WO2023151559A1 - 杂环化合物、包含其的药物组合物及其抗肿瘤应用 - Google Patents

杂环化合物、包含其的药物组合物及其抗肿瘤应用 Download PDF

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WO2023151559A1
WO2023151559A1 PCT/CN2023/074831 CN2023074831W WO2023151559A1 WO 2023151559 A1 WO2023151559 A1 WO 2023151559A1 CN 2023074831 W CN2023074831 W CN 2023074831W WO 2023151559 A1 WO2023151559 A1 WO 2023151559A1
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alkyl
membered
cycloalkyl
hydrogen
halogenated
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French (fr)
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马欣
陈永峰
章涵堃
刘瑶
吴瑶
杜勇
孔德升
梁亚楠
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和径医药科技（上海）有限公司
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • 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
    • A61K31/495—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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the field of medicinal chemistry. It specifically relates to a novel class of PROTAC molecules targeting HPK1 protein and its mutant protein, its preparation method and application, and a pharmaceutical composition containing the compound.
  • HPK1 is the abbreviation of hematopoietic progenitor kinase 1 (hematopoietic progenitor kinase 1), also known as MAP4K1, is a member of the MAP4K family, it is a serine/threonine protein kinase, mainly in hematopoietic stem cells, T cells, B cells , NK cells, dendritic cells and other hematopoietic immune-related cells.
  • HPK1 kinase can bind to many adapter proteins, such as SLP76 family, Gads, HIP-55, GRB2 family, LAT, CRK family, etc., to activate the SAPK/JNK signaling pathway of hematopoietic stem cells, thereby negatively regulating the TCR pathway.
  • HPK1 kinase is a key negative feedback regulator of TCR signaling, which can negatively regulate the activation of dendritic cells and the feedback between T cells and B cells; while inhibiting HPK1 can enhance the activity of T cells, thereby improving the response of anti-tumor immunity.
  • the ubiquitin-proteasome pathway is a common endogenous protein degradation method.
  • the protein to be degraded is first modified by ubiquitination, and then decomposed into smaller polypeptides, amino acids and reusable ubiquitin by the proteasome.
  • PROTAC proteolysis tarrgeting chimeras
  • PROTAC molecules can generally be divided into three parts, one end is a small molecule fragment (warhead) that binds to a specific target protein, the other end is an E3 ligase ligand (E3ligase ligand) with ubiquitination function, and the link between the two The connected body (linker).
  • PROTAC molecules utilize the protein ubiquitination degradation pathway of cells to selectively degrade target proteins. Specifically, since the two ends of the PROTAC molecule are the ligand fragments of the target protein and the E3 ligase respectively, the PROTAC molecule can bind to the target protein and the E3 ligase at the same time, which promotes the ubiquitination of the target protein, and then is released by the proteasome. identified and degraded.
  • HPK1 may be a potential cancer immunotherapy target, but so far no related drugs have been marketed. Designing degradants that target specific proteins is a new model for drug development.
  • International patents with publication numbers WO2021226262A1 and WO2020227325A1 disclose HPK1 protein degraders, but their selectivity and efficacy are not very ideal. Therefore, it is of great significance to provide HPK1 degraders with higher selectivity and better drug efficacy.
  • One aspect of the present invention provides a compound represented by general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, poly Crystalline forms, prodrugs or isotopic variants, and mixtures thereof,
  • HPK1Ligands is a ligand that binds to HPK1, such as an inhibitor of HPK1, expressed as general formula (II) and general formula (II'):
  • L' is connected to the ring where X 1 is located, L is connected to the ring where Z 4 is located, or L' is connected to the ring where Z 4 is located, L is connected to the ring where X 1 is located, or both L' and L are connected to the ring where X 1 is located ring;
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from N or CR X ;
  • R X is the same or different, and each of R x is independently: -(CR' 2 ) S -R # -(CR * 2 ) t -R 1 ;
  • R # is a chemical bond, O, S, NR N , C(O), C(O)NR N , NR N C(O), C(O)O, OC(O), S(O) 1-2 , S(O) 1-2 NR N , NR N S(O) 1-2 , S(O) 1-2 O, OS(O) 1-2 , C 1-6 alkylene, C 2-6 alkylene Alkenyl, C 2-6 alkynylene, C 3-8 cycloalkylene, 4-12 membered heterocyclylene, C 6-10 arylene or 5-16 membered heteroarylene; the C 1 -6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-8 cycloalkylene, 4-12 membered heterocyclylene, C 6-10 arylene or 5- The 16-membered heteroarylene is optionally substituted by 1, 2, 3 or 4 R";
  • Z 1 is O, S, N or C atom, which is optionally replaced by one or two R Z1 ;
  • Z 2 is O, S, N or C atom, which is optionally replaced by one or two R Z2 Replacement;
  • Z 3 is O, S, N or C atom, which is optionally substituted by one or two R Z3 ;
  • Z 4 is an O, S, N or C atom, which is optionally substituted by one or two R Z 4 ; or, Z 1 does not exist, and Z 2 is connected to the C atom connected to Z 1 ;
  • R 4 and R 4 ' are each independently selected from hydrogen, deuterium, NR a R b , hydroxyl, halogen, C(O)NR a R b , COR d , C 1-6 alkyl, halogenated C 1-6 alkane Base , hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; said C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl are optionally replaced by 1, 2 , 3 or 4 R"substitutions; or two R 4 connected to the
  • L and L' are independently chemical bonds or -(CR 2 2 ) p -R L -(CR 3 2 ) q -;
  • R 2 and R 3 are each independently selected from hydrogen, deuterium, NRN , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-8 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; or two R 2 or two R 3 and connected C Together form a C 3-8 cycloalkyl group or a 4-12 membered heterocyclic group; the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl , C 2-6 alkynyl, C 3-8 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl are optionally replaced by 1, 2, 3 or 4 R ## replace;
  • RL is selected from O, S, NR N , C(O), C(O)O, OC(O), C(O)NR N , NR NC (O), NR NC(O ) NR N , S(O) 1-2 ⁇ S(O) 1- 2 O ⁇ OS(O) 1-2 ⁇ S(O) 1-2 NR N ⁇ NR N S(O) 1-2 ⁇ NR N S(O ) 1-2 NR N , C 1-6 alkylene, halogenated C 1-6 alkylene, C 1-6 alkyleneoxy, C 2-6 alkenylene, C 2-6 alkynylene, C 3-8 cycloalkylene, 4-12 membered heterocyclylene, C 6-10 arylene or 5-16 membered heteroarylene; the C 1-6 alkylene, halogenated C 1- 6 alkylene, C 1-6 alkyleneoxy, C 2-6 alkenylene, C 2-6 alkynylene, C 3-8 cycloalkylene, 4-12 membered heterocycl
  • Y 1 is N or C atom, and it is optionally substituted by one or two R Y1 ;
  • Y 2 is N or C atom, and it is optionally replaced by one or two RY2 ; or, Y 2 does not exist, Y 1 is connected with Y 3 ;
  • Y 3 is N or C atom, and it is optionally replaced by one or two RY3 ;
  • Y 4 is N or C atom, and it is optionally replaced by one or two RY4 ;
  • Y 5 is N or C atom, and it is optionally replaced by one or two R Y5 ;
  • Y 6 is N or C atom, and it is optionally substituted by one or two R Y6 ;
  • R Y1 , R Y2 , R Y3 , R Y4 , R Y5 and R Y6 are independently expressed as: -(CR e 2 ) n1 -R #1 -(CR f 2 ) n2 -R #2 ;
  • R e is the same or different
  • R f is the same or different
  • R #1 is bond, O, S, NR N , C(O), C(O)NR N , NR N C(O), NR N C(O)NR N , C(O)O, OC(O ), S(O) 1-2 , S(O) 1-2 NR N , NR N S(O) 1-2 , NR N S(O) 1-2 NR N , S(O) 1-2 O , OS(O) 1-2 , C 1-6 alkylene, C 1-6 alkyleneoxy, C 2-6 alkenylene, C 2-6 alkynylene, C 3-8 cycloalkylene , 4-12 membered heterocyclylene, C 6-10 arylene or 5-16 membered heteroarylene; or, two R Y2 together with Y 2 form carbonyl, C 3-8 cycloalkyl, 4- 12-membered heterocyclic group, C 6-10 aryl group or 5-14 membered heteroaryl group;
  • L is connected to one of Y 1 , Y 2 , Y 3 , and Y 4 , and Y 5 , Y 6 and the substituents connected to them together form a C 3-8 cycloalkyl group, a 4-12 membered heterocyclic group, a C 6- 10 aryl or 5-14 membered heteroaryl; or, Y 2 does not exist, L is connected to one of Y 1 , Y 3 , Y 4 , Y 5 , Y 6 , and the remaining ring atoms are adjacent to each other.
  • the connected substituents together form a C 3-8 cycloalkyl group, a 4-12 membered heterocyclic group, a C 6-10 aryl group or a 5-14 membered heteroaryl group;
  • the C 1-6 alkylene group, C 2- 6 alkenylene, C 2-6 alkynylene, C 3-8 cycloalkylene, 4-12 membered heterocyclylene, C 6-10 arylene or 5-16 membered heteroarylene are unsubstituted or optionally replaced by 1, 2, 3 or 4 R ## ;
  • R is selected from: C 3-8 cycloalkylene, 4-12 membered heterocyclylene, C 6-10 arylene or 5-16 membered heteroarylene; the C 3-8 cycloalkylene , 4-12 membered heterocyclylene, C 6-10 arylene or 5-16 membered heteroarylene are optionally substituted by 1, 2, 3, 4 or more R ## ;
  • V 1 , V 2 , V 3 are each independently selected from N or CR V ;
  • V 4 is N, O, S or C atom, which is optionally substituted by 1 or 2 R V ;
  • Ring V is C 6-10 aryl or 5-16 membered heteroaryl, and it is optionally substituted by 1, 2, 3 or 4 R V ;
  • R V is the same or different, R V , R V1 , R V1 ', R V2 , R V2 ', R V3 , R 31 , R 32 are each independently selected from -O-(CR 5 R 5 ') m1 -R V ', -(CR 5 R 5 ') m1 -R V ' or -NR N -(CR 5 R 5 ') m1 -R V ';
  • LIN is expressed as -L 1 -L 2 -L 3 - whil-L r -,
  • L 1 , L 2 , L 3 ... L r are each independently selected from chemical bonds, O, S, NRN , -(CR 6 R 6 ') m2 -, C(O), C(O)NR N , NR N C(O), NR N C(O)NR N , C(O)O, OC(O), OC(O)O, S(O) 1-2 , S(O) 1-2 O, OS (O) 1-2 , S(O) 1-2 NR N , NR N S(O) 1-2 , NR N S(O) 1-2 NR N , -OC 1-10 alkylene, C 2 -10 alkenylene, C 2-10 alkynylene, C 3-16 cycloalkylene, 4-12 membered heterocyclylene, C 6-10 arylene or 5-16 membered heteroarylene; C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, C 3-16 cycloalkylene, 4-12
  • s, t, p, q, n1, n2, m1, m2, u are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • t 1 and t 2 are independently 0, 1 or 2;
  • r is a positive integer of 4-20;
  • G 1 , G 2 , G 3 , and G 4 are independently N or CR g ; G 1 , G 2 , G 3 , and G 4 are not N at the same time;
  • R g is the same or different and independently selected from: hydrogen, deuterium, NR a R b , hydroxyl, halogen, cyano, C(O)NR a R b , C 1-6 alkyl, halogenated C 1-6 Alkyl , hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl or 5-14 membered heteroaryl; the C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl or 5-14 membered heteroaryl are optionally replaced by 1, 2, 3 or 4 R 00 substitutions;
  • K1 is selected from O, S, C or N, which is optionally replaced by one or two R K1 ;
  • K2 is selected from O, S, C or N, which is optionally replaced by one or two R K2 Substitution;
  • K 3 is selected from O, S, C or N, which is optionally substituted by one or two R K3 ; or K 1 and K 2 do not exist, K 4 is connected to K 3 , and the aromatic group connected to K 1
  • the C atom on the ring is connected to R K ; or, K 1 , K 2 , K 3 are absent, and K 4 is connected to K 1 or K 3
  • One of the C atoms of the aromatic ring, the other C atom on the aromatic ring is connected to R K ;
  • K 4 is N or CR K4 ;
  • R K1 , R K2 , and R K3 are independently absent, hydrogen, deuterium, NR a R b , C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl or 5-14 membered heteroaryl base;
  • R K , R K4 , R 7 , R 7 ′, R 8 , and R 8 ′ are each independently selected from hydrogen, deuterium, halogen, cyano, NR a R b , C 1-6 alkyl, halogenated C 1- 6 alkyl, C 1-6 alkoxy or hydroxy C 1-6 alkyl;
  • Z 2 , Z 3 , Z 4 are C or N, and Z 3 and Z 2 are not N at the same time, or Z 3 and Z 4 are not N at the same time,
  • R a ', R b ' are selected from hydrogen, deuterium, cyano, fluorine, chlorine, bromine, hydroxyl, NR a R b , -COR d , -CONR a R b , -NR N COR d , C 1-6 alkane Base, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl , C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5 or 6
  • Elementary heteroaryl preferably hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl); said C 1-6 alkyl, C 1-6 alkoxy Group, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5 or 6 membered heteroaryl are optionally 1, 2, 3,
  • R X is selected from hydrogen, deuterium, hydroxyl, fluorine, chlorine, bromine, cyano, NR a R b , -COR d , -CONR a R b , C 1-6 alkyl, -C 1-6 alkylene NR a R b , C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl , OC 3-5 cycloalkyl, C 3-5 cycloalkyl or 4 or 5 members heterocyclyl.
  • R X is -(CR' 2 ) s -R 1 , -NR N -R 1 , -OR 1 or -O-(CR * 2 ) t -R 1 ;
  • R N , R', R * , R 1 are each independently selected from hydrogen, deuterium, NR a R b , C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxyl C 1-6 alkyl, benzene, 5 or 6-membered heteroaryl, -C 1-6 alkylene NR a R b , -C 1-6 alkylene-benzene or 5 or 6-membered heteroaryl; Or, two R' and connected C atoms together form a C 3-6 cycloalkyl group or a 4-7 membered heterocyclic group;
  • R a ' and R b ' are each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl (preferably hydrogen).
  • L and L' are independently selected from chemical bonds, NH, O, S, -C 1-6 alkylene NH-, -NHC 1-6 alkylene-, -C 1-6 alkylene Alkyl O-, -OC 1-6 alkylene-, C 1-6 alkylene, hydroxy C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, 3 -6-membered cycloalkyl, 4-7-membered heterocyclyl, benzene or 5 or 6-membered heteroaryl (preferably a chemical bond or NH);
  • L' is further preferably O, S or -(CR 2 2 )p-NR N -, R 2 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or hydroxy C 1-6 alkyl (preferably hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, hydroxymethyl, hydroxy
  • L' is C(O)NR N , NR N C(O), NR N C(O)NR N , S(O) 1-2 , S(O) 1-2 NR N , NR N S (O) 1-2 , NR N S(O) 1-2 NR N , RN is hydrogen, deuterium or C 1-6 alkyl;
  • L is preferably benzene or 5- or 6-membered heteroarylene substituted by 1 or 2 R Q , R Q selected from: hydrogen, deuterium, hydroxyl, amino, halogen, cyano, amido, acetyl, C 1- 6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl , C 3-6 cycloalkyl, -OC 3-6 cycloalkyl or
  • both L and L' are chemical bonds.
  • Each RY1 , RY2 , RY3 , RY4 , and RY are each independently selected from: hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl , Hydroxy C 1-6 alkyl, NR a R b , CONR a R b , C 3-8 cycloalkyl, -O-(CH 2 ) 0-4 -C 3-8 cycloalkyl, 4-7 membered heterocyclic group, phenyl group or 5-14 membered heteroaryl group.
  • each of RY1 , RY2 , RY3 , RY4 , RY5 , RY6 , RY , R9 is independently selected from dimethylamino, diethylamino,
  • each of R Y1 , R Y2 , R Y3 , R Y4 , R Y5 , R Y6 , R Y , and R 9 is each independently selected from amido, diformamido, diacetylamino, N,N'-methyl ethyl ethyl amido.
  • each of RY1 , RY2 , RY3 , RY4 , RY5 , RY6 , RY , R9 is independently selected from cyclopropyl, cyclobutyl, cyclo Pentyl, Cyclohexyl, Oxetyl, Azetidinyl, Oxolyl, Azacyclopentyl, Piperidyl, Piperazinyl, Morpholinyl,
  • each of RY1 , RY2 , RY3 , RY4 , RY5 , RY6 , RY, R9 is independently selected from phenyl, pyridyl , pyrimidinyl, Pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, furyl, tetrazolyl, 1,2,4-triazole Base, 1,3,4-triazolyl, indolyl, isoindolyl;
  • the substituent is selected from hydrogen, deuterium, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, difluoromethyl base, trifluoroethyl, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxyazetidinyl, cyclopentyl, nitrogen Heterocyclopentyl, hydroxyazacyclopentyl or phenyl.
  • R is selected from: hydrogen, deuterium, cyano, fluorine, chlorine, bromine, hydroxyl, amino, amido, C 1-6 alkyl, C 1-6 alkoxy, NR a R b , C(O)NR a R b , -C(O)R d , S(O) 1-2 NR a R b , -S(O) 1-2 R d , C 3-8 cycloalkyl, 4 -12-membered heterocyclic group, benzene or 5-14-membered heteroaryl group.
  • R 9 is C 3-8 cycloalkyl or 4-7 membered heterocyclic group; preferred R 9 is benzene or 5 or 6 membered heteroaryl.
  • Preferred R 9 is -NR N (CH 2 ) 1-6 NR a R b ; preferred R 9 is halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1- 6 alkyl or hydroxy C 1-6 alkyl; preferred R 9 is C(O)NR a R b ; preferred R 9 is S(O) 1-2 NR a R b .
  • Each R a , R b , R N , and R d are each independently selected from hydrogen, deuterium, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl or C 1-4 alkoxy.
  • the C 1-6 alkyl is selected from: methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, n-hexyl; halogen is fluorine, chlorine or bromine.
  • R a and R b form a 4- to 7-membered nitrogen heterocyclic ring together with the N atoms connected to them.
  • the 4- to 7-membered nitrogen heterocycle is selected from:
  • each of R Y1 , R Y2 , R Y3 , R Y4 , R Y is independently selected from: hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, NR a R b , CONR a R b ;
  • R 9 is selected from: NR a R b , C(O)NR a R b , -C(O)R d , S(O) 1-2 NR a R b , -S(O) 1-2 R d .
  • each of R Y1 , R Y2 , R Y3 , R Y4 , R Y is independently selected from: hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, NR a R b , CONR a R b ;
  • R 9 is selected from: NR a R b , C(O)NR a R b , -C(O)R d , S(O) 1-2 NR a R b , -S(O) 1-2 R d .
  • each of R Y1 , R Y2 , R Y3 , R Y4 and R Y is independently selected from: hydrogen, deuterium, halogen; R 9 is C(O)NR a R b .
  • R 0 is a bond, C 3-8 cycloalkylene, 4-12 membered heterocyclylene, phenylene, or 5-14 heteroarylene.
  • R 0 is a 4-7 membered heterocyclylene (preferably piperidinylene or piperazinylene) substituted by 1, 2, 3 or 4 R Z ′.
  • R 0 is phenylene or 5 or 6 membered heteroarylene substituted by 1 or 2 R Z ′.
  • R 0 is a 6-12 membered spirocyclylene or a 7-12 membered heterospirocyclylene substituted by 1, 2 or 3 R Z ′.
  • R Z ' is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, acetyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, -NR a R b or - CONR a R b
  • R Z ' is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, acetyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, -NR a R b or - CONR a R b
  • R Z ' preferably hydrogen, fluorine, methyl, ethyl or trifluoromethyl
  • R a , R b are selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.
  • R is expressed as:
  • R 0 and L' is the connection point between R 0 and LIN;
  • Z 5 , Z 6 , and Z 7 are each independently selected from N or CR Z ';
  • Z 8 , Z 9 , Z 10 are each independently a C, N, O or S atom, and Z 8 , Z 9 , Z 10 are optionally substituted by 1 or 2 R Z '; or Z 8 , Z 9 Together with the substituents connected to it form a 4-7-membered cycloalkyl group or a 5-7-membered heterocyclic group, and LIN is connected to the ring formed by Z 8 and Z 9 ; preferably, Z 8 , Z 9 , and Z 10 are each independently is NR N , O or CH 2 ;
  • R Z 's are the same or different, R Z 'are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, acetyl, hydroxyl, cyano, -NR a R b , -CONR a R b , C 1- 6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl , C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, 4-7 Membered heterocyclic group, benzene or 5-14 membered heteroaryl;
  • R Z ' is selected from: C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or hydroxy C 1-6 alkyl.
  • R Z ' is hydrogen, halogen, cyano, amino or amido.
  • R Z ' is selected from: hydrogen, deuterium, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl or hydroxy C 1-4 alkyl.
  • R Z ' is selected from: hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethane group, difluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl,
  • R 0 is phenylene
  • HPK1 Ligands are further represented as:
  • Z 11 and Z 12 are independently represented as N or CR Z ', and Q 1 , Q 2 , and Q 3 are independently represented as N or CR Q ;
  • R Z ', R Q are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, NR a R b , CONR a R b , C 3-6 cycloalkyl, -O-(CH 2 ) 0-4 -C 3-6 cycloalkyl or 4 or 5 membered heterocyclyl;
  • R Z is selected from C 1-6 alkylene, C 1-6 alkyleneoxy, O, S, NR N , CONR N , SO 1-2 NR N , CO or C 3-6 cycloalkylene;
  • L is connected to the ring where Y 1 is located, or is connected to the ring where Y 7 is located.
  • X 1 , X 2 , Y 1 , Y 2 , Y 3 , X 2 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10 , R 9 , R N , R a , , R b , , R z , , R z ,, , R X , RY are each independently as described above.
