene-NH-* or (C1-C3)alkylene-N(CH 3 )-* can each be independently optionally replaced by 1, 2, 3 or 4 R c substitutions; where * indicates that it is connected to the benzene ring.
  3. 如权利要求2所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，L为化学键、-O-、-NH-、-N(CH 3)-、-CH 2-、-CH 2-CH 2-、
    Figure PCTCN2023071184-appb-100003
    Figure PCTCN2023071184-appb-100004
    Figure PCTCN2023071184-appb-100005
    L优选为化学键、-O-、-CH 2-、
    Figure PCTCN2023071184-appb-100006
    L更优选为化学键、-O-或-CH 2-；其中*表示与苯环相连，**表示与R 2相连。     The compound as claimed in claim 2 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), L is a chemical bond, -O- , -NH-, -N(CH 3 )-, -CH 2 -, -CH 2 -CH 2 -,
    Figure PCTCN2023071184-appb-100003
    Figure PCTCN2023071184-appb-100004
    Figure PCTCN2023071184-appb-100005
    L is preferably a chemical bond, -O-, -CH 2 -,
    Figure PCTCN2023071184-appb-100006
    L is more preferably a chemical bond, -O- or -CH 2 -; wherein * means to be connected to a benzene ring, and ** means to be connected to R 2 .
  4. 如权利要求1-3中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，X 1为化学键、
    Figure PCTCN2023071184-appb-100007
    Figure PCTCN2023071184-appb-100008
    X 1优选为
    Figure PCTCN2023071184-appb-100009
    The compound according to any one of claims 1-3 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), X 1 is a chemical bond,
    Figure PCTCN2023071184-appb-100007
    Figure PCTCN2023071184-appb-100008
    X1 is preferably
    Figure PCTCN2023071184-appb-100009
  5. 如权利要求1-4中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，X 2为
    Figure PCTCN2023071184-appb-100010
    X 2优选为
    Figure PCTCN2023071184-appb-100011
    The compound according to any one of claims 1-4 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), X 2 for
    Figure PCTCN2023071184-appb-100010
    X2 is preferably
    Figure PCTCN2023071184-appb-100011
  6. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当X 3为N-R a时，其中R a为-H、-(CH 2) 2OR xa、-(CH 2) 2NR xaR xb、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、
    Figure PCTCN2023071184-appb-100012
    -OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。     The compound according to any one of claims 1-5 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when When X 3 is NR a , wherein R a is -H, -(CH 2 ) 2 OR xa , -(CH 2 ) 2 NR xa R xb , (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4-7 yuan) heterocycloalkyl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4 -7-membered) heterocycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D, -F, -OH, -CH 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ,
    Figure PCTCN2023071184-appb-100012
    -OCF 3 , -CH 2 N(CH 3 ) 2 , -(CH 2 ) 2 N(CH 3 ) 2 , -N(CH 3 ) 2 and -CN.