  • HPK1 Ligands are further represented as:
  • R 0 is phenylene, 4-12 membered heterocyclylene or 5-16 membered heteroarylene optionally substituted by 1, 2, 3 or 4 R ## ;
  • L is a chemical bond, NH, O, S, vinylene, ethynylene, -NHC 1-4 alkylene or -C 1-4 alkylene NH;
  • R a ', R b ' are each independently selected from: hydrogen, deuterium, F, Cl, C 1-6 alkyl, halogenated C 1-6 alkyl or C 1-6 alkoxy;
  • R X , RY2 , RY3 , and RY5 are each independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, amido, acetyl, cyano, C 1-6 alkyl, C 1-6 alkane Oxygen, halogenated C 1-6 alkyl, cyclopropyl, -O-cyclopropyl,
  • R 9 is hydrogen, deuterium, F, Cl, Br, hydroxyl, cyano, -(CH 2 ) 0-4 C(O)NR a R b , -(CH 2 ) 0-4 NR a R b , -( CH 2 ) 0-4 S(O) 1-2 NR a R b , C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl , C 3-6 cycloalkyl, 4-7 membered heterocyclyl, -O-(CH 2 ) 0-4 -C 3-6 cycloalkyl,
  • R a and R b are each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, - CH 2 CH 2 CH 2 CH 2 OH, -(CH 2 ) 1-4 N(CH 3 ) 2 , -(CH 2 ) 1-4 N(CH 3 )CH 2 CH 3 or -(CH 2 ) 1- 4-4 to 7-membered azacyclic ring, or R a , R b together with the connected N atoms form a 4-7-membered azacyclic ring;
  • the 4- to 7-membered azacyclic ring is optionally substituted by 1 or 2 substituents selected from hydrogen, deuterium, methyl, ethyl, hydroxyl, and amino.
  • HPK1 Ligands are further represented as:
  • HPK1 Ligands are further represented as:
  • Y 2 is N, Y 3 and Y 5 are CH, in some embodiments, Y 3 is N, Y 2 and Y 5 are CH, in some embodiments, Y 5 is CH, Y 2.
  • Y 5 is N, in some embodiments, Y 2 is CH, Y 3 and Y 5 are N, in some embodiments, Y 3 is CH, Y 3 and Y 5 are N, in some embodiments , Y 2 , Y 3 , and Y 5 are all CH.
  • R 0 is a 6-12 membered heterocyclylene optionally substituted by 1, 2, 3 or 4 R ## ;
  • Y 2 , Y 3 , and Y 5 are all CH;
  • L is a chemical bond, NH, O, S, vinylidene, ethynylene;
  • R a ', R b ' are each independently selected from: hydrogen, deuterium, F, Cl, C 1-6 alkyl, halogenated C 1-6 alkyl or C 1-6 alkoxy;
  • R X , RY2 , RY3 , and RY5 are each independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1- 6 alkyl;
  • R 9 is -(CH 2 ) 0-4 C(O)NR a R b , -(CH 2 ) 0-4 NR a R b , -(CH 2 ) 0-4 S(O) 1-2 NR a R b , C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl ;
  • R a and R b are each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, - CH 2 CH 2 CH 2 CH 2 OH, -(CH 2 ) 1-4 N(CH 3 ) 2 , -(CH 2 ) 1-4 N(CH 3 )CH 2 CH 3 .
  • R 0 is an 8-12 membered benzoheterocyclyl optionally substituted by 1, 2, 3, or 4 R ## ;
  • L is a chemical bond
  • Y 2 , Y 3 , and Y 5 are all CH;
  • R a ', R b ' are each independently selected from: hydrogen, deuterium;
  • R X , RY2 , RY3 , and RY5 are each independently selected from: hydrogen, deuterium;
  • R 9 is -(CH 2 ) 0-4 C(O)NR a R b , -(CH 2 ) 0-4 NR a R b , -(CH 2 ) 0-4 S(O) 1-2 NR a R b ;
  • R a and R b are each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy.
  • each R Z ' is independently selected from: hydrogen, deuterium, C 1-4 alkyl, C 1-4 alkoxy , Halogenated C 1- 4 alkyl or hydroxy C 1-4 alkyl.
  • Y 2 , Y 3 , and Y 5 are all CH; L is a chemical bond; R 9 is -(CH 2 ) 0-4 C(O)NR a R b , - (CH 2 ) 0-4 NR a R b or -(CH 2 ) 0-4 S(O) 1-2 NR a R b ; each R Z ' is independently selected from: hydrogen, deuterium, C 1-4 Alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl or hydroxy C 1-4 alkyl.
  • HPK1 Ligands are further represented as:
  • R 0 is phenylene, 4-12 membered heterocyclylene or 5-16 membered heteroarylene optionally substituted by 1, 2, 3 or 4 R ## ;
  • R a ', R b ' are each independently selected from: hydrogen, deuterium, F, Cl, C 1-6 alkyl, halogenated C 1-6 alkyl or C 1-6 alkoxy;
  • Each R X , R Y , R X1 , R X2 , R Y1 , and R Y3 are each independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, amido, acetyl, cyano, C 1-6 alkane Base, C 1-6 alkoxy, halogenated C 1-6 alkyl, cyclopropyl, -O-cyclopropyl,
  • HPK1 Ligands are further represented as:
  • HPK1 Ligands are further represented as:
  • one of X 1 and X 2 is N, the other is CH, one of Y 1 and Y 3 is N, in some embodiments, one of X 1 and X 2 is N, the other is CH, Y 1 and Y 3 are both CH, in some embodiments, X 1 is N, X 2 is CH, Y 1 and Y 3 are both CH, in some embodiments, X 2 is N, X 1 is CH, Y 1 and Y 3 are both CH.
  • R 0 is phenylene optionally substituted with 1, 2, 3, or 4 R ## ;
  • X 1 is N, X 2 is CH, Y 1 and Y 3 are both CH;
  • R a ', R b ' are each independently selected from: hydrogen, deuterium, F, Cl, C 1-6 alkyl, halogenated C 1-6 alkyl or C 1-6 alkoxy;
  • Each R X , R Y , R X1 , R X2 , R Y1 , and R Y3 are each independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy , Halo C 1-6 alkyl, cyclopropyl, -O-cyclopropyl.
  • R 0 is phenylene optionally substituted with 1, 2, 3, or 4 R ## ;
  • X 1 is N, X 2 is CH, Y 1 and Y 3 are both CH;
  • R a ', R b ' are each independently selected from: hydrogen, deuterium;
  • R X , R X1 , R X2 , RY1 , and RY3 are each independently selected from: hydrogen, deuterium;
  • Each R Y is independently selected from hydrogen, deuterium, F, Cl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl.
  • Z6 and Z7 are each independently selected from CH or N, preferably both are CH.
  • Z6 and Z7 are both CH; R a ' and R b ' are independently selected from: hydrogen, deuterium; RY is selected from Hydrogen, deuterium, F, Cl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl.
  • HPK1 Ligands are further represented as:
  • R 0 is phenylene, 4-12 membered heterocyclylene or 5-16 membered heteroarylene optionally substituted by 1, 2, 3 or 4 R ## ;
  • L is a chemical bond, NH, O, S, vinylene, ethynylene, -NHC 1-4 alkylene or -C 1-4 alkylene NH;
  • R a ' is selected from: hydrogen, deuterium, F, Cl, C 1-6 alkyl, halogenated C 1-6 alkyl or C 1-6 alkoxy;
  • R X and R Y are independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, amido, acetyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, cyclopropyl, -O-cyclopropyl,
  • HPK1 Ligands are further represented as:
  • HPK1 Ligands are further represented as:
  • Z 11 and Z 12 are independently expressed as N or CR Z ', in some embodiments, one of Z 11 and Z 12 is N, and the other is CR Z ', in some embodiments Among them, both Z 11 and Z 12 are N.
  • each R Z ' is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, Hydrogen is preferred.
  • R 0 is a 4-8 membered heterocyclylene optionally substituted by 1, 2, 3 or 4 R ## ;
  • L is a chemical bond, NH, O, S, vinylidene, ethynylene;
  • R a ' is selected from: hydrogen, deuterium, F, Cl, C 1-6 alkyl, halogenated C 1-6 alkyl or C 1-6 alkoxy;
  • Y 7 is N; Y 8 is O or S;
  • R X and R Y are independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl;
  • RN is selected from hydrogen, deuterium, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl or C 1-6 alkoxy.
  • R 0 is a 4-6 membered nitrogen-containing heterocyclylene optionally substituted by 1, 2, 3, or 4 R ## ;
  • L is a chemical bond
  • R a ' is selected from: hydrogen, deuterium
  • Y 7 is N; Y 8 is O or S;
  • R X is selected from: hydrogen, deuterium
  • Each R Y is independently selected from: hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl;
  • RN is selected from hydrogen, deuterium.
  • R N is selected from hydrogen, deuterium;
  • R a ' is selected from: hydrogen, deuterium;
  • RY is selected from: hydroxyl, amino, C 1-6 alkyl, C 1- 6 alkoxy, halogenated C 1-6 alkyl.
  • HPK1 Ligands are further represented as:
  • R 0 is a chemical bond
  • L' is -(CR 2 2 ) p NR N -;
  • R is selected from hydrogen, deuterium, amino, hydroxylamino, C 1-6 alkyl, halogenated C 1-6 alkyl or hydroxy C 1-6 alkyl (preferably hydrogen or C 1-6 alkyl); or Two R 2 form cyclopropyl, cyclobutyl, oxetanyl or azetidinyl together with the C atoms to which they are attached;
  • p 0, 1, 2 or 3;
  • R X is selected from: hydrogen, deuterium, fluorine, chlorine, bromine, amino, amido, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, -(CR' 2 ) m1 NR a R b , C 3-6 cycloalkyl, -OR 1 , -O-(CH 2 ) 1-2 R 1 ,
  • R a and R b form a 4-7 membered nitrogen heterocyclic ring substituted by 1 or 2 R" together with the N atom they are attached to;
  • R Z4 is selected from: hydrogen, deuterium, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl (preferably hydrogen);
  • L is selected from 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,6-pyridylylene, 2,5-phenylene substituted by 1 or 2 R Q Pyridyl, 2,4-pyridyl, 2,3-pyridyl, 3,4-pyridyl, 3,5-pyridyl, 2,6-pyrimidyl, 3,6-pyrimidyl , 3,6-pyridazinyl, 3,5-pyridazinyl or 4,5-pyridazinyl (preferably 2,6-pyridinyl);
  • RY is the same or different, RY3 , RY4 , RY , and RQ are each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, cyclopropyl, -O-cyclopropyl,
  • R is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or trifluoroethyl;
  • R', R are each independently selected from: hydrogen, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or trifluoroethyl;
  • R a and R b are each independently selected from: hydrogen, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or trifluoroethyl;
  • R a , R b are formed together with the N atoms connected to them:
  • R" is selected from hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl;
  • p and m1 are 0, 1 or 2.
  • HPK1 Ligands are further represented as:
  • X 2 and X 3 are independently N or CH;
  • Y1 is N or CH
  • R 0 is a chemical bond
  • L is NH, N(CH 3 ), NHCH 2 , CH 2 NH, NHCH 2 CH 2 or CH 2 CH 2 NH;
  • L' is selected from: chemical bond, O, S, -CO, -CONR N , -NR N CO, -NR N CONR N - or -(CR 2 2 ) P NR N -;
  • R b ', R N are each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, acetyl, amido, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, cyclopropyl (preferably hydrogen);
  • R is selected from: hydrogen, deuterium, hydroxyl, amino, hydroxylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, ring Propyl, cyclobutyl, oxetanyl (preferably hydrogen, methyl or ethyl);
  • two R 2 together with the connected C atoms form cyclopropyl, cyclobutyl, oxetanyl or azetidinyl;
  • R X is selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, acetyl, amido, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, -(CR ' 2 ) m1 NR a R b , C 3-6 cycloalkyl, -OR 1 , -O-(CH 2 ) 1-4 R 1 ,
  • R 1 and R' are independently selected from: hydrogen, deuterium, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkane Base, C 3-6 cycloalkyl, 4-7 membered heterocyclyl Or two R's and the C atoms connected to them together form a C 3-6 cycloalkyl group or a 4-7 membered heterocyclic group;
  • R Y is selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, acetyl, amido, hydroxylamino , C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl , Hydroxy C 1-6 alkyl, cyclopropyl, -O-cyclopropyl, Or two RY and the C atoms connected to it together form a cyclopropyl group;
  • the C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 3-6 cycloalkyl are optionally replaced by 1 or 2 Substituents selected from hydrogen, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl.
  • X 2 is CH; Y 1 is each independently N or CH; L is NH, N(CH 3 ), NHCH 2 or CH 2 NH;
  • R b ' is hydrogen;
  • R N is selected from: hydrogen or methyl;
  • R is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, hydroxycyclopropyl or fluorine Cyclopropyl;
  • R is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, Hydroxymethyl, Hydroxyethyl, Hydroxypropyl, Cyclopropyl, Hydroxycyclopropyl, Cyclobutyl,
  • R' is selected from: methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, cyclopropyl or cyclobutyl;
  • R a and R b are each independently selected from: hydrogen, deuterium, hydroxyl, amino, hydroxyl amino, methyl, ethyl, propyl, hydroxymethyl, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, Cyclopropyl, cyclobutyl
  • R a and R b form together with the N atom they are attached to
  • p 0, 1 or 2.
  • HPK1 Ligands are further represented as:
  • X 2 and X 3 are independently N or CH; Z 3 is O, -NR Z3 - or -C(R Z3 ) 2 ;
  • R Z3 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or hydroxy C 1-6 alkyl (preferably hydrogen);
  • L' is a chemical bond, NH, N(CH 3 ), NHCH 2 , CH 2 NH, NHCH 2 CH 2 or CH 2 CH 2 NH (preferably NH);
  • Y 5 and its connected substituent, RY6 and its connected ring atom together form a phenyl or 5 or 6-membered heteroaryl group substituted by 1 or 2 RY ; or RY1 , RY6 together with its connected ring atom Form phenyl or 5- or 6-membered heteroaryl substituted by 1 or 2 RY ; or, Y 3 and its attached substituent, RY1 and the ring atom attached to it together form substituted by 1 or 2 RY Phenyl or 5- or 6-membered heteroaryl; or, Y5 and its attached substituent, RY6 and its attached ring atoms together form a phenyl or 5- or 6-membered heteroaryl substituted by 1 or 2 RY ;
  • RY1 , RY3 , RY5 , RY6 , RY , R Z ' are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, amido, C 1-6 alkyl, C 1- 6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, cyclopropyl, -O-cyclopropyl,
  • RY5 , RY6 and the ring atoms connected to them together form a phenyl or pyridyl group substituted by 1 or 2 RY
  • RY1 , RY3 , RY , R Z ' are each independently selected from hydrogen, deuterium, halogen , C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl.
  • X 2 is N, X 3 is CH; in some embodiments, X 3 is N, X 2 is CH;
  • Y 3 is N, Y 5 is CRY5 , RY1 , RY6 and the ring atoms connected to them together form a phenyl or pyridyl group substituted by 1 or 2 RY ; in some embodiments, Y 3 is N, Y 5 is CRY5 , RY1 , RY6 and the ring atoms connected to them together form a phenyl or pyridyl group substituted by 1 or 2 RY ;
  • Y 3 is CRY3 , Y 5 is N, RY1 , RY6 and the ring atoms connected to them together form a phenyl or pyridyl group substituted by 1 or 2 RY ; in some embodiments, Y 3 is CR Y3 , Y 5 is N, Y 5 , RY6 and the ring atoms connected to them together form a phenyl or pyridyl group substituted by 1 or 2 RY ;
  • Y 3 is N, Y 5 is N, RY1 , Y 3 together with the ring atoms connected to them form a phenyl or pyridyl group substituted by 1 or 2 RY ; in some embodiments, Y 3 is N, Y 5 is N, RY1 , RY6 form a phenyl or pyridyl group substituted by 1 or 2 RY together with the ring atoms connected to them; in some embodiments, Y 3 is N, and Y 5 is N, RY6 , Y5 and the ring atoms connected to them together form a phenyl or pyridyl group substituted by 1 or 2 RY .
  • HPK1 Ligands are further represented as:
  • V 5 , V 6 , V 7 are each independently selected from N or CR V ;
  • R V is the same or different, and each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -C (O)NR a R b , NR a R b , C 1-6 alkyl, C 1-6 alkane Oxygen, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, (preferably hydrogen, F, amino, amido, dimethylamino, dimethylamino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl or trifluoroethyl);
  • R is selected from 5 or 6 membered heteroarylenes (preferably );
  • R V1 and R V1 ' are each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1- 6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 3-6 cycloalkyl or -OC 3-6 cycloalkyl (preferably hydrogen, halogen, methyl, ethyl, propyl , isopropyl, methoxy, ethoxy, trifluoromethyl or trifluoroethyl);
  • R 31 and R 32 are selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 3-6 cycloalkane or 4-7 membered heterocyclic group (preferably hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoroethyl, difluoro methyl, difluoroethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl);
  • R a and R b are as defined in any one of the above.
  • EL is further expressed as:
  • R N , R 7 , R 7 ', R 8 , R 8 ', R K are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1- 6 alkyl or hydroxy C 1-6 alkyl (preferably hydrogen, methyl or ethyl);
  • K 4 is CH or N, K 3 is NR K3 , CH 2 or CO;
  • R K3 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or hydroxy C 1-6 alkyl (preferably hydrogen, methyl or ethyl) ;
  • R g is selected from hydrogen, deuterium, halogen, cyano, amino, amido, dimethylamino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl Or hydroxy C 1-6 alkyl; Rg is preferably hydrogen, C 1-6 alkyl and halogenated C 1-6 alkyl, more preferably hydrogen, methyl, ethyl, propyl, isopropyl, methoxy , ethoxy, isopropoxy, trifluoromethyl, trifluoroethyl or cyano.
  • K3 is CH2 or CO.
  • the compound represented by the above general formula (I) is further represented as:
  • the compound represented by the general formula (I) is the above-mentioned general formula (II'-1), (II'-1-1), (II'-1-2), (II '-1-3), (II'-1-4) and (II'-1-5); where,
  • L is NH or N (methyl);
  • R 0 is a chemical bond, L' is -CONR N - or -COO-;
  • R 0 is L' is a chemical bond
  • X1 is N or CH
  • V 4 is NH or O
  • R V is each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano , amido, amino, dimethylamino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogen C 1-6 alkyl, hydroxy C 1-6 alkyl, C 3-6 cycloalkyl
  • R is hydrogen, deuterium, amino, hydroxylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or hydroxy C 1-6 alkyl;
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L1 is selected from: CH2 , CH2CH2 , CO, CONH, NHCO, NHCONH, SO , SO2 , SONH, NHSO, SO2NH , NHSO2 , O, S, NH, N(methyl), OCH 2.
  • CH 2 O, OCH 2 CH 2 vinylene, ethynylene, phenylene, pyridyl, pyrimidinyl, triazolylene, tetrazolyl, pyrazolylene, imidazole Base, piperidinyl, piperazinyl,
  • L 2 and L 3 are selected from: CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 , OCH 2 CH 2 , CH 2 O, phenylene, Pyridinylene, pyrimidinylene, triazolylene, tetrazolyl, pyrazolylene, imidazolyl, morpholinyl, piperidinylene, piperazinylene or CH 2 CH 2 O;
  • L 4 and L 5 are selected from chemical bonds, CH 2 or CH 2 CH 2 or CH 2 CH 2 O;
  • L 6 is selected from: chemical bonds, O, S, NH, N (methyl), CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 , CO, CONH, NHCO or CH 2 CH 2 O;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , vinylidene group or ethynylene group;
  • R N is selected from hydrogen or methyl; the hydrogen of any of the above methylene groups is optionally substituted by 1 or 2 R ## , and R ## is selected from deuterium, methyl, ethyl, propyl, cyclopropyl , amino or trifluoromethyl.
  • L is selected from a chemical bond or NH
  • Z 11 is N or CH;
  • Z 12 is N or CH;
  • R Z , , R a ', R N are each independently selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or C 3-6 cycloalkane group (preferably H or methyl);
  • R X is selected from: hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl (preferably hydrogen);
  • R Y4 is selected from: hydrogen, deuterium, halogen, cyano, amino, amido, dimethylamino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Base, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -O methylene cyclopropyl,
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L 1 is selected from: a chemical bond, CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 , CH 2 O, or
  • L 2 , L 3 are selected from: chemical bond, CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 OCH 2 , OCH 2 CH 2 , CH 2 O or CH2CH2O ;
  • L 4 and L 5 are selected from CH 2 or CH 2 CH 2 ;
  • L 6 is selected from: chemical bond, O, S, NH, N(methyl), CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CO, CONH or NHCO;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , vinylidene or ethynylene;
  • R ## is selected from hydrogen, deuterium, halogen, amido, amino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).
  • L is selected from chemical bonds
  • Both Z 11 and Z 11 are N;
  • R Z , R a ', R N are each independently selected from: hydrogen, deuterium;
  • Y 7 CH, Y 8 is O or S;
  • R X is selected from: hydrogen, deuterium
  • R Y4 is selected from: hydrogen, deuterium, halogen, cyano, amino C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl;
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L 1 is selected from: a chemical bond, CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 , CH 2 O, or
  • L 2 , L 3 are selected from: chemical bond, CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 OCH 2 , OCH 2 CH 2 , CH 2 O or CH2CH2O ;
  • L 4 and L 5 are selected from CH 2 or CH 2 CH 2 ;
  • L 6 is selected from: chemical bond, O, S, NH, N(methyl), CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CO, CONH or NHCO;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , vinylidene or ethynylene;
  • K3 is CH2 or CO
  • R is selected from hydrogen, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R ## is selected from hydrogen, deuterium, halogen, amido, amino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).