  7. 如权利要求6所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当X 3为N-R a时，其中R a为-H、-(CH 2) 2OCH 3、-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
    Figure PCTCN2023071184-appb-100013
    Figure PCTCN2023071184-appb-100014
    Figure PCTCN2023071184-appb-100015
    优选为
    Figure PCTCN2023071184-appb-100016
    Figure PCTCN2023071184-appb-100017
    更优选为
    Figure PCTCN2023071184-appb-100018
    Figure PCTCN2023071184-appb-100019
    更优选为
    Figure PCTCN2023071184-appb-100020
    更优选为
    Figure PCTCN2023071184-appb-100021
    The compound as claimed in claim 6 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when X 3 is NR a , wherein R a is -H, -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 OH, -(CH 2 ) 2 N(CH 3 ) 2 ,
    Figure PCTCN2023071184-appb-100013
    Figure PCTCN2023071184-appb-100014
    Figure PCTCN2023071184-appb-100015
    preferably
    Figure PCTCN2023071184-appb-100016
    Figure PCTCN2023071184-appb-100017
    more preferably
    Figure PCTCN2023071184-appb-100018
    Figure PCTCN2023071184-appb-100019
    more preferably
    Figure PCTCN2023071184-appb-100020
    more preferably
    Figure PCTCN2023071184-appb-100021
  8. 如权利要求1-7中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当X 3为CH-R b时，其中R b为-H、-(CH 2) 2OR xa、-NR xaR xb、-(CH 2) 2NR xaR xb、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、
    Figure PCTCN2023071184-appb-100022
    -OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。     The compound according to any one of claims 1-7 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when When X 3 is CH-R b , wherein R b is -H, -(CH 2 ) 2 OR xa , -NR xa R xb , -(CH 2 ) 2 NR xa R xb , (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4-7 yuan) heterocycloalkyl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C3- C6) Cycloalkyl or (4-7 membered) heterocycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D, -F, -OH, -CH 3 , - CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ,
    Figure PCTCN2023071184-appb-100022
    -OCF 3 , -CH 2 N(CH 3 ) 2 , -(CH 2 ) 2 N(CH 3 ) 2 , -N(CH 3 ) 2 and -CN.
  9. 如权利要求8所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当X 3为CH-R b时，其中R b为：-H、-N(CH 3) 2、-N(CD 3) 2、-(CH 2) 2OCH 3、-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
    Figure PCTCN2023071184-appb-100023
    Figure PCTCN2023071184-appb-100024
    Figure PCTCN2023071184-appb-100025
    优选为-N(CH 3) 2或-N(CD 3) 2；更优选为-N(CH 3) 2。     The compound as claimed in claim 8 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when X 3 is CH-R b , where R b is: -H, -N(CH 3 ) 2 , -N(CD 3 ) 2 , -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 OH, -(CH 2 ) 2 N(CH 3 ) 2 ,
    Figure PCTCN2023071184-appb-100023
    Figure PCTCN2023071184-appb-100024
    Figure PCTCN2023071184-appb-100025
    Preferred is -N(CH 3 ) 2 or -N(CD 3 ) 2 ; more preferred is -N(CH 3 ) 2 .
  10. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，结构单元
    Figure PCTCN2023071184-appb-100026
    选自
    Figure PCTCN2023071184-appb-100027
    Figure PCTCN2023071184-appb-100028
    Figure PCTCN2023071184-appb-100029
    优选为
    Figure PCTCN2023071184-appb-100030
    Figure PCTCN2023071184-appb-100031
    更优选为
    Figure PCTCN2023071184-appb-100032
    The compound as claimed in claim 1 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit
    Figure PCTCN2023071184-appb-100026
    selected from
    Figure PCTCN2023071184-appb-100027
    Figure PCTCN2023071184-appb-100028
    Figure PCTCN2023071184-appb-100029
    preferably
    Figure PCTCN2023071184-appb-100030
    Figure PCTCN2023071184-appb-100031
    more preferably
    Figure PCTCN2023071184-appb-100032
  11. 如权利要求1-10中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 1为-H、-D、卤素、羟基、氨基、氰基、硝基、(C1-C3)烷基、(C1-C3)烷氧基、(C1-C3)卤代烷基、(C2-C4)烯基或(C2-C4)炔基，其中所述(C1-C3)烷基、(C1-C3)烷氧基、(C1-C3)卤代烷基、(C2-C4)烯基或(C2-C4)炔基可各自独立任选被1，2，3或4个R c取代。 The compound according to any one of claims 1-10 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 1 is -H, -D, halogen, hydroxyl, amino, cyano, nitro, (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C2-C4) Alkenyl or (C2-C4) alkynyl, wherein said (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C2- C4) Alkynyl groups may each independently be optionally substituted by 1, 2, 3 or 4 R c .