  • RY1 , RY2 , and RY3 are each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
  • R 9 is selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano or -C(R f 2 ) n2 -R #2 ;
  • R #2 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, CONR a R b , NR a R b , C 3-6 cycloalkyl or 4-7 membered heterocyclyl;
  • R a and R b are each independently selected from: hydrogen, deuterium, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, -C 1- 6 alkylene -4 to 7 membered azacyclic ring or -(CH 2 ) 1-6 -NR e1 R f1 ;
  • R e1 and R f1 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycle radical (preferably hydrogen, methyl or ethyl);
  • R a and R b form a 4 to 7-membered azacyclic ring together with their connected N atoms, preferably R e1 and R f1 together form a 4 to 7-membered azacyclic ring with their connected N atoms, and the C 3-6 cycloalkane Base, 4-7 membered heterocyclic group or 4 to 7 membered nitrogen heterocycle are optionally replaced by 1 or 2 members selected from deuterium, fluorine, amino, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl substituted;
  • X 1 and X 2 are each independently selected from CH or N;
  • Z 5 , Z 6 , and Z 7 are each independently CH or N;
  • R a ', R b ' are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl (preferably hydrogen);
  • R X , R Z ' are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, amido, acetyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or hydroxy C 1-6 alkyl;
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L 1 is selected from: CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 , OCH 2 CH 2 , CH 2 O, CH 2 CH 2 O or
  • L2 is selected from: chemical bond, CH2 , CH2CH2 , CO, CONH, NHCO , O, S, NH, N(methyl), OCH2 , OCH2CH2 , CH2O , CH2CH2O , piperidinyl or piperazinyl;
  • L 3 and L 4 are selected from: CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 , CH 2 O, OCH 2 CH 2 , CH 2 CH 2 O or piperidinylene;
  • L 5 is selected from a chemical bond, CH 2 , CH 2 CH 2 or CH 2 CH 2 O;
  • L 6 is selected from: chemical bond, O, S, NH, N(methyl), CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CO, CONH or NHCO;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , vinylidene or ethynylene;
  • R ## is selected from hydrogen, deuterium, halogen, amido, amino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).
  • RY1 , RY2 , and RY3 are each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
  • R 9 is -C(R f 2 ) n2 -R #2 ; n2 is an integer of 0-5;
  • R #2 is CONR a R b , NR a R b ;
  • R a and R b are each independently selected from: hydrogen, deuterium, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl;
  • X 1 is N, X 2 is CH;
  • Z 5 , Z 6 and Z 7 are all CH;
  • R a ', R b ' are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl (preferably hydrogen);
  • R X and each R Z ' are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or hydroxy C 1-6 alkyl;
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L 1 is selected from: CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 , OCH 2 CH 2 , CH 2 O, CH 2 CH 2 O or
  • L2 is selected from: chemical bond, CH2 , CH2CH2 , CO, CONH, NHCO , O, S, NH, N(methyl), OCH2 , OCH2CH2 , CH2O , CH2CH2O , piperidinyl or piperazinyl;
  • L 3 and L 4 are selected from: CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 , CH 2 O, OCH 2 CH 2 , CH 2 CH 2 O or piperidinylene;
  • L 5 is selected from a chemical bond, CH 2 , CH 2 CH 2 or CH 2 CH 2 O;
  • L 6 is selected from: chemical bond, O, S, NH, N(methyl), CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CO, CONH or NHCO;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , vinylidene or ethynylene;
  • K3 is CH2 or CO
  • Rg is selected from hydrogen, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R ## is selected from hydrogen, deuterium, halogen, amido, amino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).
  • Z 6 and Z 7 are independently CH or N;
  • RY is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
  • R Z ', RY1 , RY2 , RY3 , and RY4 are each independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, cyano, amido, acetyl, dimethylamino, diethylamino, di Formamide, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
  • R a ', R b ', R X are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1- 6 alkyl;
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L 1 is selected from: chemical bond, CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl) or
  • L 2 , L 3 , and L 4 are each independently selected from: chemical bond, CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N (methyl), OCH 2 , OCH 2 CH 2 , CH2CH2O ;
  • L 5 and L 6 are selected from chemical bonds, CH 2 or CH 2 CH 2 ;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , vinylidene or ethynylene;
  • R ## is selected from hydrogen, deuterium, halogen, amido, amino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl)
  • RN is selected from hydrogen, methyl or ethyl.
  • Z 6 and Z 7 are both CH; Y 1 , Y 2 , Y 3 and Y 4 are all CH;
  • Each RY is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
  • R Z ', RY1 , RY2 , RY3 , and RY4 are each independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1 - 6 alkyl groups;
  • R a ', R b ', R X are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl ;
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L 1 is selected from: chemical bond, CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl) or
  • L 2 , L 3 , and L 4 are each independently selected from: chemical bond, CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N (methyl), OCH 2 , OCH 2 CH 2 , CH2CH2O ;
  • L 5 and L 6 are selected from chemical bonds, CH 2 or CH 2 CH 2 ;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , vinylidene or ethynylene;
  • K3 is CH2 or CO
  • R is selected from hydrogen, C 1-6 alkyl and halogenated C 1-6 alkyl
  • RN is selected from hydrogen, methyl or ethyl
  • R ## is selected from hydrogen, deuterium, halogen, amido, amino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).
  • R b ', RY1 , RY2 , RY3 , RY4 , and R X are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, amido, cyano, C 1-6 alkyl, C 1 -6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;
  • R X is selected from hydrogen, halogen, C 1-6 alkyl, -OR 1 , -O-(CH 2 ) 1-4 R 1 , C 3-6 cycloalkyl or 4-7 membered heterocyclyl;
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;
  • RY is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
  • L' is expressed as -(CR 2 2 ) p -NR N -;
  • p 0, 1, 2 or 3
  • L is selected from a chemical bond, NH or N(methyl);
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L 1 is selected from: chemical bond, CH 2 , CH 2 CH 2 , O, S, NH, N(methyl), OCH 2 , CH 2 O, OCH 2 CH 2 , CH 2 CH 2 O;
  • L2 is selected from: chemical bond, CH2 , CH2CH2 , CO, CONH, NHCO , O, S, NH, N(methyl), OCH2 , CH2O , OCH2CH2 , CH2CH2O , piperidinyl;
  • L 3 and L 4 are selected from: CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 , CH 2 O or OCH 2 CH 2 ;
  • L 5 and L 6 are selected from chemical bonds, CH 2 , CH 2 CH 2 , OCH 2 CH 2 , O, S or NH;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , vinylidene or ethynylene;
  • R ## is selected from hydrogen, deuterium, halogen, amido, amino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).
  • RY1 , RY2 , RY3 , RY4 , and R b ' are each independently selected from hydrogen, deuterium, fluorine, amino, cyano, amido , acetyl, C 1-6 alkyl, C 1-6 alkoxy Base, halogenated C 1-6 alkyl, cyclopropyl, cyclobutyl or oxetanyl;
  • RY is selected from hydrogen, deuterium, fluorine, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl or difluoromethyl;
  • R X is selected from -O-(CH 2 ) s -R 1 or -(CR' 2 ) s -R 1
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl; said C 3-6 cycloalkyl or 4-7 membered heterocyclic
  • the group is preferably cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, and the C 3-6 cycloalkyl or 4-7 membered heterocyclic group is optionally selected from 1 or 2 deuterium , fluorine, methyl, ethyl, hydroxyl, hydroxymethyl, amino substituents;
  • R X is selected from hydrogen, deuterium, fluorine, chlorine, cyano, NR a R b , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkane base or 4-7 membered azacyclic ring; preferred R X is expressed as -(CR' 2 ) s -NR a R b ,
  • R Z4 is selected from hydrogen, deuterium, fluorine, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, isopropoxy A group, or two R Z4 form a cyclopropyl group, a cyclobutyl group or a cyclopentyl group together with the C atom connected to it;
  • R Y1 , R Y2 , R Y3 , R Y4 , and R Q are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, CONR a R b , NR a R b , C 1-6 alkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 4-7 membered nitrogen heterocycle;
  • Y 8 is O, S or CH 2 ;
  • R', R a , R b are each independently selected from hydrogen, deuterium, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, cyclopropyl, cyclobutyl
  • two R's form a cyclopropyl or cyclobutyl group together with their connected C atoms;
  • preferred R a and R b form a 4-7 membered azacyclic ring together with their connected N atoms
  • the C 3-6 cycloalkyl or 4-7 membered azacyclic ring is optionally replaced by 1 or 2 members selected from F, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl
  • the substituent of the group is substituted;
  • L' is selected from: NR N , O, S, or -(CR 2 2 ) p -NR N -;
  • R 2 and R N are each independently selected from hydrogen, deuterium, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl or C 3-6 cycloalkyl;
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L 1 is selected from: a chemical bond, CH 2 , CH 2 CH 2 , O, S, NH, N(methyl), OCH 2 or CH 2 O;
  • L2 is selected from: chemical bond, CH2 , CH2CH2 , CO, CONH, NHCO , O, S, NH, N(methyl) , OCH2 , CH2O , OCH2CH2 or CH2CH2O ;
  • L 3 and L 4 are selected from: CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 , CH 2 O or OCH 2 CH 2 ;
  • L 5 and L 6 are selected from chemical bonds, CH 2 , CH 2 CH 2 , OCH 2 CH 2 , O, S or NH;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , vinylidene or ethynylene;
  • R ## is selected from hydrogen, deuterium, halogen, amido, amino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl) .
  • Z 4 is CH 2 ;
  • Z 3 is NH;
  • Y 5 is N or C
  • Y 6 is N or C
  • Y 7 , Y 8 , Y 9 , and Y 10 are each independently NH or CRY ;
  • RY1 , RY3 , RY4 , and RY are each independently selected from hydrogen, deuterium, halogen, amido, amino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1 -6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;
  • L is a chemical bond
  • L' is NH
  • U 9 is selected from N or CR U "
  • U 8 is selected from N or CR U "
  • R U is selected from hydrogen, deuterium, halogen, amino, amido, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl or C
  • a 3-6 cycloalkyl group (preferably hydrogen, methyl or ethyl), preferably two R U "to form a 3-8-membered cycloalkyl group or a 4-7-membered heterocyclic group with the ring atoms connected to it;
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L 1 is selected from C 3-6 cycloalkyl, 4-12 membered heterocyclyl, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , O, S, NH, N(methyl), CO, SO , SO 2 ,
  • L 2 is selected from C 3-6 cycloalkyl, 4-7 membered heterocyclyl, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , O, S, NH, N(methyl), OCH 2 , CH2O , CONH or NHCO;
  • L 3 is selected from: CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 OCH 2 , OCH 2 CH 2 , CH 2 O, CH2CH2O ;
  • L4 is selected from a chemical bond, CH2 , CH2CH2 , CO, CONH, NHCO , O, S , NH, N(methyl), OCH2 , OCH2CH2 , CH2O or CH2CH2O ;
  • L 5 is selected from chemical bonds, CH 2 or CH 2 CH 2 ;
  • L 6 is selected from: chemical bond, O, S, NH, N(methyl), CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CO, CONH or NHCO;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , vinylidene or ethynylene;
  • R ## is selected from hydrogen, deuterium, halogen, amido, amino, dimethylamino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group.
  • Y 7 is N
  • Y 9 is CRY
  • Y 7 is CRY
  • Y9 is N; in some embodiments, both Y 7 and Y 9 are CRY .
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L 1 is selected from: chemical bond, O, S, NRN , CH 2 , C(CH 3 ) 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , OCH 2 CH 2 , CH 2 CH 2 O, CO, CONR N , NR N CO, NR N CONR N , SO 1-2 , SO 1-2 NR N , NR N SO 1-2 , NR N SO 1-2 NR N , vinylidene Base, ethynylene, phenylene, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, piperazinyl, piperidinyl, triazolene, tetrazolyl, Pyrazolylene, imidazolyl, C 3-6 cycloalkylene, 4-12 membered heterocyclylene,
  • L 2 are each independently selected from: chemical bond, O, S, NRN , CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , C(CH 3 ) 2 , CO, CONR N , NR N CO, OCH 2 CH 2 , CH 2 CH 2 O, vinylene, ethynylene, phenylene, pyridinylene, pyrimidinylene, piperazinylene, triazolylene, Tetrazolyl, pyrazolylene, imidazolyl, C 3-6 subring Alkyl or 4-12 membered heterocyclylene;
  • L 3 and L 4 are each independently selected from: chemical bond, O, S, NRN , CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 , CO, CONR N , NR N CO, OCH 2 CH 2 , CH 2 CH 2 O, vinylene, ethynylene, phenylene, pyridinylene, pyrimidinylene, piperazinylene, triazolylene, tetrazolyl , pyrazolylene, imidazolyl;
  • L 5 and L 6 are each independently selected from: chemical bond, O, S, NRN , CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 , CO, CONR N , NR N CO, OCH 2 CH 2 , CH 2 CH 2 O, vinylene, ethynylene, phenylene, pyridinylene, pyrimidinylene, piperazinylene, triazolylene, tetrazolyl , pyrazolylene, imidazolyl;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , vinylidene, ethynylene, CONR N , NR N CO, NR N CONR N , SO 1- 2 , SO 1-2 NR N , NR N SO 1-2 or NR N SO 1-2 NR N ;
  • R N is selected from hydrogen or methyl; the hydrogen of any of the above methylene groups is optionally substituted by 1 or 2 R ## ;
  • the C 3-6 cycloalkylene and 4-12 membered heterocyclylene are optionally replaced by 1 or 2 members selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, Substituents of halogenated C 1-6 alkyl or hydroxy C 1-6 alkyl.
  • LIN is expressed as: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, L 7 is connected to EL;
  • L 1 is selected from: CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 , OCH 2 CH 2 , CH 2 O, CH 2 CH 2 O or
  • L2 is selected from: chemical bond, CH2 , CH2CH2 , CO, CONH, NHCO , O, S, NH, N(methyl), OCH2 , OCH2CH2 , CH2O , CH2CH2O ;
  • L 3 and L 4 are selected from: CH 2 , CH 2 CH 2 , CO, CONH, NHCO, O, S, NH, N(methyl), OCH 2 , CH 2 O, OCH 2 CH 2 , CH 2 CH 2 O;
  • L 5 is selected from a chemical bond, CH 2 , CH 2 CH 2 or CH 2 CH 2 O;
  • L 6 is selected from: chemical bond, O, S, NH, N(methyl), CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CO, CONH or NHCO;
  • L 7 is selected from: O, S, NH, N(methyl), CH 2 , ethenylene or ethynylene.
  • each of the above-mentioned groups is independently the corresponding group in the compounds EX-1 to EX-32 prepared in the examples.
  • the compound represented by general formula (I) is selected from Table 1.
  • compositions which contains any of the above compounds, or pharmaceutically acceptable salts, enantiomers, diastereoisomers, racemates, solvates Compounds, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, and pharmaceutically acceptable excipients; preferably, it also contains other therapeutic agents.
  • Another aspect of the present invention provides any of the above compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs Type, prodrug or isotope variant, and their mixture, or the application of the above-mentioned pharmaceutical composition in the preparation of protein inhibitor or degradation agent.
  • the protein is HPK1 protein.
  • Another aspect of the present invention also provides the compound as any one of the above or its pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorphic form , prodrugs or isotope variants, and their mixtures in the preparation of medicines for treating and/or preventing cancer.
  • Another aspect of the present invention also provides a method for treating and/or preventing cancer in a subject, the method comprising administering to the subject any compound or a pharmaceutically acceptable salt thereof, Enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants and their mixtures or pharmaceutical compositions of the above.
  • Another aspect of the present invention also provides the compound as any one of the above or its pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorphic form , prodrugs or isotopic variants and their mixtures or pharmaceutical compositions as described above, which are used for the treatment and/or prevention of cancer.
  • the cancer is selected from bladder cancer, breast cancer, colorectal cancer, gastric cancer, squamous cell carcinoma of the head and neck, Hodgkin's lymphoma, Melkel -cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, ovarian cancer, uterine cancer, esophageal cancer, liver cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, thyroid cancer, small cell lung cancer, transitional cell carcinoma, Urothelial carcinoma, tumors resistant to targeted agents; or tumors or diseases dependent on HPK1 mutant proteins.
  • the cancer is selected from bladder cancer, breast cancer, colorectal cancer, gastric cancer, squamous cell carcinoma of the head and neck, Hodgkin's lymphoma, Melkel -cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, ovarian cancer, uterine cancer, esophageal cancer, liver cancer, pancreatic cancer, prostate cancer, renal cell carcinoma
  • C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5, C 3-4 , C 4-6 , C 4-5 and C 5 -6 alkyl.
  • C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl is preferred. Examples of C 1-6 alkyl groups include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), t-butyl Base (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl ( C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ).
  • C 1-6 alkyl also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-6 alkenyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments , C 2-4 alkenyl is preferred. Examples of C 2-6 alkenyl include: ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentenyl (C 5 ), hexenyl (C 6 ), and the like.
  • C alkenyl also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-6 alkynyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl include, but are not limited to: ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • C alkynyl also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkynyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • Halo or "halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • halogenated C 1-6 alkyl refers to the above-mentioned “C 1-6 alkyl", which is substituted with one or more halogen groups.
  • haloC1-4alkyl is particularly preferred, more preferably haloC1-2alkyl .
  • Exemplary haloalkyl groups include, but are not limited to: -CF 3 , -CH 2 F, -CHF 2 , -CHFCH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CCl 3 , -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
  • a haloalkyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 3-8 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 cycloalkyl and C 3-6 cycloalkyl are particularly preferred, more preferably C 5-6 cycloalkyl. Cycloalkyl also includes ring systems wherein the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to indicate The number of carbons in the cycloalkyl system.
  • cycloalkyl groups include, but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene Cycloheptadienyl (C 7 ), Cycloheptadienyl (C 7 ), Cycloheptatrienyl (C 7 ), and the like. Cycloalkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 4-12 membered heterocyclic group refers to a group of 4 to 12 membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, Sulfur, boron, phosphorus and silicon.
  • the point of attachment can be a carbon or nitrogen atom, as valence permits.
  • 3-10 membered heterocyclyl which is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, is preferred; in some embodiments, 3-7 membered
  • the heterocyclic group is more preferably a 3-6 membered heterocyclic group, further preferably a 4-8 membered heterocyclic group, and more preferably a 5-6 membered heterocyclic group.
  • Heterocyclyl also includes ring systems wherein the aforementioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or wherein the aforementioned heterocyclyl ring is fused to one or more aryl or Heteroaryl-fused ring systems wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system.
  • heterocyclyl groups include, but are not limited to: aziridinyl, oxirandyl, thiorenyl, azetidinyl, oxetanyl, thietanyl Alkyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, piperidinyl, tetrahydropyranyl, Dihydropyridyl, thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 5-membered heterocyclyls (also referred to herein as 5,6-bicyclic heterocyclyls) fused to a C6 aryl ring include, but are not limited to: indolinyl, isoindolinyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocyclyls (also referred to herein as 6,6 -bicyclic heterocyclyls) fused to a C aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.
  • a heterocyclyl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 6-10 aryl refers to a monocyclic or polycyclic (e.g. bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (e.g. For example, groups with 6 or 10 ⁇ electrons shared in a ring arrangement).
  • an aryl group has six ring carbon atoms ("C aryl”; eg, phenyl).
  • an aryl group has ten ring carbon atoms ("C 10 aryl”; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • Aryl also includes ring systems wherein the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system.
  • An aryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 5-14 membered heteroaryl means a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6, 10 or 14 ⁇ electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • the point of attachment can be a carbon or nitrogen atom, as valence permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems wherein the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said heteroaryl ring, in which case the carbon atoms Numbers continue to indicate the number of carbon atoms in the heteroaryl ring system.
  • 5-10 membered heteroaryls are preferred, and in other embodiments, 5-6 membered heteroaryls are especially preferred.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl.
  • heteroaryl groups include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl (e.g., 1,2,4 -oxadiazolyl), thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azepanyl, oxepeptyl Trienyl, Thiepatrienyl.
  • oxadiazolyl e.g., 1,2,4 -oxadiazolyl
  • thiadiazolyl e.g., thiadiazolyl
  • tetrazolyl e.g., 1,2,4 -oxadiazolyl
  • pyridyl pyridaziny
  • Exemplary 5,6-bicyclic heteroaryls include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl , Benzisofuryl, Benzimidazolyl, Benzoxazolyl, Benzisoxazolyl, Benzoxadiazolyl, Benzthiazolyl, Benzisothiazolyl, Benzthiadiazolyl, Indenazinyl and Purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, multiplinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
  • a heteroaryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 6-10 arylene group and “5-14 membered heteroarylene group” represent the above-mentioned “C 6-10 aryl group” and “5-14 membered heteroaryl group”, respectively, wherein another hydrogen is removed to form divalent groups, and may be substituted or unsubstituted.
  • Preferred are C 6-10 arylene and 5-10 membered heteroarylene.
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, etc. are defined herein as optionally substituted groups.
  • Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are combined to form a heterocyclyl or Heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R groups group replacement;
  • Each of Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Rcc groups are combined to form a heterocycle radical or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;
  • cancer includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal and pharynx (mouth), lips, Cancers of the tongue, oral cavity, pharynx, small intestine, colorectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, Adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphoid disorders, Hodgkin's disease, hair cell carcinoma, and leukemia.
  • cancers include, but are not limited to, HER2-positive metastatic breast cancer, HER2-overexpressed metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, non-small cell lung cancer with sensitive mutations in the epidermal growth factor receptor (EGFR) gene, non-small cell lung cancer containing Locally advanced or metastatic non-small cell lung cancer with squamous histology, metastatic advanced breast cancer, castration-resistant prostate cancer with disease progression during or after platinum chemotherapy.
  • EGFR epidermal growth factor receptor
  • treating refers to reversing, alleviating, inhibiting the progression of the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition.
  • the noun “treat” as used herein refers to the action of the verb treat, which is as just defined.
  • the term "pharmaceutically acceptable salt” refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention, which are suitable for use in contact with patient tissues within the scope of sound medical judgment without undue toxicity, Irritation, allergic effects, etc., commensurate with a reasonable benefit/risk ratio, are valid for their intended use, including, where possible, zwitterionic forms of the compounds of the invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, for example alkali and alkaline earth metal hydroxides or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, Ethylenediamine, N-methylglucamine, and procaine.
  • Base addition salts of acidic compounds may be prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt, in conventional manner.
  • the free acid may be regenerated by contacting the salt form with the acid and isolating the free acid in a conventional manner.
  • the free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the salts are nevertheless equivalent to their respective free acids for the purposes of the present invention.
  • Salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphoric acids prepared from inorganic acids Salts, chlorides, bromides, iodides, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc.
  • Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, and the like.
  • Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, and the like.
  • Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also contemplated are salts of amino acids, such as arginine salts, gluconate salts, galacturonate salts, and the like.
  • Subjects for administration include, but are not limited to: human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adult, middle-aged adult or older adult)) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human", “patient” and “subject” are used interchangeably herein.
  • treating includes an effect on a subject suffering from a particular disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or slows down the disease, disorder or the development of a disease, disorder or condition ("therapeutic treatment”) and also includes effects that occur before a subject begins to suffer from a particular disease, disorder or condition (“prophylactic treatment").
  • an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response.
  • an effective amount of a compound of the invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the condition of the subject. Age Health conditions and symptoms.
  • An effective amount includes a therapeutically effective amount and a prophylactically effective amount.
  • a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to induce one or more symptoms associated with the disease, disorder or condition. Amount to delay or minimize.
  • a therapeutically effective amount of a compound refers to that amount of the therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease, disorder or condition, or to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent a disease , the amount of recurrence of the disorder or condition.
  • a prophylactically effective amount of a compound refers to that amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” may include amounts that improve overall prophylaxis, or that enhance the prophylactic effect of other prophylactic agents.
  • Combination and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent.
  • the compounds of the invention may be administered with the other therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together with the other therapeutic agent in a single unit dosage form.
  • the compounds of the present invention may include one or more asymmetric centers, and thus may exist in various stereoisomeric forms, eg, enantiomeric and/or diastereomeric forms.
  • compounds of the invention may be individual enantiomers, diastereomers or geometric isomers (eg cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
  • Isomers can be separated from mixtures by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be obtained by prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • organic compounds may form complexes with solvents in which they react or from which they are precipitated or crystallized. These complexes are known as "solvates”. When the solvent is water, the complex is called a "hydrate”. The invention covers all solvates of the compounds of the invention.
  • solvate refers to a form of a compound, or a salt thereof, which is associated with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes both solution state solvates and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • hydrate refers to a compound that combines with water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound can be represented, for example, by the general formula R x H2O, where R is the compound, and x is a number greater than zero.
  • a given compound may form more than one hydrate type, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrate (R 0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R 2H2O) and hexahydrate (R 6H2O)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and less than 1, e.g., hemihydrate (R 0.5H2O)
  • polyhydrates x is a number greater than 1, for example, dihydrate (R 2H2O) and hexahydrate (R 6H2O)
  • the compounds of the invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • the invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I), but with one or more atoms represented by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature replaced.
  • isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, respectively , 35S, 18F and 36Cl.
  • the compounds of the present invention their prodrugs and pharmaceutically acceptable salts of the compounds or the prodrugs containing the above-mentioned isotopes and/or other isotopes of other atoms all belong to the scope of the present invention.
  • Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes (eg 3H and 14C), are useful in drug and/or substrate tissue distribution assays. Tritium, ie 3H, and carbon-14, ie 14C isotopes are particularly preferred because of their ease of preparation and detection.
  • isotope-labeled compound of formula (I) of the present invention and its prodrug can generally be prepared in this way.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted in vivo into its active form having a medicinal effect, for example by hydrolysis in the blood
  • a prodrug is any covalently bonded compound of the invention which, when administered to a patient, releases the parent compound in vivo.
  • Prodrugs are typically prepared by modifying a functional group in such a way that the modification can be cleaved by routine manipulation or in vivo to yield the parent compound of.
  • Prodrugs include, for example, compounds of the invention wherein a hydroxy, amino, or thiol group is bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amino, or thiol group.
  • prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxy, sulfhydryl and amino functional groups of the compounds of formula (I).
  • esters such as methyl ester, ethyl ester and the like can be used.
  • the esters themselves may be reactive and/or hydrolyzable under human in vivo conditions.
  • Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those which break down readily in the human body to release the parent acid or a salt thereof.
  • the present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms are included in the present invention.
  • the invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a prophylactically effective amount of a compound of the invention.
  • a pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- Block polymers, polyethylene glycol
  • kits eg, pharmaceutical packs.
  • kits can include a compound of the invention, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packs or other suitable container).
  • first and second containers e.g., vials, ampoules, bottles, syringes, and/or dispersible packs or other suitable container.
  • provided kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent.
  • a compound of the invention and other therapeutic agent provided in a first container and a second container are combined to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intracerebrospinal administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of the compound actually administered can be determined by the physician according to the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
  • the compounds provided herein are administered to a subject at risk of developing the condition, typically on the advice and supervision of a physician, at dosage levels as described above.
  • Subjects at risk of developing a particular condition generally include those with a family history of the condition, or those determined by genetic testing or screening to be particularly susceptible to developing the condition.
  • Chronic administration refers to administering a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, For example, the rest of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within the therapeutic window.
  • compositions may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to effective levels.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose provides slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV intravenous infusion) ) can be delivered more rapidly, so that the concentration of the active ingredient in the blood rises rapidly to effective levels.
  • the pharmaceutical compositions may be administered as a continuous infusion, eg, by IV infusion, to provide a steady state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
  • Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More usually, however, the compositions will be presented in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound will generally be a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various components useful for forming the desired administration form. Carriers or excipients and processing aids.
  • a typical regimen is one to five oral dosages per day, especially two to four oral dosages, typically three oral dosages.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.
  • the transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injection dosage levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given in order to achieve adequate steady state levels.
  • the maximum total dose should not exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffering, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may comprise, for example, any of the following components, or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, water Methyl sylate or orange flavoring.
  • binders such as microcrystalline cellulose, tragacanth, or gelatin
  • excipients such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically a minor component, often from about 0.05 to 10% by weight, the remainder being injectable excipients and the like.
  • Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active ingredients When formulated in an ointment, the active ingredients are typically combined with a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream, with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art, and generally include other ingredients for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.
  • transdermal administration can be achieved using patches of the reservoir or porous membrane type, or various solid matrices.
  • compositions for oral administration, injection or topical administration are representative only.
  • the compounds of the invention may also be administered in sustained release form, or from a sustained release delivery system.
  • sustained release form or from a sustained release delivery system.
  • the invention also relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ -, and ⁇ -cyclodextrins composed of 6, 7, and 8 ⁇ -1,4-linked glucose units, respectively, optionally including a or multiple substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, eg, sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, eg, U.S. 5,376,645.
  • the formulation includes hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • Treatment as defined herein may be applied as a sole therapy, or may include conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the invention. Accordingly, the compounds of the present invention may also be used in combination with existing therapeutic agents for the treatment of cancer.
  • antineoplastic agents In addition to treatment with the compounds of the invention, conventional surgery or radiotherapy or chemotherapy or immunotherapy is involved. Such chemotherapy and the compounds of the present invention may be administered simultaneously, sequentially, or separately, and may contain one or more of the following types of antineoplastic agents:
  • Antiproliferative/antineoplastic agents and combinations thereof used in medical oncology such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, phentermine mustard, busulfan, temozolomide, nitrosoureas); antimetabolites (such as gemcitabine and antifolates such as fluoropyrimidines (such as 5-fluorouracil and tegafur), raltitrexed, methotrexed arabicin, cytarabine, hydroxyurea); antineoplastic antibiotics (such as anthracyclines, such as adriamycin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin C, actinomycin, mithramycin); antimitotic agents (eg, vinca alkaloids,
  • Cytostatic agents such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, iodoxyfene), antiandrogenic agents Hormone drugs (such as bicalutamide, flutamide, nilutamide, cyproterone acetate), LHRH antagonists or LHRH agonists (such as goserelin, leuprolide, and buserelin), Progestogens (eg, megestrol acetate), aromatase inhibitors (eg, anastrozole, letrozole, vorazole, exemestane), 5 ⁇ -reductase inhibitors (eg, finasteride );
  • antiestrogens e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, iodoxyfene
  • anti-invasion agents such as c-Src kinase family inhibitors, [such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-( 4-Methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline [AZD0530 (Seracatinib)], N-(2-chloro-6- Methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino ⁇ thiazole-5-carboxamide (dasatinib Ni, BMS-354825) and bosutinib (SKI-606), and metalloproteinase inhibitors (such as marimastat), inhibitors of urokinase plasminogen activator receptor function, or heparanase ( heparanas),
  • Inhibitors of growth factor function examples include growth factor antibodies and growth factor receptor antibodies (eg anti-erbB2 antibody trastuzumab [Herceptin], anti-EGFR antibody panitumumab, anti- erbB1 antibody cetuximab [Erbitux, C225]; such inhibitors also include: tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g.
  • EGFR family tyrosine kinase inhibitors such as N-( 3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-quinazolin-4-amine (gefitinib, ZD1839), N-(3 -ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774), 6-acrylamido-N-(3 -Chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI1033), erbB2 tyrosine kinase inhibitors (e.g.
  • liver Inhibitors of the cellular growth factor family include inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and/or nilotinib (AMN107); inhibition of serine/threonine kinases agents (such as Ras/Raf signaling inhibitors, such as farnesyl transferase inhibitors, such as sorafenib (BAY43-9006), tipifarnib (R115777), lonafarnib (SCH66336)), through mEK and/or cell signaling inhibitors of AKT kinase, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors ( For example AZD1152, PH739358,
  • Anti-angiogenic agents such as agents that inhibit the action of vascular endothelial growth factor, [such as the anti-human vascular endothelial growth factor antibody bevacizumab (Avastin) and such as VEGF receptor tyrosine kinase inhibitors, For example vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034), 4-(4-fluoro- 2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171), and compounds that act by other mechanisms (e.g. ranolamid, an inhibitor of integrin ⁇ v ⁇ 3 function, and angiostatin)];
  • vascular endothelial growth factor such as the anti-human vascular endothelial growth factor antibody bevacizumab (
  • vascular injury agents such as compretin A4
  • endothelin receptor antagonists such as zipotetan (ZD4054) or atrasentan;
  • antisense therapeutics such as those directed to the targets listed above, such as ISIS2503 (an anti-ras antisense therapeutic);
  • Gene therapy methods including, for example, methods of replacing abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2); GDEPT (Gene-Directed Enzyme Prodrug Therapy) methods, such as using cytosine deaminase, thymidine kinase, or bacterial those with nitroreductases; methods of increasing a patient's resistance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; and
  • Immunotherapy methods including, for example, in vitro and in vivo methods of increasing the immunogenicity of tumor cells in patients, such as transfection with cytokines (such as interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor); methods for reducing T cell anergy; methods using transfected immune cells (e.g., cytokine-transfected dendritic cells); methods using cytokine-transfected tumor cell lines; methods using anti-idiotypic antibodies ; methods of reducing the function of immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells, or dendritic cells expressing IDO (indoleamine 2,3-deoxygenase); and Methods using cancer vaccines composed of proteins or peptides derived from tumor-associated antigens (eg NY-ESO-1, mAGE-3, WT1 or Her2/neu).
  • cytokines such as interleukin 2, interleukin 4, or granul
  • Step 1 Dissolve compound 1-1 (32g, 98.79mmol) in anhydrous THF (50mL), slowly add sodium hydride (5.93g, 148.19mmol, 60%wt) under nitrogen protection at 0°C, and stir for 30 minutes.
  • a solution of di-tert-butyl dicarbonate (28.03 g, 29.50 mL) in anhydrous THF (10 mL) was slowly added dropwise, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, water (10 mL) was added to quench, and concentrated under reduced pressure to obtain a crude product.
  • Step 1 Using compound Int-1 and compound 3.1 as raw materials, according to the synthesis method of compound Int-1, dark brown oily compound 3-1 (5.6 g, yield 61.5%) was obtained. LCMS [M+H] + 598.5.
  • Step 2 Dissolve compound 3-1 (3.3g, 5.52mmol) in dichloromethane (10mL), add trifluoroacetic acid (46.20g, 30mL), and react at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain crude compound Int-3 (2.3 g) as a yellow solid.
  • Step 2 Dissolve compound 4-2 (6.42g, 15.45mmol) in dichloromethane (50mL), add trifluoroacetic acid (9.89g, 86.71mmol, 6.42mL), and stir at room temperature for 3 hours. After concentration under reduced pressure and lyophilization, compound Int-4 (3.4 g, yield 61.2%) was obtained as a yellow solid. LCMS [M+H] + 360.1.
  • Step 2 Under nitrogen protection, compound 14-1 (330 mg, 645.02 ⁇ mol) was dissolved in hydrochloric acid in dioxane (4M, 10 mL) and reacted at room temperature for 3 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain compound Int-14 (200 mg, yield 69.2%) as a yellow solid. LCMS [M+H] + 412.3.
  • Step 1 Under nitrogen protection, compound Int-3 (100 mg, 251.59 ⁇ mol), (6-bromohexyl) tert-butyl carbamate (70.50 mg, 251.59 ⁇ mol) and DIPEA (97.55 mg, 131.47 ⁇ L) were dissolved in DMF ( 10 mL), heated at 70°C for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched by adding a small amount of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate.
  • Step 2 Under nitrogen protection, compound 15-1 (90 mg, 150.81 ⁇ mol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.54 g, 1 mL) was added dropwise, and reacted at room temperature for 2 hours. After the reaction, it was concentrated under reduced pressure to obtain the crude compound Int-15 (70 mg, yield 76.0%) as a yellow solid. LCMS [M+H] + 497.4.
  • compound 17-1 (49.90mg, 355.95 ⁇ mol), compound 17-2 (100mg, 296.63 ⁇ mol), Pd(PPh) 2 C l2 (20.82mg, 29.66 ⁇ mol), CuI (11.30mg, 59.33 ⁇ mol ) and triethylamine (2.91g, 4.00mL) were dissolved in DMF (4mL), heated at 80°C for 10 hours. After the reaction, it was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (2 ⁇ 20 mL), and the organic phase was dried over anhydrous sodium sulfate.
  • Step 2 Under nitrogen protection, compound 21-3 (300 mg, 634.88 ⁇ mol) was dissolved in a solution of hydrochloric acid in 1,4-dioxane (4M, 5 mL), and reacted at room temperature for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain compound Int-21 (260 mg, yield 98.3%) as a gray oil. LCMS [M+H] + 417.2.
  • compound Int-23 was prepared according to the synthesis method of compound Int-15, LCMS [M+H] + 456.3.
  • Step 2 Under nitrogen protection, compound 28-1 (3 g, 6.32 mmol, 1 eq) was dissolved in anhydrous 1,4-dioxane (100 mL), and then Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 ( 516.48mg, 632.45 ⁇ mol), anhydrous potassium acetate (1.24g, 12.65mmol) and bisanthyl borate (3.21g, 12.65mmol), heated at 100°C for 3 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (20 mL), extracted with dichloromethane (3 ⁇ 30 mL), and the combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain dark brown gum compound 28-2 (5.7 g, crude product), which was directly used in the next reaction. LCMS [M+H] + 440.1.
  • Step 3 Under nitrogen protection, compound 28-2 (2.2g, 5mmol, 1.4eq) and compound 28.2 (801.39mg, 3.54mmol) were added to 1,4-dioxane (20mL) and water (2mL) To the mixed solution, Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (120.60mg, 147.68 ⁇ mol) and potassium carbonate (816.39mg, 5.91mmol) were added, and the reaction was heated at 80°C for 3 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (20 mL), then extracted with dichloromethane (3 ⁇ 30 mL), and the combined organic layers were dried over anhydrous sodium sulfate.
  • Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 120.60mg, 147.68 ⁇ mol
  • potassium carbonate 816.39mg, 5.91mmol
  • Step 4 Compound 28-3 (600 mg, 1.10 mmol) was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (5.54 mmol, 410.84 ⁇ L) was added, and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound Int-28 (640 mg, crude product). The yellow solid was directly used in the next reaction. LCMS [M+H] + 385.2.
  • Step 2 Compound 29-2 (600mg, 1.73mmol) and hydrazine hydrate (3.46mmol, 198.07 ⁇ L, 85%purity) were dissolved in In water ethanol (10 mL), the reaction was heated at 60°C for 1 hour. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to obtain the crude compound 29-3 (370 mg, yield 98.8%), which was directly used in the next reaction.
  • Step 4 Dissolve compound 29-4 (50 mg, 105.81 ⁇ mol) in dichloromethane (10 mL), add trifluoroacetic acid (121.0 mg, 1.06 mmol), and react at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude compound Int-29 (60 mg) as a yellow oil.
  • Step 1 Compound 31-1 (500mg, 2.17mmol), phthalic anhydride (321.51mg, 2.17mmol), DIPEA (420.81mg, 3.26mmol) were dissolved in anhydrous toluene (15mL), heated at 110°C for 10 Hour. After the reaction, cool to room temperature, add saturated ammonium chloride aqueous solution, extract with ethyl acetate, and dry the organic phase with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain colorless oily compound 31-2 (700 mg, yield 89.5%). LCMS [M+Na] + 383.2.
  • Steps 2-4 refer to the synthesis steps 2-4 of compound Int-29 to obtain compound Int-31, LCMS [M+H] + 401.3.
  • Step 2 Dissolve compound 34-2 (2.3g, 7.13mmol) in anhydrous methanol (50mL), slowly add wet palladium on carbon (1.5g, 10%Pd) under nitrogen protection, and react at room temperature for 2 hours. After the reaction was completed, it was filtered and the filtrate was concentrated under reduced pressure to obtain compound 34-3 (4 g, crude product) as a brown solid.
  • Step 5 Dissolve compound 34-5 (50 mg, 107.17 ⁇ mol) in dichloromethane (5 mL), add trifluoroacetic acid (13.51 mmol, 1 mL), and stir at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound Int-34 (50 mg, crude product) as a brown solid. LCMS [M+H] + 366.9.
  • Step 1 Dissolve compound Int-34 (65.56 mg, 136.45 ⁇ mol) in DMF (5 mL), slowly add tert-butyl bromoacetate (109.16 ⁇ mol, 16.13 ⁇ L) and DIEA (409.34 ⁇ mol, 71.30 ⁇ L), and react at 0°C 3 hours. After the reaction, it was diluted with water (15 mL), extracted with ethyl acetate (3 ⁇ 10 mL), and the organic phase was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the crude compound 35-1 (43 mg, yield 65.6%) was obtained as a brown oil. LCMS [M+H] + 481.2.
  • Step 2 Compound 35-1 (43 mg, 89.47 ⁇ mol) was dissolved in hydrochloric acid in 1,4-dioxane (3 mL), and reacted at room temperature for 2 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to obtain compound Int-35 (180 mg, crude product) as a brown solid. LCMS [M+H] + 425.2.
  • Step 1 Under nitrogen protection, compound 39-1 (378.63mg, 1.75mmol), compound 39-2 (400.00mg, 1.46mmol), triphenylphosphine (1.15g, 4.38mmol) were dissolved in tetrahydrofuran (10mL) solution , the mixture was cooled to 0°C, then diisopropyl azodicarboxylate (884.85mg, 4.38mmol) was slowly added, and the mixture was stirred and reacted at 0°C for 5 hours. After the reaction, the reaction mixture was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase column chromatography (formic acid system) to obtain compound 39-3 (100 mg, yield 14.5%) as a white solid. LCMS [M+Na] + 495.4.
  • Step 2 Under nitrogen protection, compound 39-3 (100mg, 211.63 ⁇ mol), trifluoroacetic acid (3.08g, 27.01mmol, 2.00mL) were dissolved in anhydrous dichloromethane (10ML) solution, and the mixture was heated at 25°C The reaction was stirred for 10 hours. After the reaction, the reaction mixture was directly concentrated under reduced pressure to obtain compound Int-39 (80 mg, yield 90.8%) as a yellow oil. LCMS [M+H] + 417.2.
  • Example 1 4-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl )amino)butanoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N-di Synthesis of Toluamide (EX-1)
  • Embodiment 2 the synthesis of compound EX-2 ⁇ EX-16
  • compound EX-18 was prepared according to the synthesis method of EX-17, LCMS [M+H] + 739.4.
  • Example 5 4-(2-(2-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -4-yl)amino)propyl)amino)-2-oxoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b Synthesis of ]pyrazin-7-yl)-N,N-dimethylbenzamide (EX-19)
  • Embodiment 6 the synthesis of compound EX-20 ⁇ EX-21
  • Embodiment 8 the synthesis of compound EX-23 ⁇ EX-027
  • Example 9 4-((6-(4-(2-(7-amino-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-6-yl)-1H- Benzo[d]imidazol-6-yl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline Synthesis of -1,3-diketone (EX-28)
  • compound EX-28 was prepared according to the synthesis method of EX-1, LCMS [M+H] + 736.2.
  • Example 11 4-(2-(2-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol Indoline-5-yl)amino)ethoxy)ethoxy)acetyl)-1,2,3,4-tetrahydroisoindoline-6-yl)-5H-pyrrolo[2,3- b] Synthesis of pyrazin-7-yl)-N,N-dimethylbenzamide (EX-30)
  • Example 12 4-(2-(2-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl )oxy)octanoyl)-1,2,3,4-tetrahydroisoindolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N -Synthesis of dimethylbenzamide (EX-31)
  • Example 13 4-(2-(2-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- Base)amino)octanoyl)-8-methoxy-1,2,3,4-tetrahydroisoindoline-6-yl)-5H-pyrrolo[2,3-b]pyrazine-7- Synthesis of -N,N-dimethylbenzamide (EX-32)
  • compound EX-32 was prepared according to the synthesis method of EX-1. LCMS [M+H] + 825.6.
  • the activity of the compounds of the invention can be demonstrated using the following assays.
  • the human acute lymphoblastic leukemia cell Jurkat stably expressing the HPK1-HiBiT marker protein was cultured in a petri dish in a culture medium containing 10% fetal bovine serum (FBS, Gibco, product number 10099141), 0.1% penicillin/streptomycin solution ( P/S) RPMI 1640 (Gibco, product number 11875093), placed in a sterile incubator with a temperature of 37° C., a relative humidity of 95%, and 5% CO 2 .
  • the cells in the exponential growth phase were seeded into a 96-well plate (Corning, product number 3903) at a density of 20,000 cells/well, and 100 ⁇ L of medium was added to each well.
  • the compounds disclosed herein at different concentrations were added to the wells inoculated with cells (10 concentration gradients were set for each compound, the highest detection concentration was 10 ⁇ M, and 4-fold serial dilution), and the final concentration of DMSO was 0.1%.