  12. 如权利要求11所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 1为-H、-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-CH 3、-OCH 3、-OCH 2CH 3、-OCH 2F、-OCHF 2、-OCF 3、-NHCH 3、-N(CH 3) 2、-C(O)CH 3、-CO 2CH 3、-S(O)CH 3、-S(O) 2CH 3、-C(O)NH 2、-C(O)NHCH 3、-CH 2F、-CHF 2或-CF 3；R 1优选为-F、-Cl、-Br、-CN、-NO 2、-CF 3或-C(O)NH 2；R 1更优选为-Cl、-Br、-CN、-CF 3或-C(O)NH 2；R 1更优选为-Cl或-CF 3；R 1更优选为-Cl。 The compound as claimed in claim 11 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 1 is -H, - D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -NHCH 3 , -N(CH 3 ) 2 , -C(O)CH 3 , -CO 2 CH 3 , -S(O)CH 3 , -S(O) 2 CH 3 , -C (O)NH 2 , -C(O)NHCH 3 , -CH 2 F, -CHF 2 or -CF 3 ; R 1 is preferably -F, -Cl, -Br, -CN, -NO 2 , -CF 3 Or -C(O)NH 2 ; R 1 is more preferably -Cl, -Br, -CN, -CF 3 or -C(O)NH 2 ; R 1 is more preferably -Cl or -CF 3 ; R 1 is more Preferred is -Cl.
  13. 如权利要求1-12中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 2为(C3-C10)环烷基、(3-10元)杂环烷基、(C6-C10)芳基或(5-10元)杂芳基，其中所述(C3-C8)环烷基、(3-8元)杂环烷基、(C6-C10)芳基或(5-10元)杂芳基可各自独立任选被1，2，3或4个R c取代。 The compound according to any one of claims 1-12 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 2 is (C3-C10) cycloalkyl, (3-10) heterocycloalkyl, (C6-C10) aryl or (5-10) heteroaryl, wherein the (C3-C8) cycloalkane The radical, (3-8 membered) heterocycloalkyl group, (C6-C10) aryl group or (5-10 membered) heteroaryl group may each independently be optionally substituted by 1, 2, 3 or 4 R c .
  14. 如权利要求13所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 2为
    Figure PCTCN2023071184-appb-100033
    The compound as claimed in claim 13 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 2 is
    Figure PCTCN2023071184-appb-100033
    Figure PCTCN2023071184-appb-100034
    Figure PCTCN2023071184-appb-100035
    R 2优选为
    Figure PCTCN2023071184-appb-100036
    Figure PCTCN2023071184-appb-100037
    Figure PCTCN2023071184-appb-100038
    R 2更优选为
    Figure PCTCN2023071184-appb-100039
    Figure PCTCN2023071184-appb-100034
    Figure PCTCN2023071184-appb-100035
    R2 is preferably
    Figure PCTCN2023071184-appb-100036
    Figure PCTCN2023071184-appb-100037
    Figure PCTCN2023071184-appb-100038
    R 2 is more preferably
    Figure PCTCN2023071184-appb-100039
  15. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，结构单元-L-R 2为
    Figure PCTCN2023071184-appb-100040
    Figure PCTCN2023071184-appb-100041
    The compound as claimed in claim 1 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit -LR 2 is
    Figure PCTCN2023071184-appb-100040
    Figure PCTCN2023071184-appb-100041
    Figure PCTCN2023071184-appb-100042
    Figure PCTCN2023071184-appb-100042
  16. 如权利要求1-15中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 3和R 4各自独立为-H、-D、卤素、羟基、氨基、氰基、硝基、-OR a、-NR aR b、-C(O)R a、-CO 2R a、-(CH 2) mR a、-(CH 2) mCO 2R a、-(CH 2) mCONR aR b、-S(O) pR a、-S(O) pNR aR b、-CONR aR b、-C(＝NR a)-NR aR b、-NR aCOR b、-CR aCONR aR b、-NR aCO 2R a、-NR aS(O) pNR aR b、-NR aS(O) pR a、-POR aR b、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)卤代烷基、(C2-C6)烯基，(C2-C6)炔基，(C3-C12)环烷基、(3-12元)杂环烷基、(C6-C10)芳基、(5-12元)杂芳基、-(C1-C3)亚烷基-(C3-C12)环烷基、-(C1-C3)亚烷基-(3-12元)杂环烷基、-(C1-C3)亚烷基-(C6-C10)芳基、-(C1-C3)亚烷基-(5-12元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)卤代烷基、(C2-C6)烯基，(C2-C6)炔基，(C3-C12)环烷基、(3-12元)杂环烷基、(C6-C10)芳基、(5-12元)杂芳基、-(C1-C3)亚烷基-(C3-C12)环烷基、-(C1-C3)亚烷基-(3-12元)杂环烷基、-(C1-C3)亚烷基-(C6-C10)芳基、-(C1-C3)亚烷基-(5-12元)杂芳基可各自独立任选被1，2，3或4个R c取代。 The compound according to any one of claims 1-15 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 3 and R 4 are each independently -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO 2 R a , - (CH 2 ) m R a , -(CH 2 ) m CO 2 R a , -(CH 2 ) m CONR a R b , -S(O) p R a , -S(O) p NR a R b , -CONR a R b , -C(=NR a )-NR a R b , -NR a COR b , -CR a CONR a R b , -NR a CO 2 R a , -NR a S(O) p NR a R b , -NR a S(O) p R a , -POR a R b , (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6 ) alkenyl, (C2-C6) alkynyl, (C3-C12) cycloalkyl, (3-12) heterocycloalkyl, (C6-C10) aryl, (5-12) heteroaryl, -(C1-C3)alkylene-(C3-C12)cycloalkyl, -(C1-C3)alkylene-(3-12)heterocycloalkyl,-(C1-C3)alkylene- (C6-C10) aryl, -(C1-C3) alkylene-(5-12 yuan) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, (C1 -C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C12) cycloalkyl, (3-12) heterocycloalkyl, (C6-C10) aryl, (5-12) heteroaryl, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene-(3-12) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-(5-12 yuan) heteroaryl can be independently selected by 1,2,3 or 4 A R c substitution.
  17. 如权利要求16所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当
    Figure PCTCN2023071184-appb-100043
    代表单键和m是2时，2个R 3可以连接在2个不同的碳原子上或连接在同一个碳原子上；2个R 3可以相同也可以不同；连接在同一个碳原子上的2个R 3与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可各自独立任选被1，2，3或4个R c取代。     The compound as claimed in claim 16 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when
    Figure PCTCN2023071184-appb-100043
    When it represents a single bond and m is 2, the two R 3 can be connected to two different carbon atoms or the same carbon atom; the two R 3 can be the same or different; the two R 3 can be connected to the same carbon atom 2 R 3 and the carbon atoms to which they are connected can jointly form (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl, wherein said (4-7 member) heterocycloalkyl or (C3 -C6)cycloalkyl can each independently be optionally substituted by 1, 2, 3 or 4 R c .