  • HC90-51 (see WO 2020/227325) is a positive control compound, and its structural formula is as follows:

Abstract

提供了通式(I)所示的化合物，以及含有所述化合物的药物组合物，及其抗肿瘤应用。通式中各变量如权利要求书和说明书所定义； HPK1 Ligands——LIN——EL (I)。

Description

杂环化合物、包含其的药物组合物及其抗肿瘤应用 技术领域：
本发明属于药物化学领域。具体涉及一类新型的靶向HPK1蛋白及其突变蛋白的PROTAC分子，及其制备方法和应用，以及包含该类化合物的药物组合物。
背景技术：
HPK1是hematopoietic progenitor kinase 1(造血祖细胞激酶1)的简称，又名MAP4K1，是MAP4K家族的成员之一，它是一种丝/苏氨酸蛋白激酶，主要在造血干细胞，T细胞，B细胞，NK细胞，树突细胞等造血免疫相关的细胞中表达。
HPK1激酶可与许多接头蛋白结合，如SLP76家族，Gads、HIP-55、GRB2家族，LAT、CRK家族等相互作用，活化造血干细胞的SAPK/JNK信号途径，从而对TCR通路进行负向调节。HPK1激酶是TCR信号的关键负反馈调节因子，能负调控树突细胞活化和T细胞与B细胞反馈；而抑制HPK1可增强T细胞活性，从而提高抗肿瘤免疫的应答。
泛素-蛋白酶体途径是较普遍的一种内源蛋白降解方式，需要降解的蛋白先被泛素化修饰，然后被蛋白酶体分解为较小的多肽、氨基酸以及可以重复使用的泛素。PROTAC(proteolysis targeting chimeras)，即蛋白降解靶向嵌合体，是近年来新兴的热门研究领域。PROTAC分子一般可分为三个部分，一端为与特定靶蛋白结合的小分子片段(warhead)，另一端为具有泛素化功能的E3连接酶的配体(E3ligase ligand)，以及将两者连接起来的连接体(linker)。PROTAC分子利用了细胞的蛋白泛素化降解途径，可选择性的降解目标靶蛋白。具体而言，由于PROTAC分子的两端分别为靶蛋白与E3连接酶的配体片段，所以PROTAC分子可同时与靶蛋白和E3连接酶结合，促进了靶蛋白的泛素化，进而被蛋白酶体识别并加以降解。
十多年前，研发人员就发现了HPK1可能是一种潜在的癌症免疫治疗靶点，但截止目前尚还没有相关药物上市。设计具有靶向特定蛋白的降解剂是药物开发的新模式，公开号WO2021226262A1、WO2020227325A1的国际专利披露了HPK1蛋白降解剂，然而其选择性、药效等并不十分理想。因此，提供更高选择性和更好药效的HPK1降解剂具有重要的意义。我们希望利用蛋白降解技术，开发可以降解HPK1蛋白的化合物，以期解决未满足的临床需求。
发明内容
本发明一方面提供通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，
HPK1 Ligands——LIN——EL  (I)
其中，HPK1Ligands为与HPK1结合的配体，如HPK1的抑制剂，表示为通式(II)和通式(II‘)：
为单键或双键；
为HPK1Ligands与LIN的连接点；
L’连接至X1所在的环，L连接至Z4所在的环，或L’连接Z4所在的环，L连接至X1所在的环，或L’、L同时连接至X1所在的环；
X1、X2、X3、X4各自独立的选自N或CRX；
RX相同或不同，且Rx各自独立的为：-(CR’2)S-R#-(CR* 2)t-R1；
R’相同或不同，R*相同或不同，R’、R*、R1各自独立的为氢、氘、NRaRb、羟基、卤素、氰基、CORd、C(O)NRaRb、NRNC(O)Rd、NRNC(O)NRaRb、C(O)ORd、OC(O)Rd、S(O)1-2Rd、S(O)1-2NRaRb、NRNS(O)1- 2Rd、S(O)1-2ORd、OS(O)1-2Rd、P(＝O)RaRb、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，两个R’或两个R*与其相连的C原子一起形成C3-8环烷基或4-12元杂环基；所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R”所取代；
R#为化学键、O、S、NRN、C(O)、C(O)NRN、NRNC(O)、C(O)O、OC(O)、S(O)1-2、S(O)1-2NRN、NRNS(O)1-2、S(O)1-2O、OS(O)1-2、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基；所述C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基任选的被1、2、3或4个R”所取代；
Z1为O、S、N或C原子，其任选的被一或两个RZ1所取代；Z2为O、S、N或C原子，其任选的被一或两个RZ2所取代；Z3为O、S、N或C原子，其任选的被一或两个RZ3所取代；
Z4为O、S、N或C原子，其任选的被一或两个RZ4所取代；或，Z1不存在，Z2连接至与Z1相连的C原子上；
RZ1、RZ2、RZ3、RZ4各自独立的为不存在、氢、氘、NRaRb、羟基、卤素、氰基、C(O)NRaRb、CORd、-(C(R4)2)1-6-R4’、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-O-C3-8环烷基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，Z1与两个RZ1一起形成C＝O、C3-8环烷基或4-12元杂环基；或，Z2与两个RZ2一起形成C＝O、C3-8环烷基或4-12元杂环基；或，Z3与两个RZ3一起形成C＝O、C3-8环烷基或4-12元杂环基；或，Z4与两个RZ4一起形成C＝O、C3-8环烷基或4-12元杂环基；所述C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R”取代；
R4、R4’各自独立的选自氢、氘、NRaRb、羟基、卤素、C(O)NRaRb、CORd、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；所述C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R”取代；或两个R4与其相连的C原子一 起形成C3-8环烷基或4-12元杂环基；
L、L’各自独立的为化学键或-(CR2 2)p-RL-(CR3 2)q-；
R2、R3各自独立的选自氢、氘、NRN、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或两个R2或两个R3与相连的C一起形成C3-8环烷基或4-12元杂环基；所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R##取代；
RL选自O、S、NRN、C(O)、C(O)O、OC(O)、C(O)NRN、NRNC(O)、NRNC(O)NRN、S(O)1-2、S(O)1- 2O、OS(O)1-2、S(O)1-2NRN、NRNS(O)1-2、NRNS(O)1-2NRN、C1-6亚烷基、卤代C1-6亚烷基、C1-6亚烷氧基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基；所述C1-6亚烷基、卤代C1-6亚烷基、C1-6亚烷氧基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基任选的被1、2、3或4个R##所取代；
Y1为N或C原子，且其任选地被一或两个RY1所取代；
Y2为N或C原子，且其任选地被一或两个RY2所取代；或，Y2不存在，Y1与Y3连接；
Y3为N或C原子，且其任选地被一或两个RY3所取代；
Y4为N或C原子，且其任选地被一或两个RY4所取代；
Y5为N或C原子，且其任选地被一或两个RY5所取代；
Y6为N或C原子，且其任选地被一或两个RY6所取代；
RY1、RY2、RY3、RY4、RY5、RY6各自独立的表示为：-(CRe 2)n1-R#1-(CRf 2)n2-R#2；
Re相同或不同，Rf相同或不同，Re、Rf、R#2各自独立的为氢、氘、NRaRb、羟基、卤素、氰基、C(O)Rd、C(O)ORd、OC(O)Rd、C(O)NRaRb、NRNC(O)Rd、S(O)1-2Rd、S(O)1-2NRaRb、NRNS(O)1-2Rd、S(O)1-2ORd、OS(O)1-2Rd、P(＝O)RaRb、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，两个Re或两个Rf与其相连的C原子一起形成C3-8环烷基或4-12元杂环基；所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R##所取代；
R#1为化学键、O、S、NRN、C(O)、C(O)NRN、NRNC(O)、NRNC(O)NRN、C(O)O、OC(O)、S(O)1-2、S(O)1-2NRN、NRNS(O)1-2、NRNS(O)1-2NRN、S(O)1-2O、OS(O)1-2、C1-6亚烷基、C1-6亚烷氧基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基；或，两个RY2与Y2一起形成羰基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；
或，L与Y1、Y2、Y3、Y4之一连接，Y5、Y6与其相连的取代基一起形成C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，Y2不存在，L与Y1、Y3、Y4、Y5、Y6之一连接，剩余的环原子中相邻两环原子与其相连的取代基一起形成C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；所述C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基为未取代的或任选的被1、2、3或4个R##所取代；
R0选自：C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基；所述C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基任选的被1、2、3、4或更多个R##所取代；
V1、V2、V3各自独立的选自N或CRV；V4为N、O、S或C原子，其任选的被1或2个RV所取代；
环V为C6-10芳基或5-16元杂芳基，且其任选的被1、2、3或4个RV所取代；
RV相同或不同，RV、RV1、RV1’、RV2、RV2’、RV3、R31、R32各自独立的选自-O-(CR5R5’)m1-RV’、-(CR5R5’)m1-RV’或-NRN-(CR5R5’)m1-RV’；
RV’、R5、R5’各自独立的选自氢、氘、卤素、NRaRb、羟基、氰基、C(O)NRaRb、-NRNCORd、-NRNCONRaRb、-CORd、-COORd、-OCORd、S(O)1-2Rd、S(O)1-2NRaRb、NRNS(O)1-2Rd、NRNS(O)1-2NRaRb、S(O)1-2ORd、OS(O)1-2Rd、P(＝O)RaRb、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或R5、R5’或R31、R32与其相连的C原子一起形成C3-8环烷基或4-12元杂环基；所述C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3、4或更多个R##所取代；
LIN表示为-L1-L2-L3-……-Lr-,
L1、L2、L3……Lr各自独立的选自化学键、O、S、NRN、-(CR6R6’)m2-、C(O)、C(O)NRN、NRNC(O)、NRNC(O)NRN、C(O)O、OC(O)、OC(O)O、S(O)1-2、S(O)1-2O、OS(O)1-2、S(O)1-2NRN、NRNS(O)1-2、NRNS(O)1-2NRN、-OC1-10亚烷基、C2-10亚烯基、C2-10亚炔基、C3-16亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基；所述C1-10亚烷基、C2-10亚烯基、C2-10亚炔基、C3-16亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基任选的被1、2、3、4或更多个R##所取代；
R6、R6’各自独立的选自氢、氘、NRaRb、卤素、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，R6、R6’与相连的C一起形成C＝O、C3-8环烷基或4-12元亚杂环基；所述C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3、4或更多个R##所取代；
s、t、p、q、n1、n2、m1、m2、u各自独立的为0、1、2、3、4、5、6、7或8；
t1、t2各自独立的为0、1或2；
r为4-20的正整数；
EL表示为通式(III)：
其中，G1、G2、G3、G4各自独立的为N或CRg；G1、G2、G3、G4不同时为N；
Rg相同或不同且各自独立的选自：氢、氘、NRaRb、羟基、卤素、氰基、C(O)NRaRb、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；所述C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R00取代；
K1选自O、S、C或N，其任选的被一个或两个RK1所取代；K2选自O、S、C或N，其任选的被一个或两个RK2所取代；K3选自O、S、C或N，其任选的被一个或两个RK3所取代；或K1、K2不存在，K4与K3连接，与K1相连的芳环上的C原子与RK连接；或，K1、K2、K3均不存在，K4连接至与K1或K3相连的 芳环的C原子之一，芳环上的另一C原子与RK连接；
K4为N或CRK4；
RK1、RK2、RK3各自独立的为不存在、氢、氘、NRaRb、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1- 6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；
或者，K1与两个RK1一起形成C＝O、C3-8环烷基或4-12元杂环基；或者，K2与两个RK2一起形成C＝O、C3-8环烷基或4-12元杂环基；或者，K3与两个RK3一起形成C＝O、C3-8环烷基或4-12元杂环基；
RK、RK4、R7、R7’、R8、R8’各自独立的选自氢、氘、卤素、氰基、NRaRb、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或羟代C1-6烷基；
Ra、Rb、Rd、RN各自独立的选自氢、氘、卤素、＝NH、NRe1Rf1、羟基、羟氨基、-C1-6亚烷基NRe1Rf1、CONRe1Rf1、乙酰基、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，Ra、Rb与相连的N原子共同形成4-12元杂环基；所述C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R00取代；
R00、R”、R##各自独立的选自氢、氘、＝O、卤素、羟基、羟氨基、＝NH、NRe1Rf1、CONRe1Rf1、COR01、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、-(CR** 2)1-6-R01、-O-(CR** 2)1-6-R01、-S-R01、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；
Re1、Rf1、R**、R01各自独立的选自氢、氘、氨基、＝NH、羟基、羟氨基、乙酰基、酰胺基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，Re1、Rf1与相连的N原子共同形成4-12元杂环基；或两个R**与其相连的C原子一起形成C3-6环烷基或4-12元杂环基；所述C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个选自氢、氘、氨基、＝NH、羟基、羟氨基、乙酰基、酰胺基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1- 6烷基、C2-6烯基或C2-6炔基的取代基所取代；
条件是，
(1)式(II)中，当Z1不存在时：
a)Z2、Z3、Z4为C或N，且Z3与Z2不同时为N，或Z3与Z4不同时为N,
且当为时，X1、X2、X3、X4中至少两者为N；
且当为时，L与R0中或L与L’中至少一者不为亚苯基或取代的亚苯基；或b)Z2或Z4为C＝O；
c)当Z2、Z3、Z4中一者为S时，L、L’不同时与X1所在的环连接；
(2)式(II’)中，L’不为
(3)式(II)中，当Z1、Z2、Z3、Z4均存在时，L’与X1所在芳环的C原子连接，且L不为化学键。
在一些实施方式中，进一步表示为：
表示环原子与L’的连接点表示环原子与L的连接点；
Ra‘、Rb’选自氢、氘、氰基、氟、氯、溴、羟基、NRaRb、-CORd、-CONRaRb、-NRNCORd、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基、4-7元杂环基、苯基或5或6元杂芳基(优选氢、卤素、C1-6烷基、C1-6烷氧基或卤代C1-6烷基)；所述C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基、4-7元杂环基、苯基或5或6元杂芳基任选的被1、2、3、4或更多个选自R4的取代基所取代；
RX选自氢、氘、羟基、氟、氯、溴、氰基、NRaRb、-CORd、-CONRaRb、C1-6烷基、-C1-6亚烷基NRaRb、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、OC3-5环烷基、C3-5环烷基或4或5元杂环基。
优选RX为-(CR’2)s-R1、-NRN-R1、-O-R1或-O-(CR* 2)t-R1；
RN、R’、R*、R1各自独立的选自氢、氘、NRaRb、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、苯、5或6元杂芳基、-C1-6亚烷基NRaRb、-C1-6亚烷基-苯或5或6元杂芳基；或，两个R’与相连的C原子一起形成C3-6环烷基或4-7元杂环基；
Ra、Rb、R4各自独立的选自氢、氘、羟基、氨基、卤素、酰胺基、乙酰基、＝NH、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-8环烷基、4-7元杂环基、苯或5或6元杂芳基；或Ra、Rb与相连的N原子一起形成4-7元氮杂环；
所述C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C1-6亚烷基、C3-6环烷基、4-7元杂环基4-7元氮杂环任选的被1、2或3个R”取代；s、t为0、1、2、3或4。
在一些实施方式中，进一步选自：
其中，Ra’、Rb’各自独立的选自氢、氘、甲基、乙基、丙基、异丙基(优选氢)。
在一些实施方式中表示环原子与L’的连接点表示环原子与L的连接点。
在一些实施方式中，L、L’各自独立的选自化学键、NH、O、S、-C1-6亚烷基NH-、-NHC1-6亚烷基-、-C1-6亚烷基O-、-OC1-6亚烷基-、C1-6亚烷基、羟代C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、3-6元环烷基、4-7元杂环基、苯或5或6元杂芳基(优选为化学键或NH)；L’进一步优选O、S或-(CR2 2)p-NRN-，R2选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基(优选氢、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、羟代甲基、羟代乙基或环丙基)，或R2、R2’与其相连的C原子一起形成环丙基、环丁基、氧杂环丁基或氮杂环丁基；P为0、1、2或3。
优选的，L’为C(O)NRN、NRNC(O)、NRNC(O)NRN、S(O)1-2、S(O)1-2NRN、NRNS(O)1-2、NRNS(O)1-2NRN，RN为氢、氘或C1-6烷基；
L优选为被1或2个RQ取代的苯或5或6元亚杂芳基，RQ选自：氢、氘、羟基、氨基、卤素、氰基、酰胺基、乙酰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基、-O-C3-6环烷基或
在一些实施方式中，L、L’均为化学键。
在一些实施方式中，进一步选自：
Y7为N或＝CRY；Y9为N或＝CRY；Y8为O或S；
各个RY1、RY2、RY3、RY4、RY各自独立的选自：氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、NRaRb、CONRaRb、C3-8环烷基、-O-(CH2)0-4-C3-8环烷基、4-7元杂环基、苯基或5-14元杂芳基。
在一些实施方式中，各个RY1、RY2、RY3、RY4、RY5、RY6、RY、R9各自独立的选自氢、氘、氟、氯、溴、氨基、＝NH、甲基、乙基、丙基、异丙基、正丁基、正戊基、正己基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、二氟甲基、三氟乙基、羟代甲基或羟代乙基。
优选的，各个RY1、RY2、RY3、RY4、RY5、RY6、RY、R9各自独立的选自二甲氨基、二乙氨基、
优选的，各个RY1、RY2、RY3、RY4、RY5、RY6、RY、R9各自独立的选自酰胺基、二甲酰胺基、二乙酰氨基、N,N’-甲基乙基酰胺基。
优选的，各个RY1、RY2、RY3、RY4、RY5、RY6、RY、R9各自独立的选自被1或2个取代基取代的环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、氧杂环戊基、氮杂环戊基、哌啶基、哌嗪基、吗啉基、
优选的，各个RY1、RY2、RY3、RY4、RY5、RY6、RY、R9各自独立的选自被1或2个取代基取代的苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻吩基、噻唑基、呋喃基、四氮唑基、1,2,4-三氮唑基、1,3,4-三氮唑基、吲哚基、异吲哚基；
所述取代基选自氢、氘、氨基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、二氟甲基、三氟乙基、羟代甲基、羟代乙基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、羟代氮杂环丁基、环戊基、氮杂环戊基、羟代氮杂环戊基或苯基。
在一些实施方式中，R9选自：氢、氘、氰基、氟、氯、溴、羟基、氨基、酰胺基、C1-6烷基、C1-6烷氧基、NRaRb、C(O)NRaRb、-C(O)Rd、S(O)1-2NRaRb、-S(O)1-2Rd、C3-8环烷基、4-12元杂环基、苯或5-14元杂芳基。
优选的R9为C3-8环烷基或4-7元杂环基；优选的R9为苯或5或6元杂芳基。
优选的R9为-NRN(CH2)1-6NRaRb；优选的R9为卤素、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基；优选的R9为C(O)NRaRb；优选的R9为S(O)1-2NRaRb。
各个Ra、Rb、RN、Rd各自独立的选自氢、氘、氨基、羟氨基、＝NH、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基或C1-6烷氧基。
各个Ra、Rb、RN、Rd各自独立的选自氢、氘、C1-4烷基、卤代C1-4烷基、羟代C1-4烷基或C1-4烷氧基。
所述C1-6烷基选自：甲基、乙基、丙基、异丙基、正丁基、正戊基、正己基；卤素为氟、氯或溴。
优选Ra、Rb与其相连的N原子一起形成4至7元氮杂环。
所述C1-6烷基、所述C1-6烷氧基、所述C3-8环烷基、所述4-12元杂环基、所述4-7元杂环基、所述苯、所述5-14元杂芳基、所述5或6元杂芳基、所述4至7元氮杂环任选的被1或2个选自氢、氘、卤素、＝O、羟基、氨基、氰基、酰胺基、乙酰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、4-6元杂环基、羟代4-6元杂环基的取代基所取代。
所述4至7元氮杂环选自：
在一些实施方式中，各个RY1、RY2、RY3、RY4、RY各自独立的选自：氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、NRaRb、CONRaRb；
R9选自：NRaRb、C(O)NRaRb、-C(O)Rd、S(O)1-2NRaRb、-S(O)1-2Rd。
在一些实施方式中，各个RY1、RY2、RY3、RY4、RY各自独立的选自：氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、NRaRb、CONRaRb；
R9选自：NRaRb、C(O)NRaRb、-C(O)Rd、S(O)1-2NRaRb、-S(O)1-2Rd。
在一些实施方式中，各个RY1、RY2、RY3、RY4、RY各自独立的选自：氢、氘、卤素；R9为C(O)NRaRb。
在一些实施方式中，R0为化学键、C3-8亚环烷基、4-12元亚杂环基、亚苯基或5-14亚杂芳基。
优选的R0为被1、2、3或4个RZ’所取代的4-7元亚杂环基(优选亚哌啶基或亚哌嗪基)。
优选的R0为被1或2个RZ’所取代的亚苯基或5或6元亚杂芳基。
优选的R0为被1、2或3个RZ’所取代的6-12元亚螺环基或7-12元亚杂螺环基。
RZ’选自氢、氘、卤素、羟基、氰基、乙酰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、-NRaRb或-CONRaRb 的取代基所取代(RZ’优选氢、氟、甲基、乙基或三氟甲基)，Ra、Rb选自氢、氨基、甲基、乙基、丙基、异丙基、正丁基或异丁基。
在一些实施方式中，R0表示为：
为R0与L’的连接点，为R0与LIN的连接点；
Z5、Z6、Z7各自独立的选自N或CRZ’；
Z8、Z9、Z10各自独立的为C、N、O或S原子，且Z8、Z9、Z10任选的被1或2个RZ’所取代；或Z8、Z9与其相连的取代基一起形成4-7元环烷基或5-7元杂环基，而LIN与Z8、Z9形成的环连接；优选的，Z8、Z9、Z10各自独立的为NRN、O或CH2；
RZ’相同或不同，RZ’各自独立的选自氢、氘、氟、氯、溴、氨基、乙酰基、羟基、氰基、-NRaRb、-CONRaRb、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基、-O-C3-6环烷基、4-7元杂环基、苯或5-14元杂芳基；
或，两个RZ’与其相连的C原子一起形成C＝O。
优选的，RZ’选自：C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基。优选RZ’为氢、卤素、氰基、氨基或酰胺基。
优选的，RZ’选自：氢、氘、C1-4烷基、C1-4烷氧基、卤代C1-4烷基或羟代C1-4烷基。
优选的，RZ’选自：氢、氘、甲基、乙基、丙基、异丙基、正丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、二氟甲基、三氟乙基、羟代甲基、羟代乙基、环丙基、环丁基、
在一些实施方式中，R0为亚苯基。
在一些实施方式中，HPK1Ligands进一步表示为：

Z11、Z12各自独立的表示为N或CRZ’，Q1、Q2、Q3各自独立的表示为N或CRQ；
RZ’、RQ各自独立的选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、NRaRb、CONRaRb、C3-6环烷基、-O-(CH2)0-4-C3-6环烷基或4或5元杂环基；
RZ”选自C1-6亚烷基、C1-6亚烷氧基、O、S、NRN、CONRN、SO1-2NRN、CO或C3-6亚环烷基；
通式(II-f)中，L与Y1所在的环连接，或与Y7所在的环连接。
在一些实施方式中，在式(II-a)、式(II-b)、式(II-c)、式(II-d)、式(II-e)、式(II-f)中，各个X1、X2、Y1、Y2、Y3、X2、Z5、Z6、Z7、Z8、Z9、Z10、R9、RN、Ra ,、Rb ,、Rz ,、Rz ,,、RX、RY各自独立地如上所述。
在一些实施方式中，HPK1Ligands进一步表示为：
R0为任选被1、2、3或4个R##取代的亚苯基、4-12元亚杂环基或5-16元亚杂芳基；
L为化学键、NH、O、S、亚乙烯基、亚乙炔基、-NHC1-4亚烷基或-C1-4亚烷基NH；
Ra’、Rb’各自独立的选自：氢、氘、F、Cl、C1-6烷基、卤代C1-6烷基或C1-6烷氧基；
RX、RY2、RY3、RY5各自独立的选自：氢、氘、F、Cl、羟基、氨基、酰胺基、乙酰基、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、环丙基、-O-环丙基、
R9为氢、氘、F、Cl、Br、羟基、氰基、-(CH2)0-4C(O)NRaRb、-(CH2)0-4NRaRb、-(CH2)0-4S(O)1-2NRaRb、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基、4-7元杂环基、-O-(CH2)0-4-C3-6环烷基、
Ra、Rb各自独立的为氢、氘、甲基、乙基、丙基、异丙基、正丁基、正戊基、正己基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、-CH2OH、-CH2CH2OH、-CH2CH2CH2OH、-CH2CH2CH2CH2OH、-(CH2)1-4N(CH3)2、-(CH2)1-4N(CH3)CH2CH3或-(CH2)1-4-4至7元氮杂环，或Ra、Rb与相连的N原子一起形成4-7元氮杂环；
所述4至7元氮杂环任选被1或2个选自氢、氘、甲基、乙基、羟基、氨基的取代基所取代。
在一些实施方式中，HPK1Ligands进一步表示为：
在一些实施方式中，HPK1Ligands进一步表示为：
在一些实施方式中，Y2为N，Y3、Y5为CH，在一些实施方式中，Y3为N，Y2、Y5为CH，在一些实施方式中，Y5为CH，Y2、Y5为N，在一些实施方式中，Y2为CH，Y3、Y5为N，在一些实施方式中，Y3为CH，Y3、Y5为N，在一些实施方式中，Y2、Y3、Y5均为CH。
在一些实施方式中，R0为任选被1、2、3或4个R##取代的6-12元亚杂环基；
Y2、Y3、Y5均为CH；
L为化学键、NH、O、S、亚乙烯基、亚乙炔基；
Ra’、Rb’各自独立的选自：氢、氘、F、Cl、C1-6烷基、卤代C1-6烷基或C1-6烷氧基；
RX、RY2、RY3、RY5各自独立的选自：氢、氘、F、Cl、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1- 6烷基；
R9为-(CH2)0-4C(O)NRaRb、-(CH2)0-4NRaRb、-(CH2)0-4S(O)1-2NRaRb、C1-6烷基、C1-6烷氧基、卤代C1- 6烷基、羟代C1-6烷基；
Ra、Rb各自独立的为氢、氘、甲基、乙基、丙基、异丙基、正丁基、正戊基、正己基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、-CH2OH、-CH2CH2OH、-CH2CH2CH2OH、-CH2CH2CH2CH2OH、-(CH2)1-4N(CH3)2、-(CH2)1-4N(CH3)CH2CH3。
在一些实施方式中，R0为任选被1、2、3或4个R##取代的8-12元亚苯并杂环基；
L为化学键；
Y2、Y3、Y5均为CH；
Ra’、Rb’各自独立的选自：氢、氘；
RX、RY2、RY3、RY5各自独立的选自：氢、氘；
R9为-(CH2)0-4C(O)NRaRb、-(CH2)0-4NRaRb、-(CH2)0-4S(O)1-2NRaRb；
Ra、Rb各自独立的为氢、氘、甲基、乙基、丙基、异丙基、正丁基、正戊基、正己基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基。
在上述通式(II-a-2)或式(II-a-3)中，各个RZ’各自独立地选自：氢、氘、C1-4烷基、C1-4烷氧基、卤代C1- 4烷基或羟代C1-4烷基。
在上述通式(II-a-3)中，Y2、Y3、Y5均为CH；L为化学键；R9为-(CH2)0-4C(O)NRaRb、-(CH2)0-4NRaRb或-(CH2)0-4S(O)1-2NRaRb；各个RZ’各自独立地选自：氢、氘、C1-4烷基、C1-4烷氧基、卤代C1-4烷基或羟代C1-4烷基。
在一些实施方式中，HPK1Ligands进一步表示为：
R0为任选被1、2、3或4个R##取代的亚苯基、4-12元亚杂环基或5-16元亚杂芳基；
Ra’、Rb’各自独立的选自：氢、氘、F、Cl、C1-6烷基、卤代C1-6烷基或C1-6烷氧基；
各个RX、RY、RX1、RX2、RY1、RY3各自独立的选自：氢、氘、F、Cl、羟基、氨基、酰胺基、乙酰基、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、环丙基、-O-环丙基、
在一些实施方式中，HPK1Ligands进一步表示为：
在一些实施方式中，HPK1Ligands进一步表示为：
在一些实施方式中，X1、X2的其中之一为N，另一个为CH，Y1、Y3的其中之一为N，在一些实施方式中，X1、X2的其中之一为N，另一个为CH，Y1、Y3均为CH，在一些实施方式中，X1为N，X2为CH，Y1、Y3均为CH，在一些实施方式中，X2为N，X1为CH，Y1、Y3均为CH。
在一些实施方式中，R0为任选被1、2、3或4个R##取代的亚苯基；
X1为N，X2为CH，Y1、Y3均为CH；
Ra’、Rb’各自独立的选自：氢、氘、F、Cl、C1-6烷基、卤代C1-6烷基或C1-6烷氧基；
各个RX、RY、RX1、RX2、RY1、RY3各自独立的选自：氢、氘、F、Cl、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、环丙基、-O-环丙基。
在一些实施方式中，R0为任选被1、2、3或4个R##取代的亚苯基；
X1为N，X2为CH，Y1、Y3均为CH；
Ra’、Rb’各自独立的选自：氢、氘；
RX、RX1、RX2、RY1、RY3各自独立的选自：氢、氘；
各个RY各自独立地选自氢、氘、F、Cl、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基。
在上述通式(II-b-2)或式(II-b-3)或式(II-b-4)中，Z6、Z7各自独立地选自CH或N，优选均为CH。
在上述通式(II-b-3)或式(II-b-4)中，Z6、Z7均为CH；Ra’、Rb’各自独立的选自：氢、氘；RY选自氢、氘、F、Cl、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基。
在一些实施方式中，HPK1Ligands进一步表示为：
R0为任选被1、2、3或4个R##取代的亚苯基、4-12元亚杂环基或5-16元亚杂芳基；
L为化学键、NH、O、S、亚乙烯基、亚乙炔基、-NHC1-4亚烷基或-C1-4亚烷基NH；
Ra’选自：氢、氘、F、Cl、C1-6烷基、卤代C1-6烷基或C1-6烷氧基；
Y7为N或＝CRY；Y8为O或S；
各个RX、RY各自独立的选自：氢、氘、F、Cl、羟基、氨基、酰胺基、乙酰基、氰基、C1-6烷基、C1- 6烷氧基、卤代C1-6烷基、环丙基、-O-环丙基、
RN选自氢、氘、氨基、羟氨基、＝NH、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基或C1-6烷氧基。
在一些实施方式中，HPK1Ligands进一步表示为：
在一些实施方式中，HPK1Ligands进一步表示为：
在一些实施方式中，Y7为N或＝CRY，Y8为O或S，在一些实施方式中，Y7为＝CRY，Y8为S，在一些实施方式中，Y7为＝CRY，Y8为O，在一些实施方式中，Y7为＝CRY，Y8为S。
在一些实施方式中，Z11、Z12各自独立的表示为N或CRZ’，在一些实施方式中，Z11、Z12的其中一个为N，另一个为CRZ’，在一些实施方式中，Z11、Z12均为N。其中，各个RZ’各自独立地选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基，优选为氢。
在一些实施方式中，R0为任选被1、2、3或4个R##取代的4-8元亚杂环基；
L为化学键、NH、O、S、亚乙烯基、亚乙炔基；
Ra’选自：氢、氘、F、Cl、C1-6烷基、卤代C1-6烷基或C1-6烷氧基；
Y7为N；Y8为O或S；
各个RX、RY各自独立的选自：氢、氘、F、Cl、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基；
RN选自氢、氘、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基或C1-6烷氧基。
在一些实施方式中，R0为任选被1、2、3或4个R##取代的4-6元含氮亚杂环基；
L为化学键；
Ra’选自：氢、氘；
Y7为N；Y8为O或S；
RX选自：氢、氘；
各个RY各自独立的选自：羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基；
RN选自氢、氘。
在上述通式(II-c-3)中，RN选自氢、氘；Ra’选自：氢、氘；RY选自：羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基。
在一些实施方式中，HPK1Ligands进一步表示为：
R0为化学键；L’为-(CR2 2)pNRN-；
RN选自：氢、氘、氨基、羟氨基、＝NH、C1-6烷基或卤代C1-6烷基(优选氢或C1-6烷基)；
R2选自氢、氘、氨基、羟氨基、C1-6烷基、卤代C1-6烷基或羟代C1-6烷基(优选氢或C1-6烷基)；或两个R2与其相连的C原子一起形成环丙基、环丁基、氧杂环丁基或氮杂环丁基；
p为0、1、2或3；
RX选自：氢、氘、氟、氯、溴、氨基、酰胺基、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、-(CR’2)m1NRaRb、C3-6环烷基、-O-R1、-O-(CH2)1-2R1、
Ra、Rb各自独立的选自：氢、氘、氟、氯、溴、羟基、氨基、乙酰基、酰胺基、羟氨基、＝NH、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基优选Ra、Rb与其相连的N原子一起形成被1或2个R”取代的4-7元氮杂环；
R1、R’各自独立的选自：氢、氘、氟、氯、溴、羟基、氨基、乙酰基、酰胺基、羟氨基、＝NH、C1-6烷 基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基或两个R’与其相连的C原子一起形成3-6元环烷基或4-7元氮杂环；
RZ4选自：氢、氘、卤素、C1-6烷基或卤代C1-6烷基(优选氢)；
L选自被1或2个RQ所取代的1,2-亚苯基、1,3-亚苯基、1,4-亚苯基、2,6-亚吡啶基、2,5-亚吡啶基、2,4-亚吡啶基、2,3-亚吡啶基、3,4-亚吡啶基、3,5-亚吡啶基、2,6-亚嘧啶基、3,6-亚嘧啶基、3,6-亚哒嗪基、3,5-亚哒嗪基或4,5-亚哒嗪基(优选2,6-亚吡啶基)；
RY相同或不同，RY3、RY4、RY、RQ各自独立的选自氢、氘、羟基、氨基、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、环丙基、-O-环丙基、
R”选自氢、氘、羟基、氨基、C＝O、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基。
在上述实施方式的通式(II-e-1)、(II-e-2)或(II-e-3)中，
R2选自氢、氘、甲基、乙基、丙基、异丙基、羟代甲基、羟代乙基、三氟甲基或三氟乙基；
R’、R1各自独立的选自：氢、甲基、乙基、丙基、异丙基、羟代甲基、羟代乙基、三氟甲基或三氟乙基；
Ra、Rb各自独立的选自：氢、甲基、乙基、丙基、异丙基、羟代甲基、羟代乙基、三氟甲基或三氟乙基；
优选的Ra、Rb与其相连的N原子一起形成：
R”选自氢、羟基、甲基、乙基、丙基、异丙基、羟代甲基、羟代乙基；
p、m1为0、1或2。
在一些实施方式中，HPK1Ligands进一步表示为：
X2、X3各自独立的为N或CH；
Y1为N或CH；
R0为化学键；
L为NH、N(CH3)、NHCH2、CH2NH、NHCH2CH2或CH2CH2NH；
L’选自：化学键、O、S、-CO、-CONRN、-NRNCO、-NRNCONRN-或-(CR2 2)PNRN-；
Rb’、RN各自独立的选自：氢、氘、氟、氯、溴、羟基、氨基、乙酰基、酰胺基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、环丙基(优选氢)；
R2选自：氢、氘、羟基、氨基、羟氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、环丙基、环丁基、氧杂环丁基(优选氢、甲基或乙基)；
或，两个R2与相连的C原子一起形成环丙基、环丁基、氧杂环丁基或氮杂环丁基；
RX选自氢、氘、氟、氯、溴、羟基、乙酰基、酰胺基、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、-(CR’2)m1NRaRb、C3-6环烷基、-O-R1、-O-(CH2)1-4R1、
R1、R’各自独立的选自：氢、氘、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基、4-7元杂环基或两个R’与其相连的C原子一起形成C3-6环烷基或4-7元杂环基；
Ra、Rb各自独立的选自：氢、氘、羟基、氨基、羟氨基、＝NH、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基、或Ra、Rb与其相连的N原子一起形成4-7元氮杂环；
RY选自氢、氘、氟、氯、溴、羟基、氨基、乙酰基、酰胺基、羟氨基、C1-6烷基、C1-6烷氧基、卤代C1- 6烷基、羟代C1-6烷基、环丙基、-O-环丙基、或两个RY与其相连的C原子一起形成环丙基；
所述C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基任选的被1或2个选自氢、卤素、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基的取代基所取代。
在上述实施方式中的通式(II-d-1)、(II-d-2)或(II-d-3)中，
X2为CH；Y1各自独立的为N或CH；L为NH、N(CH3)、NHCH2或CH2NH；
Rb’为氢；RN选自：氢或甲基；
R2选自：氢、甲基、乙基、丙基、异丙基、羟代甲基、羟代乙基、羟代丙基、环丙基、环丁基、羟代环丙基或氟代环丙基；
R1选自：氢、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟代甲基、羟代乙基、羟丙基、环丙基、羟代环丙基、环丁基、
R’选自：甲基、乙基、丙基、三氟甲基、三氟乙基、羟代甲基、环丙基或环丁基；
Ra、Rb各自独立的选自：氢、氘、羟基、氨基、羟氨基、甲基、乙基、丙基、羟代甲基、CH2CH2OH、CH2CH2CH2OH、环丙基、环丁基
优选的Ra、Rb与其相连的N原子一起形成
p为0、1或2。
在一些实施方式中，HPK1Ligands进一步表示为：
X2、X3各自独立的为N或CH；Z3为O、-NRZ3-或-C(RZ3)2；
RZ3选自氢、氘、氟、氯、溴、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基(优选氢)；
L’为化学键、NH、N(CH3)、NHCH2、CH2NH、NHCH2CH2或CH2CH2NH(优选NH)；
Y5与其相连的取代基、RY6及与其相连的环原子一起形成被1或2个RY取代的苯基或5或6元杂芳基；或RY1、RY6与其相连的环原子一起形成被1或2个RY取代的苯基或5或6元杂芳基；或，Y3与其相连的取代基、RY1及与其相连的环原子一起形成被1或2个RY取代的苯基或5或6元杂芳基；或，Y5与其相连的取代基、RY6及与其相连的环原子一起形成被1或2个RY取代的苯基或5或6元杂芳基；
RY1、RY3、RY5、RY6、RY、RZ’各自独立的选自氢、氘、氟、氯、溴、羟基、氨基、酰胺基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、环丙基、-O-环丙基、
优选RY5、RY6与其相连的环原子一起形成被1或2个RY取代的苯基或吡啶基，RY1、RY3、RY、RZ’各自独立的选自氢、氘、卤素、C1-6烷基、C1-6烷氧基或卤代C1-6烷基。
在上述通式(II-f’)中，X2为N，X3为CH；在一些实施方式中，X3为N，X2为CH；
在一些实施方式中，Y3为N，Y5为CRY5，RY1、RY6与其相连的环原子一起形成被1或2个RY取代的苯基或吡啶基；在一些实施方式中，Y3为N，Y5为CRY5，RY1、RY6与其相连的环原子一起形成被1或2个RY取代的苯基或吡啶基；
在一些实施方式中，Y3为CRY3，Y5为N，RY1、RY6与其相连的环原子一起形成被1或2个RY取代的苯基或吡啶基；在一些实施方式中，Y3为CRY3，Y5为N，Y5、RY6与其相连的环原子一起形成被1或2个RY取代的苯基或吡啶基；
在一些实施方式中，Y3为N，Y5为N，RY1、Y3与其相连的环原子一起形成被1或2个RY取代的苯基或吡啶基；在一些实施方式中，Y3为N，Y5为N，RY1、RY6与其相连的环原子一起形成被1或2个RY取代的苯基或吡啶基；在一些实施方式中，Y3为N，Y5为N，RY6、Y5与其相连的环原子一起形成被1或2个RY取代的苯基或吡啶基。
在一些实施方式中，HPK1Ligands进一步表示为：
V5、V6、V7各自独立的选自N或CRV；
RV相同或不同，且各自独立的选自氢、氘、卤素、氰基、羟基、-C(O)NRaRb、NRaRb、C1-6烷基、C1- 6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基、-O-C3-6环烷基、(优选氢、F、氨基、酰胺基、二甲氨基、二甲酰胺基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、三氟甲基、二氟甲基或三氟乙基)；
R0选自5或6元亚杂芳基(优选)；
RV1、RV1’各自独立的选自氢、氘、氟、氯、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基、4-7元杂环基、C3-6环烷基或-O-C3-6环烷基(优选氢、卤素、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、三氟甲基或三氟乙基)；
R31 、R32选自氢、氘、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基或4-7元杂环基(优选氢、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、三氟甲基、三氟乙基、二氟甲基、 二氟乙基、羟甲基、羟乙基或羟丙基)；
Ra、Rb如上任一项所定义。
在一些实施方式中，EL进一步表示为：
RN、R7、R7’、R8、R8’、RK各自独立的选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基(优选氢、甲基或乙基)；
K4为CH或N，K3为NRK3、CH2或CO；
RK3选自氢、氘、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基(优选氢、甲基或乙基)；
Rg选自氢、氘、卤素、氰基、氨基、酰胺基、二甲氨基、二甲酰胺基、C1-6烷基、C1-6烷氧基、卤代C1- 6烷基或羟代C1-6烷基；Rg优选氢、C1-6烷基和卤代C1-6烷基，进一步优选氢、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、三氟甲基、三氟乙基或氰基。
在一些实施方式中，K3为CH2或CO。
在一些实施方式中，上述通式(I)所示的化合物，其进一步表示为：




在一些实施方式中，所述通式(I)所示的化合物，其为上述通式(II’-1)、(II’-1-1)、(II’-1-2)、(II’-1-3)、(II’-1-4)和(II’-1-5)；其中，
L为NH或N(甲基)；
R0为化学键，L’为-CONRN-或-COO-；
优选R0为L’为化学键；
X1为N或CH；
RV1、RV1’、RV2、RV2’、R31、R32各自独立的选自：氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基或C3-6环烷基；或RV2、RV2’或RV1、RV1’与其相连的C原子一起形成C＝O或C3-6环烷基；
V4为NH或O；
RV各自独立的选自氢、氘、氟、氯、溴、氰基、酰胺基、氨基、二甲氨基、二甲酰胺基、C1-6烷基、C1- 6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基
Ra为氢、氘、氨基、羟氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基；
LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自：CH2、CH2CH2、CO、CONH、NHCO、NHCONH、SO、SO2、SONH、NHSO、SO2NH、NHSO2、O、S、NH、N(甲基)、OCH2、CH2O、OCH2CH2、亚乙烯基、亚乙炔基、亚苯基、亚吡啶基、亚嘧啶基、亚三氮唑基、亚四氮唑基、亚吡唑基、亚咪唑基、亚哌啶基、亚哌嗪基、
L2、L3选自：CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、OCH2CH2、CH2O、亚苯基、亚吡啶基、亚嘧啶基、亚三氮唑基、亚四氮唑基、亚吡唑基、亚咪唑基、亚吗啉基、亚哌啶基、亚哌嗪基或CH2CH2O；
L4、L5选自化学键、CH2或CH2CH2或CH2CH2O；L6选自：化学键、O、S、NH、N(甲基)、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CO、CONH、NHCO或CH2CH2O；L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基或亚乙炔基；
RN选自氢或甲基；上述任一亚甲基的氢任选的被1或2个R##所取代，R##选自氘、甲基、乙基、丙基、环丙基、氨基或三氟甲基。
在一些实施方式中，所述通式(I)所示的化合物，其为通式(II-3)、(II-3-1)、(II-3-2)、(II-3-3)、(II-3-4)、(II-3-5)、(II-3-6)、(II-3-7)；其中，
L选自化学键或NH；
Z11为N或CH；Z12为N或CH；
RZ ,、Ra’、RN各自独立的选自：氢、氘、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或C3-6环烷基(优选为H或甲基)；
Y7为＝CH，Y8为O或S；或Y7为O或S，Y8为＝CH；
RX选自：氢、氘、卤素、C1-6烷基、C1-6烷氧基或卤代C1-6烷基(优选氢)；
RY4选自：氢、氘、卤素、氰基、氨基、酰胺基、二甲氨基、二甲酰胺基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基、-OC3-6环烷基、-O亚甲基环丙基、
LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、CH2O、或
L2、L3选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2OCH2、OCH2CH2、CH2O或CH2CH2O；
L4、L5选自CH2或CH2CH2；
L6选自：化学键、O、S、NH、N(甲基)、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CO、CONH或NHCO；
L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基或亚乙炔基；
上述任一亚甲基的氢任选的被1或2个R##所取代，R##选自氢、氘、卤素、酰胺基、氨基、二甲氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基(优选甲基、乙基或丙基)。
在一些实施方式中，所述通式(I)所示的化合物，其为通式(II-3)、(II-3-1)、(II-3-2)、(II-3-3)、(II-3-4)、(II-3-5)、(II-3-6)、(II-3-7)；其中，
L选自化学键；
Z11和Z11均为N；
RZ ,、Ra’、RN各自独立的选自：氢、氘；
Y7为＝CH，Y8为O或S；
RX选自：氢、氘；
RY4选自：氢、氘、卤素、氰基、氨基C1-6烷基、C1-6烷氧基、卤代C1-6烷基；
LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、CH2O、或
L2、L3选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2OCH2、OCH2CH2、CH2O或CH2CH2O；
L4、L5选自CH2或CH2CH2；
L6选自：化学键、O、S、NH、N(甲基)、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CO、CONH或NHCO；
L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基或亚乙炔基；
K3为CH2或CO；
Rg选自氢、C1-6烷基和卤代C1-6烷基；
上述任一亚甲基的氢任选的被1或2个R##所取代，R##选自氢、氘、卤素、酰胺基、氨基、二甲氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基(优选甲基、乙基或丙基)。
在一些实施方式中，所述通式(I)所示的化合物，其为通式(II-4)、(II-4-1)、(II-4-2)、(II-4-3)、(II-4-4)、(II-4-5)；其中，
RY1、RY2、RY3各自独立的选自：氢、氘、氟、氯、溴、羟基、氰基、C1-6烷基、C1-6烷氧基或卤代C1- 6烷基；
R9选自：氢、氘、氟、氯、溴、羟基、氰基或-C(Rf 2)n2-R#2；
Rf选自：氢、氘、氟、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基；或两个Rf与其相连的C原子一起形成C＝O、C3-6环烷基或4-7元杂环基；
R#2为氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、CONRaRb、NRaRb、C3-6环烷基或4-7元杂环基；
Ra、Rb各自独立的选自：氢、氘、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、-C1- 6亚烷基-4至7元氮杂环或-(CH2)1-6-NRe1Rf1；
Re1、Rf1各自独立的选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基(优选氢、甲基或乙基)；
优选Ra、Rb与其相连的N原子一起形成4至7元氮杂环，优选Re1、Rf1与其相连的N原子一起形成4至7元氮杂环，所述C3-6环烷基、4-7元杂环基或4至7元氮杂环任选的被1或2个选自氘、氟、氨基、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基所取代；
X1、X2各自独立的选自CH或N；
Z5、Z6、Z7各自独立的为CH或N；
Ra’、Rb’各自独立的选自氢、氘、C1-6烷基、C1-6烷氧基或卤代C1-6烷基(优选氢)；