  18. 如权利要求16或17所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 3各自独立为-H、-D、-F、-Cl、-Br、-I、-CH 3、-CH 2CH 3、-CH 2OH、-CH 2CH 2OH、
    Figure PCTCN2023071184-appb-100044
    Figure PCTCN2023071184-appb-100045
    Figure PCTCN2023071184-appb-100046
    或连接在同一个碳原子上的2个R 3与他们所连接的碳原子能够共同组成
    Figure PCTCN2023071184-appb-100047
    R 3优选为-H、-CH 3、-CH 2OH、
    Figure PCTCN2023071184-appb-100048
    Figure PCTCN2023071184-appb-100049
    R 3更优选为-H、-CH 3、
    Figure PCTCN2023071184-appb-100050
    Figure PCTCN2023071184-appb-100051
    R 3更优选为-CH 3或
    Figure PCTCN2023071184-appb-100052
    The compound as claimed in claim 16 or 17 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 3 are each independently -H, -D, -F, -Cl, -Br, -I, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH,
    Figure PCTCN2023071184-appb-100044
    Figure PCTCN2023071184-appb-100045
    Figure PCTCN2023071184-appb-100046
    Or two R3s connected to the same carbon atom and the carbon atom they are connected to can form together
    Figure PCTCN2023071184-appb-100047
    R 3 is preferably -H, -CH 3 , -CH 2 OH,
    Figure PCTCN2023071184-appb-100048
    Figure PCTCN2023071184-appb-100049
    R 3 is more preferably -H, -CH 3 ,
    Figure PCTCN2023071184-appb-100050
    Figure PCTCN2023071184-appb-100051
    R 3 is more preferably -CH 3 or
    Figure PCTCN2023071184-appb-100052
  19. 如权利要求18所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 4为-H、-D、-F、-Cl、-Br、-I、-CHF 2、-CF 3、-OCH 3、-OCHF 2、-OCF 3或
    Figure PCTCN2023071184-appb-100053
    R 4优选为-H、-F、-Cl、-Br、-OCH 3或
    Figure PCTCN2023071184-appb-100054
    R 4更优选为-H或-F；R 4更优选为-H；R 4更优选为-F。     The compound as claimed in claim 18 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 4 is -H, - D, -F, -Cl, -Br, -I, -CHF 2 , -CF 3 , -OCH 3 , -OCHF 2 , -OCF 3 or
    Figure PCTCN2023071184-appb-100053
    R 4 is preferably -H, -F, -Cl, -Br, -OCH 3 or
    Figure PCTCN2023071184-appb-100054
    R 4 is more preferably -H or -F; R 4 is more preferably -H; R 4 is more preferably -F.
  20. 权利要求1-19中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：The compound according to any one of claims 1-19 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the compound has one of the following structures:
    Figure PCTCN2023071184-appb-100055
    Figure PCTCN2023071184-appb-100055
    Figure PCTCN2023071184-appb-100056
    Figure PCTCN2023071184-appb-100056
    Figure PCTCN2023071184-appb-100057
    Figure PCTCN2023071184-appb-100057
    Figure PCTCN2023071184-appb-100058
    Figure PCTCN2023071184-appb-100058
    Figure PCTCN2023071184-appb-100059
    Figure PCTCN2023071184-appb-100059
  21. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-20中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1-20, or its isomers, crystal forms, A pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
  22. 一种如权利要求1-20中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求21所述的药物组合物在制备治疗HPK1蛋白激酶相关疾病药物中的用途。A compound as described in any one of claims 1-20, or each isomer thereof, each crystal form, a pharmaceutically acceptable salt, hydrate or solvate, or a drug as claimed in claim 21 Use of the composition in preparing medicines for treating diseases related to HPK1 protein kinase.
PCT/CN2023/071184 2022-01-11 2023-01-09 Fused ring compounds serving as hpk1 inhibitors WO2023134608A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011120026A1 (en) * 2010-03-26 2011-09-29 Glaxo Group Limited Pyrazolyl-pyrimidines as kinase inhibitors
CN110402248A (en) * 2017-03-15 2019-11-01 豪夫迈·罗氏有限公司 Azaindoles as HPK1 inhibitor
WO2021000935A1 (en) * 2019-07-04 2021-01-07 Qilu Regor Therapeutics Inc. Hpk1 inhibitors and uses thereof
WO2021032148A1 (en) * 2019-08-21 2021-02-25 Beigene, Ltd. Aminopyrazine compounds as hpk1 inhibitor and the use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011120026A1 (en) * 2010-03-26 2011-09-29 Glaxo Group Limited Pyrazolyl-pyrimidines as kinase inhibitors
CN110402248A (en) * 2017-03-15 2019-11-01 豪夫迈·罗氏有限公司 Azaindoles as HPK1 inhibitor
WO2021000935A1 (en) * 2019-07-04 2021-01-07 Qilu Regor Therapeutics Inc. Hpk1 inhibitors and uses thereof
WO2021032148A1 (en) * 2019-08-21 2021-02-25 Beigene, Ltd. Aminopyrazine compounds as hpk1 inhibitor and the use thereof

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