RX、RZ’各自独立的选自氢、氘、氟、氯、溴、氨基、氰基、酰胺基、乙酰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基；
LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自：CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、OCH2CH2、CH2O、CH2CH2O或
L2选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、OCH2CH2、CH2O、CH2CH2O、亚哌啶基或亚哌嗪基；
L3、L4选自：CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、CH2O、OCH2CH2、CH2CH2O或亚哌啶基；
L5选自化学键、CH2、CH2CH2或CH2CH2O；
L6选自：化学键、O、S、NH、N(甲基)、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CO、CONH或NHCO；
L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基或亚乙炔基；
上述任一亚甲基的氢任选的被1或2个R##所取代，R##选自氢、氘、卤素、酰胺基、氨基、二甲氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基(优选甲基、乙基或丙基)。
在一些实施方式中，所述通式(I)所示的化合物，其为通式(II-4)、(II-4-1)、(II-4-2)、(II-4-3)、(II-4-4)、(II-4-5)；其中，
RY1、RY2、RY3各自独立的选自：氢、氘、氟、氯、溴、C1-6烷基、C1-6烷氧基或卤代C1-6烷基；
R9为-C(Rf 2)n2-R#2；n2为0-5的整数；
Rf选自：氢、氘、氟、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基；或两个Rf与其相连的C原子一起形成C＝O、C3-6环烷基或4-7元杂环基；
R#2为CONRaRb、NRaRb；
Ra、Rb各自独立的选自：氢、氘、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基；
X1为N，X2为CH；
Z5、Z6、Z7均CH；
Ra’、Rb’各自独立的选自氢、氘、C1-6烷基、C1-6烷氧基或卤代C1-6烷基(优选氢)；
RX和各个RZ’各自独立的选自氢、氘、氟、氯、溴、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基；
LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自：CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、OCH2CH2、CH2O、CH2CH2O或
L2选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、OCH2CH2、CH2O、CH2CH2O、亚哌啶基或亚哌嗪基；
L3、L4选自：CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、CH2O、OCH2CH2、CH2CH2O或亚哌啶基；
L5选自化学键、CH2、CH2CH2或CH2CH2O；
L6选自：化学键、O、S、NH、N(甲基)、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CO、CONH或NHCO；
L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基或亚乙炔基；
K3为CH2或CO；
Rg选自氢、C1-6烷基和卤代C1-6烷基；
上述任一亚甲基的氢任选的被1或2个R##所取代，R##选自氢、氘、卤素、酰胺基、氨基、二甲氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基(优选甲基、乙基或丙基)。
在一些实施方式中，所述通式(I)所示的化合物，其为通式(II-5)、(II-5-1)、(II-5-2)、(II-5-3)、(II-5-4)、(II-5-5)；其中，
Z6、Z7各自独立的为CH或N；
RY选自氢、氘、卤素、C1-6烷基、C1-6烷氧基或卤代C1-6烷基；
RZ’、RY1、RY2、RY3、RY4各自独立的选自：氢、氘、氟、氯、氨基、氰基、酰胺基、乙酰基、二甲氨基、二乙胺基、二甲酰胺基、C1-6烷基、C1-6烷氧基或卤代C1-6烷基；
Ra’、Rb’、RX各自独立的选自氢、氘、氟、氯、溴、氨基、氰基、C1-6烷基、C1-6烷氧基或卤代C1-6烷基；
LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)或
L2、L3、L4各自独立的选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、OCH2CH2、CH2CH2O；
L5、L6选自化学键、CH2或CH2CH2；
L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基或亚乙炔基；
上述任一亚甲基的氢任选的被1或2个R##所取代；，R##选自氢、氘、卤素、酰胺基、氨基、二甲氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基(优选甲基、乙基或丙基)
RN选自氢、甲基或乙基。
在一些实施方式中，所述通式(I)所示的化合物，其为通式(II-5)、(II-5-1)、(II-5-2)、(II-5-3)、(II-5-4)、(II-5-5)；其中，
Z6、Z7均为CH；Y1、Y2、Y3、Y4均为CH；
各个RY各自独立地选自氢、氘、卤素、C1-6烷基、C1-6烷氧基或卤代C1-6烷基；
RZ’、RY1、RY2、RY3、RY4各自独立的选自：氢、氘、氟、氯、氨基、C1-6烷基、C1-6烷氧基或卤代C1- 6烷基；
Ra’、Rb’、RX各自独立的选自氢、氘、氟、氯、溴、氨基、C1-6烷基、C1-6烷氧基或卤代C1-6烷基；
LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)或
L2、L3、L4各自独立的选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、OCH2CH2、CH2CH2O；
L5、L6选自化学键、CH2或CH2CH2；
L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基或亚乙炔基；
K3为CH2或CO；
Rg选自氢、C1-6烷基和卤代C1-6烷基；
RN选自氢、甲基或乙基；
上述任一亚甲基的氢任选的被1或2个R##所取代；R##选自氢、氘、卤素、酰胺基、氨基、二甲氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基(优选甲基、乙基或丙基)。
在一些实施方式中，所述通式(I)所示的化合物，其为通式(II-6)、(II-6-1)、(II-6-2)、(II-6-3)、(II-6-4)、(II-6-5)、(II-6-6)；其中，
Rb’、RY1、RY2、RY3、RY4、RX各自独立的选自氢、氘、氟、氯、溴、氨基、酰胺基、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基；
RX选自氢、卤素、C1-6烷基、-O-R1、-O-(CH2)1-4R1、C3-6环烷基或4-7元杂环基；
R1选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基；
RY选自氢、氘、卤素、C1-6烷基、C1-6烷氧基或卤代C1-6烷基；
L’表示为-(CR2 2)p-NRN-；
p为0、1、2或3，
R2选自：氢、氘、氨基、C1-6烷基、C1-6烷氧基或卤代C1-6烷基，或两个R2与相连的C原子一起形成C＝O、环丙基、氧杂环丁基或氮杂环丁基；
RN选自：氢、氘、甲基、乙基、丙基、异丙基、氨基、＝NH或羟氨基；
L选自化学键、NH或N(甲基)；
LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自：化学键、CH2、CH2CH2、O、S、NH、N(甲基)、OCH2、CH2O、OCH2CH2、CH2CH2O；
L2选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、CH2O、OCH2CH2、CH2CH2O、亚哌啶基；
L3、L4选自：CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、CH2O或OCH2CH2；
L5、L6选自化学键、CH2、CH2CH2、OCH2CH2、O、S或NH；
L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基或亚乙炔基；
上述任一亚甲基的氢任选的被1或2个R##所取代，R##选自氢、氘、卤素、酰胺基、氨基、二甲氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基(优选甲基、乙基或丙基)。
在一些实施方式中，所述通式(I)所示的化合物，其为通式(II-7-1)、(II-7-2)、(II-7-3)、(II-7-4)；其中，
RY1、RY2、RY3、RY4、Rb’各自独立的选自氢、氘、氟、氨基、氰基、酰胺基、乙酰基、C1-6烷基、C1- 6烷氧基、卤代C1-6烷基、环丙基、环丁基或氧杂环丁基；
RY选自氢、氘、氟、C1-6烷基、C1-6烷氧基、三氟甲基或二氟甲基；
RX选自-O-(CH2)s-R1或-(CR’2)s-R1，R1选自氢、氘、卤素、氨基、羟基、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基；所述C3-6环烷基或4-7元杂环基优选环丙基、环丁基、氧杂环丁基或氮杂环丁基，所述C3-6环烷基或4-7元杂环基任选的被1或2个选自氘、氟、甲基、乙基、羟基、羟甲基、氨基的取代基所取代；
s为0、1、2或3；LIN如上一项所定义。
在一些实施方式中，所述通式(I)所示的化合物，其为通式(II-8)、(II-8-1)、(II-8-2)、(II-8-3)、(II-8-4)、(II-8-5)、(II-8-6)、(II-8-7)或(II-8-8)；其中，
RX选自氢、氘、氟、氯、氰基、NRaRb、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C3-6环烷基或4-7元氮杂环；优选的RX表示为-(CR’2)s-NRaRb，
RZ4选自氢、氘、氟、氨基、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、丙氧基、异丙氧基，或两个RZ4与其相连的C原子一起形成环丙基、环丁基或环戊基；
Q1、Q2、Q3各自独立的为N＝或CRQ；
RY1、RY2、RY3、RY4、RQ各自独立的选自氢、氘、氟、氯、溴、氨基、氰基、CONRaRb、NRaRb、C1- 6烷基、卤代C1-6烷基、C1-6烷氧基、C3-6环烷基或4-7元氮杂环；
Y8为O、S或CH2；
RY各自独立的选自氢、氘、氟、氨基、C1-6烷基、卤代C1-6烷基或C1-6烷氧基；或两个RY与其相连的C原子一起形成C＝O；
R’、Ra、Rb各自独立的选自氢、氘、氨基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、环丙基、环丁基优选的两个R’与其相连的C原子一起形成环丙基或环丁基；优选的Ra、Rb与其相连的N原子一起形成4-7元氮杂环，
所述C3-6环烷基或4-7元氮杂环任选的被1或2个选自F、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基的取代基所取代；
L’选自：NRN、O、S、或-(CR2 2)p-NRN-；
R2、RN各自独立的选自氢、氘、氨基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、羟代C1-6烷基或C3-6环烷基；
LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自：化学键、CH2、CH2CH2、O、S、NH、N(甲基)、OCH2或CH2O；
L2选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、CH2O、OCH2CH2或CH2CH2O；
L3、L4选自：CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、CH2O或OCH2CH2；
L5、L6选自化学键、CH2、CH2CH2、OCH2CH2、O、S或NH；
L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基或亚乙炔基；
上述任一亚甲基的氢任选的被1或2个R##所取代，R##选自氢、氘、卤素、酰胺基、氨基、二甲氨基、 C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基(优选甲基、乙基或丙基)。
在一些实施方式中，所述通式(I)所示的化合物，其为通式(II-9)、(II-9-1)、(II-9-2)、(II-9-3)、(II-9-4)、(II-9-5)、(II-9-6)；其中，
Z4为CH2；Z3为NH；
Y5为N或C，Y6为N或C，Y7、Y8、Y9、Y10各自独立的为NH或CRY；
RY1、RY3、RY4、RY各自独立的选自氢、氘、卤素、酰胺基、氨基、二甲氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基；
L为化学键；L’为NH；
U9选自N或CRU”，U8选自N或CRU”，
RU”选自氢、氘、卤素、氨基、酰胺基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基或C3-6环烷基(优选氢、甲基或乙基)，优选两个RU”与其相连的环原子一起形成3-8元环烷基或4-7元杂环基；
LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自C3-6环烷基、4-12元杂环基、CH2、CH2CH2、CH2CH2CH2、O、S、NH、N(甲基)、CO、SO、SO2、
L2选自C3-6环烷基、4-7元杂环基、CH2、CH2CH2、CH2CH2CH2、O、S、NH、N(甲基)、OCH2、CH2O、CONH或NHCO；
L3选自：CH2、CH2CH2、CH2CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2OCH2、OCH2CH2、CH2O、CH2CH2O；
L4选自化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、OCH2CH2、CH2O或CH2CH2O；
L5选自化学键、CH2或CH2CH2；
L6选自：化学键、O、S、NH、N(甲基)、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CO、CONH或NHCO；
L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基或亚乙炔基；
上述任一亚甲基的氢任选的被1或2个R##所取代，R##选自氢、氘、卤素、酰胺基、氨基、二甲氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-6环烷基或4-7元杂环基。
在上述实施方式中，Y7为N，Y9为CRY，在一些实施方式中，Y7为CRY，Y9为N；在一些实施方式中，Y7、Y9均为CRY。
在一些实施方式中，LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自：化学键、O、S、NRN、CH2、C(CH3)2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、OCH2CH2、CH2CH2O、CO、CONRN、NRNCO、NRNCONRN、SO1-2、SO1-2NRN、NRNSO1-2、NRNSO1-2NRN、亚乙烯基、亚乙炔基、亚苯基、亚吡啶基、亚嘧啶基、亚吡嗪基、亚哒嗪基、亚哌嗪基、亚哌啶基、亚三氮唑基、亚四氮唑基、亚吡唑基、亚咪唑基、C3-6亚环烷基、4-12元亚杂环基、
L2各自独立的选自：化学键、O、S、NRN、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、C(CH3)2、CO、CONRN、NRNCO、OCH2CH2、CH2CH2O、亚乙烯基、亚乙炔基、亚苯基、亚吡啶基、亚嘧啶基、亚哌嗪基、亚三氮唑基、亚四氮唑基、亚吡唑基、亚咪唑基、C3-6亚环 烷基或4-12元亚杂环基；
L3、L4各自独立的选自：化学键、O、S、NRN、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CO、CONRN、NRNCO、OCH2CH2、CH2CH2O、亚乙烯基、亚乙炔基、亚苯基、亚吡啶基、亚嘧啶基、亚哌嗪基、亚三氮唑基、亚四氮唑基、亚吡唑基、亚咪唑基；
L5、L6各自独立的选自：化学键、O、S、NRN、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CO、CONRN、NRNCO、OCH2CH2、CH2CH2O、亚乙烯基、亚乙炔基、亚苯基、亚吡啶基、亚嘧啶基、亚哌嗪基、亚三氮唑基、亚四氮唑基、亚吡唑基、亚咪唑基；
L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基、亚乙炔基、CONRN、NRNCO、NRNCONRN、SO1- 2、SO1-2NRN、NRNSO1-2或NRNSO1-2NRN；
RN选自氢或甲基；上述任一亚甲基的氢任选的被1或2个R##所取代；
所述C3-6亚环烷基、4-12元亚杂环基任选的被1或2个选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基的取代基所取代。
在一些实施方式中，LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
L1选自：CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、OCH2CH2、CH2O、CH2CH2O或
L2选自：化学键、CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、OCH2CH2、CH2O、CH2CH2O；
L3、L4选自：CH2、CH2CH2、CO、CONH、NHCO、O、S、NH、N(甲基)、OCH2、CH2O、OCH2CH2、CH2CH2O；
L5选自化学键、CH2、CH2CH2或CH2CH2O；
L6选自：化学键、O、S、NH、N(甲基)、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CO、CONH或NHCO；
L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基或亚乙炔基。
在一些实施方式中，上述各个基团各自独立地为实施例中所制备的化合物EX-1至EX-32中的对应基团。
在一些实施例中，通式(I)所示的化合物，其选自表1。
表1：















本发明另一方面提供一种药物组合物，其含有如上任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及他们的混合物，和药学上可接受的赋形剂；优选地，其还含有其它治疗剂。
本发明另一方面提供如上任一所述的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及他们的混合物，或如上所述的药物组合物在制备蛋白抑制剂或降解剂上的应用。
在一些实施方式中，所述蛋白为HPK1蛋白。
本发明另一方面还提供如上任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及他们的混合物在制备用于治疗和/或预防癌症的药物中的用途。
本发明另一方面还提供一种在受试者中治疗和/或预防癌症的方法，所述方法包括向所述受试者给药如上任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体以及他们的混合物或上述的药物组合物。
本发明另一方面还提供如上任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体以及他们的混合物或上述的药物组合物，其用于治疗和/或预防癌症。
如上所述的用途、方法或上述化合物或组合物的用途，其中所述癌症选自膀胱癌,乳腺癌,结直肠癌,胃癌,头颈鳞状细胞癌,霍奇金淋巴瘤,梅尔克尔-细胞癌,间皮瘤,黑素瘤,非小细胞肺癌,卵巢癌,子宫癌,食道癌,肝癌,胰腺癌,前列腺癌,肾细胞癌,甲状腺癌,小细胞肺癌,过渡性细胞癌,尿路上皮癌,对靶向药物耐药的肿瘤；或依赖HPK1突变蛋白的肿瘤或疾病。
具体实施方式
定义
化学定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时，既定包括每个值和在所述范围内的子范围。例如“C1-6烷基”包括C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5和C5-6烷基。
“C1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团。在一些实施方案中，C1-4烷基是优选的。C1-6烷基的例子包括：甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、叔丁基(C4)、仲丁基(C4)、异丁基(C4)、正戊基(C5)、3-戊基(C5)、戊基(C5)、新戊基(C5)、3-甲基-2-丁基(C5)、叔戊基(C5)和正己基(C6)。术语“C1-6烷基”还包括杂烷基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C2-6烯基”是指具有2至6个碳原子和至少一个碳碳双键的直链或支链烃基团。在一些实施方案中，C2- 4烯基是优选的。C2-6烯基的例子包括：乙烯基(C2)、1-丙烯基(C3)、2-丙烯基(C3)、1-丁烯基(C4)、2-丁烯基(C4)、丁二烯基(C4)、戊烯基(C5)、戊二烯基(C5)、己烯基(C6)，等等。术语“C2-6烯基”还包括杂烯基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烯基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C2-6炔基”是指具有2至6个碳原子、至少一个碳-碳叁键以及任选地一个或多个碳-碳双键的直链或支链烃基团。在一些实施方案中，C2-4炔基是优选的。C2-6炔基的例子包括但不限于：乙炔基(C2)、1-丙炔基(C3)、2-丙炔基(C3)、1-丁炔基(C4)、2-丁炔基(C4)，戊炔基(C5)、己炔基(C6)，等等。术语“C2-6炔基”还包括杂炔基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。炔基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。
因此，“卤代C1-6烷基”是指上述“C1-6烷基”，其被一个或多个卤素基团取代。在一些实施方案中，卤代C1-4烷基是特别优选的，更优选卤代C1-2烷基。示例性的所述卤代烷基包括但不限于：-CF3、-CH2F、-CHF2、-CHFCH2F、-CH2CHF2、-CF2CF3、-CCl3、-CH2Cl、-CHCl2、2,2,2-三氟-1,1-二甲基-乙基，等等。卤代烷基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。
“C3-8环烷基”是指具有3至8个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，C3-7环烷基和C3-6环烷基是特别优选的，更优选C5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在环烷基环上，且在这样的情况中，碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于：环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环已二烯基(C6)、环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7)，等等。环烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“4-12元杂环基”是指具有环碳原子和1至5个环杂原子的4至12元非芳香环系的基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，优选3-10元杂环基，其为具有环碳原子和1至5个环杂原子的3至10元非芳香环系；在一些实施方案中，优选3-7元杂环基，进一步优选3-6元杂环基，进一步优选4-8元杂环基，更优选5-6元杂环基。杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系，其中连接点在环烷基环上，或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在杂环基环上；且在这样的情况下，环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的杂环基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基、吡咯基-2,5-二酮、哌啶基、四氢吡喃基、二氢吡啶基、硫杂环己烷基(thianyl)、哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的与C6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于：二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基，等等。示例性的与C6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于：四氢喹啉基、四氢异喹啉基，等等。杂环基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如，双环)4n+2芳族环体系(例 如，具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中，芳基具有六个环碳原子(“C6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C10芳基”；例如，萘基，例如，1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环系统中的碳原子数目。芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“5-14元杂芳基”是指具有环碳原子和1-4个环杂原子的5-14元单环或双环的4n+2芳族环体系(例如，具有以环状排列共享的6、10或14个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述杂芳基环上，在这种情况下，碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。
在一些实施方案中，5-10元杂芳基是优选的，在另一些实施方案中，5-6元杂芳基是特别优选的。示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、噁二唑基(例如，1,2,4-噁二唑基)、噻二唑基、四唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、四嗪基、氮杂环庚三烯基、氧杂环庚三烯基、硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于：萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。杂芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C6-10亚芳基”和“5-14元亚杂芳基”分别表示上述“C6-10芳基”和“5-14元杂芳基”，其中另一个氢被除去而形成的二价基团，并且可以是取代或未取代的。优选C6-10亚芳基和5-10元亚杂芳基。
本文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等为任选取代的基团。
示例性的碳原子上的取代基包括但不局限于：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(＝O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(＝O)Raa、-OCO2Raa、-C(＝O)N(Rbb)2、-OC(＝O)N(Rbb)2、-NRbbC(＝O)Raa、-NRbbCO2Raa、-NRbbC(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-OC(＝NRbb)Raa、-OC(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-OC(＝NRbb)N(Rbb)2、-NRbbC(＝NRbb)N(Rbb)2、-C(＝O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(＝O)Raa、-OS(＝O)Raa、-Si(Raa)3、-OSi(Raa)3、-C(＝S)N(Rbb)2、-C(＝O)SRaa、-C(＝S)SRaa、-SC(＝S)SRaa、-SC(＝O)SRaa、-OC(＝O)SRaa、-SC(＝O)ORaa、-SC(＝O)Raa、-P(＝O)2Raa、-OP(＝O)2Raa、-P(＝O)(Raa)2、-OP(＝O)(Raa)2、-OP(＝O)(ORcc)2、-P(＝O)2N(Rbb)2、-OP(＝O)2N(Rbb)2、-P(＝O)(NRbb)2、-OP(＝O)(NRbb)2、-NRbbP(＝O)(ORcc)2、-NRbbP(＝O)(NRbb)2、-P(Rcc)2、-P(Rcc)3、-OP(Rcc)2、-OP(Rcc)3、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc)、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
或者在碳原子上的两个偕氢被基团＝O、＝S、＝NN(Rbb)2、＝NNRbbC(＝O)Raa、＝NNRbbC(＝O)ORaa、＝NNRbbS(＝O)2Raa、＝NRbb或＝NORcc取代；
Raa的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Raa基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rbb的每个独立地选自：氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rbb基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rcc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rcc基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rdd的每个独立地选自：氢、氘、卤素、羧基、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-SH、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟代C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基、5-14元杂芳基，或者两个偕Rdd取代基可结合以形成＝O或＝S。
示例性的氮原子上取代基包括但不局限于：氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRbb)Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者连接至氮原子的两个Rcc基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代，且其中Raa、Rbb、Rcc和Rdd如上所述。
其它定义
术语“癌症”包括但不限于下列癌症：乳腺、卵巢、子宫颈、前列腺、睾丸、食道、胃、皮肤、肺、骨、结肠、胰腺、甲状腺、胆道、颊腔与咽(口)、唇、舌、口腔、咽、小肠、结肠直肠、大肠、直肠、脑与中枢神经系统的癌症、成胶质细胞瘤、神经母细胞瘤、角化棘皮瘤、表皮样癌、大细胞癌、腺癌、腺瘤、滤泡癌、未分化的癌、乳头状癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓障碍、淋巴障碍、霍奇金氏病、毛细胞癌和白血病。更具体地，癌症包括但不限于HER2阳性的转移性乳腺癌、HER2过度表达的转移性胃腺癌或胃食管交界腺癌、表皮生长因子受体(EGFR)基因敏感突变的非小细胞肺癌、含铂化疗期间或化疗后疾病进展的局部晚期或转移性鳞状组织学类型非小细胞肺癌、转移性晚期乳腺癌、去势抵抗性前列腺癌。
本文所用的术语“治疗”涉及逆转、减轻、抑制该术语适用的障碍或病症的进展或者这类障碍或病症的一种或多种症状。本文所用的名词“治疗”涉及动词治疗的动作，后者是如刚才所定义的。
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐，它们在可靠的医学判断范围内适用于与患者组织接触，不会产生不恰当的毒性、刺激作用、变态反应等，与合理的益处/风险比相称，就它们的预期应用而言是有效的，包括(可能的话)本发明化合物的两性离子形式。
药学上可接受的碱加成盐是与金属或胺生成的，例如碱金属与碱土金属氢氧化物或有机胺。用作阳离子的金属的实例有钠、钾、镁、钙等。适合的胺的实例有N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、 乙二胺、N-甲基葡糖胺和普鲁卡因。
酸性化合物的碱加成盐可以这样制备，按照常规方式使游离酸形式与足量所需的碱接触，生成盐。按照常规方式使盐形式与酸接触，再分离游离酸，可以使游离酸再生。游离酸形式在某些物理性质上多少不同于它们各自的盐形式，例如在极性溶剂中的溶解度，但是出于本发明的目的，盐还是等价于它们各自的游离酸。
盐可以是从无机酸制备的硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物，酸例如盐酸、硝酸、硫酸、氢溴酸、氢碘酸、磷酸等。代表性盐包括：氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐等。盐也可以是从有机酸制备的，例如脂肪族一元与二元羧酸、苯基取代的烷酸、羟基烷酸、烷二酸、芳香族酸、脂肪族与芳香族磺酸等。代表性盐包括乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐等。药学上可接受的盐可以包括基于碱金属与碱土金属的阳离子，例如钠、锂、钾、钙、镁等，以及无毒的铵、季铵和胺阳离子，包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。还涵盖氨基酸的盐，例如精氨酸盐、葡糖酸盐、半乳糖醛酸盐等。
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括在受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗益处的量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化的量。化合物的治疗有效量是指单独使用或与其它疗法联用时，治疗剂的量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其它治疗剂的治疗效果的量。
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的量，或足以预防与疾病、障碍或病症有关的一或多种症状的量，或防止疾病、障碍或病症复发的量。化合物的预防有效量是指单独使用或与其它药剂联用时，治疗剂的量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的量，或增强其它预防药剂的预防效果的量。
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如，本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药，或与其它治疗剂一起在单一单位剂型中同时给药。
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺 式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R x H2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R 0.5H2O))和多水合物(x为大于1的数，例如，二水合物(R 2H2O)和六水合物(R 6H2O))。
本发明化合物可以是无定形或结晶形式(多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本发明还包括同位素标记的化合物(同位素变体)，它们等同于式(I)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如3H和14C)的那些可用于药物和/或底物组织分布测定。氚、即3H和碳-14、即14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物
前药为任何共价键合的本发明化合物，当将这种前药给予患者时，其在体内释放母体化合物。通常通过修饰官能团来制备前药，修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行 的。前药包括，例如，其中羟基、氨基或巯基与任意基团键合的本发明化合物，当将其给予患者时，可以裂解形成羟基、氨基或巯基。因此，前药的代表性实例包括(但不限于)式(I)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。另外，在羧酸(-COOH)的情况下，可以使用酯，例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。
本发明还提供药物制剂，包含治疗有效量的式(I)化合物或其治疗学上可接受的盐和其药学上可接受的载体、稀释剂或赋形剂。所有这些形式都属于本发明。
药物组合物和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的本发明化合物。在一些实施方案中，所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中，所述药物组合物包含预防有效量的本发明化合物。
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
给药
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描 述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
联合用药
本文中定义的治疗可作为单独治疗应用，或除本发明化合物之外，可包括常规外科手术或放疗或化疗。因此，本发明化合物还可与用于治疗癌症的现有治疗药剂联合使用。
除了使用本发明化合物治疗以外，还涉及到常规的手术或放射疗法或化学疗法或免疫疗法。这种化学疗法与本发明化合物可以同时地、连续地、或分别地给药，并且可包含以下类型的抗肿瘤剂的一种或多种：
(i)医学肿瘤学中所使用的抗增殖/抗肿瘤药物及其组合，例如烷化剂(例如顺铂、奥沙利铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安、替莫唑胺、亚硝基脲类)；抗代谢药(例如吉西他滨和抗叶酸剂，例如氟嘧啶(如5-氟尿嘧啶和替加氟)、雷替曲塞、甲氨喋呤、阿糖胞苷、羟基脲)；抗肿瘤抗生素(例如蒽环类，如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素C、放线菌素、光神霉素)；抗有丝分裂药剂(例如长春花生物碱，如长春新碱、长春碱、长春地辛、长春瑞滨；以及紫杉烷类，如紫杉醇、泰索帝、polo激酶抑制剂)；拓扑异构酶抑制剂(例如表鬼臼毒素(如依托泊苷、替尼泊苷)，安吖啶、托泊替康、喜树碱)；
(ii)细胞生长抑制剂，例如抗雌激素药(例如他莫昔芬、氟维司群、托瑞米芬、雷洛昔芬、屈洛昔芬、碘昔芬(iodoxyfene))、抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特、醋酸环丙孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林、和布舍瑞林)、孕激素类(例如醋酸甲地孕酮)、芳香酶抑制剂(例如阿那曲唑、来曲唑、伏罗唑(vorazole)、伊西美坦)、5α-还原酶抑制剂(例如非那雄胺)；
(iii)抗侵袭剂(anti-invasion)，例如c-Src激酶家族抑制剂，[如4-(6-氯-2,3-亚甲基二氧基苯胺基)-7-[2-(4-甲基哌嗪-1-基)乙氧基]-5-四氢吡喃-4-基氧基喹唑啉[AZD0530(塞卡替尼)]、N-(2-氯-6-甲基苯基)-2-{6-[4-(2-羟乙基)哌嗪-1-基]-2-甲基嘧啶-4-基氨基}噻唑-5-甲酰胺(达沙替尼，BMS-354825)和波舒替尼(SKI-606)，以及金属蛋白酶抑制剂(如马立马司他)、尿激酶纤溶酶原激活物受体功能的抑制剂或者类肝素酶(heparanase)的抗体]；
(iv)生长因子功能的抑制剂：例如这种抑制剂包括生长因子抗体和生长因子受体抗体(例如抗erbB2抗体曲妥珠单抗[赫赛汀]、抗EGFR抗体帕尼单抗、抗erbB1抗体西妥昔单抗[Erbitux，C225]；这种抑制剂还包括：酪氨酸激酶抑制剂，例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂，如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉基丙氧基)-喹唑啉-4-胺(吉非替尼，ZD1839)、N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼，OSI-774)、6-丙烯酰胺基-N-(3-氯-4-氟苯基)-7-(3-吗啉基丙氧基)-喹唑啉-4-胺(CI1033)、erbB2酪氨酸激酶抑制剂(例如拉帕替尼)；肝细胞生长因子家族的抑制剂；胰岛素生长因子家族的抑制剂；血小板衍生的生长因子家族的抑制剂，例如伊马替尼和/或尼洛替尼(AMN107)；丝氨酸/苏氨酸激酶的抑制剂(例如Ras/Raf信号传导抑制剂，例如法呢基转移酶抑制剂，例如索拉非尼(BAY43-9006)、替匹法尼(R115777)、氯那法尼(SCH66336))、通过mEK和/或AKT激酶的细胞信号传导抑制剂、 c-kit抑制剂、abl激酶抑制剂、PI3激酶抑制剂、Plt3激酶抑制剂、CSF-1R激酶抑制剂、IGF受体(胰岛素样生长因子)激酶抑制剂；极光激酶(aurora kinase)抑制剂(例如AZD1152、PH739358、VX-680、MLN8054、R763、MP235、MP529、VX-528、AX39459)，细胞周期蛋白依赖性激酶抑制剂，例如CDK2和/或CDK4抑制剂；
(v)抗血管生成剂，例如抑制血管内皮生长因子作用的药剂，[例如抗人血管内皮细胞生长因子抗体贝伐珠单抗(阿瓦斯丁)以及例如VEGF受体酪氨酸激酶抑制剂，例如凡德他尼(ZD6474)、伐他拉尼(PTK787)、舒尼替尼(SU11248)、阿西替尼(AG-013736)、帕唑帕尼(GW786034)、4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯烷-1-基丙氧基)喹唑啉(AZD2171)，以及通过其它机制起作用的化合物(例如雷诺胺，整联蛋白αvβ3功能的抑制剂和血管抑素(angiostatin))]；
(vi)血管损伤剂，例如康普瑞汀A4；
(vii)内皮素受体拮抗剂，例如齐泊腾坦(ZD4054)或者阿曲生坦；
(viii)反义治疗剂，例如导向上面列出的靶点的那些，例如ISIS2503(一种anti-ras反义治疗剂)；
(ix)基因治疗方法，包括例如替换异常基因(例如异常p53或者异常BRCA1或BRCA2)的方法；GDEPT(基因定向的酶前药治疗)法，例如使用胞嘧啶脱氨酶、胸苷激酶或者细菌硝基还原酶的那些；提高患者对化学治疗或放射治疗的耐受性的方法，例如多重耐药基因治疗；和
(x)免疫治疗方法，包括例如提高患者肿瘤细胞的免疫原性的体外和体内方法，例如用细胞因子(例如白细胞介素2、白细胞介素4或者粒细胞巨噬细胞集落刺激因子)进行转染；降低T细胞无效能的方法；使用转染的免疫细胞(例如细胞因子转染的树突状细胞)的方法；使用细胞因子转染的肿瘤细胞系的方法；使用抗独特型抗体的方法；降低免疫抑制性细胞(例如调节性T细胞、髓源性(myeloid-derived)抑制细胞、或表达IDO(吲哚胺2,3-脱氧酶)的树突状细胞)的功能的方法；以及使用衍生自肿瘤相关抗原(例如NY-ESO-1，mAGE-3、WT1或Her2/neu)的蛋白质类或肽类组成的癌症疫苗的方法。
实施例
化合物制备实施例
后文所用缩写含义如下所示：

下述各合成步骤中的原料，对于非商品化试剂，其合成步骤均已提供。各步骤原料对应的批次，不一定与其合成方法中所述的批次一致。
中间体的制备
化合物Int-1的合成
步骤1：将化合物1-1(32g,98.79mmol)溶于无水THF(50mL)，0℃，氮气保护下缓慢加入氢化钠(5.93g,148.19mmol,60％wt),搅拌30分钟后，缓慢滴加二碳酸二叔丁酯(28.03g,29.50mL)的无水THF(10mL)溶液，室温搅拌反应3小时。反应结束后，加水(10mL)淬灭，减压浓缩，得到粗品。 粗品用PE:EA＝10:1(200mL)的混合溶液进行打浆。过滤，得到化合物1-2(41g,收率97.9％)。
步骤2：将化合物1-2(15g,35.37mmol)溶于1,4-二氧六环(300mL)，在氮气保护下依次加入4-(N,N-二甲酰胺基)苯硼酸(5.12g,26.53mmol)，Pd(dppf)Cl2·CH2Cl2(1.44g,1.77mmol)和碳酸钾(9.78g,70.75mmol)水溶液(30mL)，80℃加热反应3小时。反应完成后，冷却至室温，减压浓缩，得到粗品。粗品经柱层析分离纯化(PE：EA＝1:1～0:1)，得到化合物Int-1(5.43g,收率45.9％)。LCMS[M+H]+445.0,447.0。
化合物Int-2的合成
以化合物Int-1和双联频哪醇硼酸酯(9.24g,36.38mmol)为原料，参照化合物Int-1的合成方法得到化合物Int-2(6.4g,粗品)，直接用于下一步反应。LCMS[M+H]+411.1。
化合物Int-3的合成
步骤1：以化合物Int-1和化合物3.1为原料，参照化合物Int-1的合成方法得到深棕色油状化合物3-1(5.6g，收率61.5％)。LCMS[M+H]+598.5。
步骤2：将化合物3-1(3.3g,5.52mmol)溶于二氯甲烷(10mL)，加入三氟乙酸(46.20g,30mL)，室温反应2小时。反应完成后，减压浓缩，得到黄色固体粗品化合物Int-3(2.3g)。LCMS[M+H]+398.1。化合物Int-4的合成
步骤1：将化合物4-1(4.41g，15.97mmol)溶于NMP(50mL)中，依次加入4-氨基丁酸叔丁酯盐酸盐(5.0g,25.55mmol)和DIPEA(6.19g,47.91mmol)，100℃加热反应3小时。冷却至室温，加入水(150mL)，用乙酸乙酯(90mL)萃取，有机层用饱和食盐水洗涤，无水硫酸钠干燥。过滤，减压浓缩，得到粗品。粗品经柱层析分离纯化(PE：EA＝1:1-0:1),得到淡黄色固体化合物4-2(6.42g,收率 96.7％)。LCMS[M+H]+415.2。
步骤2：将化合物4-2(6.42g,15.45mmol)溶解于二氯甲烷(50mL)中，加入三氟乙酸(9.89g,86.71mmol,6.42mL)，室温搅拌3小时。减压浓缩并冻干后，得到黄色固体化合物Int-4(3.4g,收率61.2％)。LCMS[M+H]+360.1。
以下中间体的合成以相应的胺为原料，采用与Int-4类似的制备方法。
化合物Int-8的合成
将化合物8-1(1.38g,8.69mmol)和化合物8-2(2g,7.24mmol)溶于NMP(20mL)，加入DIPEA(2.81g,3.78mL)，120℃加热反应3小时。反应结束后，冷却至室温，减压浓缩，得到粗品。粗品经反相制备HPLC纯化(三氟乙酸体系)，得到化合物Int-8(1g,收率33.3％)，绿色固体。LCMS[M+H]+416.2。
以下中间体的合成以化合物4-1为原料，采用与Int-8类似的方法制备。

化合物Int-13的合成
氮气保护下，将化合物13-1(12g,54.03mmol)溶于冰乙酸(80mL)中，然后缓慢向其中加入硼氢化钠(7.15g,189.12mmol)，室温搅拌3小时。反应结束后，加入饱和氯化铵溶液淬灭，用水和乙酸乙酯萃取后，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，得到粗品。粗品经柱层析分离纯化(DCM：MeOH＝100:1～10:1)，得到黄色固体化合物Int-13(5g,收率40.9％)。LCMS[M+H]+226.1。
化合物Int-14的合成
步骤1：氮气保护下，将化合物Int-2(718.60mg,1.46mmol)，Int-13(300mg,1.33mmol)，Pd(dppf)Cl2·CH2Cl2(108.35mg,132.68μmol)和碳酸钾(366.74mg,2.65mmol)溶于1,4-二氧六环(20mL)和水(0.8mL)的混合溶液中，80℃加热反应2小时。反应完成后，冷却至室温，减压浓缩，得到粗品。粗品经柱层析分离纯化(DCM：MeOH＝100:1～10:1)，得到化合物14-1(330mg,收率48.6％)，黄色固体。LCMS[M+H]+512.5。
步骤2：氮气保护下，将化合物14-1(330mg,645.02μmol)溶于盐酸的二氧六环(4M,10mL)溶液，室温反应3小时。反应结束后，将反应混合物减压浓缩，得化合物Int-14(200mg,收率69.2％)，黄色固体。LCMS[M+H]+412.3。
化合物Int-15的合成
步骤1：氮气保护下，将化合物Int-3(100mg,251.59μmol)，(6-溴己基)氨基甲酸叔丁酯(70.50mg,251.59μmol)和DIPEA(97.55mg,131.47μL)溶于DMF(10mL)，70℃加热反应2小时。反应完成后，冷却至室温，加入少量饱和氯化铵水溶液淬灭后，用乙酸乙酯(20mL)萃取，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，得到粗品，薄层层析分离纯化(DCM：MeOH＝8:1)，得化合物15-1(90mg,收率59.9％)，黄色固体。LCMS[M+H]+597.6。
步骤2：氮气保护下，将化合物15-1(90mg,150.81μmol)溶于二氯甲烷(6mL)中,滴加三氟乙酸(1.54g,1mL)，室温反应2小时。反应结束后，减压浓缩，得到粗品化合物Int-15(70mg,收率76.0％)，黄色固体。LCMS[M+H]+497.4。
化合物Int-16的合成
在氮气保护下，将来那度胺16-1(3.76g,14.52mmol)，6-溴己醛16-2(2.6g,14.52mmol),氰基硼氢化钠(1.00g,15.97mmol)和冰乙酸(546.00mg,520.0μL)溶于无水甲醇(10mL)中，室温反应10小时。反应结束后，减压浓缩，得到粗品,经柱层析分离纯化(PE：EA＝10:1～1:1)，得化合物Int-16(2g，收率32.6％)，白色固体。LCMS[M+H]+423.9。
化合物Int-17的合成
氮气保护下，将化合物17-1(49.90mg,355.95μmol)，化合物17-2(100mg,296.63μmol)，Pd(PPh)2Cl2(20.82mg,29.66μmol)，CuI(11.30mg,59.33μmol)和三乙胺(2.91g,4.00mL)溶于DMF(4mL)中，80℃加热反应10小时。反应结束后，冷却至室温，加水(20mL)稀释，乙酸乙酯(2×20mL)萃取，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，得到粗品,经柱层析分离纯化(DCM：MeOH＝100:1～10:1)，得黄色油状化合物Int-17(110mg,收率93.6％)。LCMS[M+H]+397.2。
以下中间体的合成，采用与Int-17类似的方法制备。

化合物Int-21的合成
步骤1：氮气保护下，将化合物21-1(293.44mg,1.36mmol)，化合物21-2(310mg,1.13mmol)，三苯基膦(889.50mg,3.39mmol)溶于无水THF(15mL)中，反应液降温到0℃，缓慢加入DIAD(685.75mg,659.38μL)的无水四氢呋喃(1mL)溶液，滴完后室温反应10小时。反应结束后，将反应混合物减压浓缩，得到粗品,经柱层析分离纯化(PE：EA＝5:1～1:1)，得化合物21-3(350mg,收率65.5％)，灰色固体。
步骤2：氮气保护下，将化合物21-3(300mg,634.88μmol)溶于盐酸的1,4-二氧六环(4M,5mL)溶液中，室温反应2小时。反应结束后，将反应混合物减压浓缩，得化合物Int-21(260mg,收率98.3％)，灰色油状物。LCMS[M+H]+417.2。
化合物Int-22的合成
以7-溴-1,2,3,4-四氢异喹啉为原料，采用与Int-14类似的合成方法制得化合物Int-22，LCMS[M+H]+398.2。化合物Int-23的合成
以化合物Int-3和溴乙酸叔丁酯为原料，参照化合物Int-15的合成方法制得化合物Int-23，LCMS[M+H]+456.3。
化合物Int-24的合成
以化合物4-1(和(3-氨基丙基)氨基甲酸叔丁酯为原料，参照化合物Int-15的合成方法得到化合物Int-24，LCMS[M+H]+331.1。
以下中间体的合成，采用与Int-15类似的方法制备。
中间体28：化合物Int-28的合成
步骤1：氮气保护下，将化合物1-2(11g,25.94mmol)和4-(叔丁氧羰基)苯硼酸(2.82g,12.71mmol)加入到1,4-二氧六环(100mL)和水(10mL)的混合溶液中，然后加入Pd(dppf)Cl2·CH2Cl2(741.47mg, 907.95μmol)和碳酸钾(5.02g,36.32mmol)，80℃加热反应3小时。反应完成后，冷却至室温，减压浓缩。残余物用水(70mL)稀释，二氯甲烷(3×50mL)萃取，合并有机层，无水硫酸钠干燥。过滤，滤液浓缩，得到粗品。粗品经柱层析分离纯化(PE:EA＝100:1～25:1)，得化合物28-1(3.2g,收率53.0％)，白色固体。
LCMS[M+H]+474.0。
步骤2：氮气保护下，将化合物28-1(3g,6.32mmol,1eq)溶于无水1,4-二氧六环(100mL)，然后加入Pd(dppf)Cl2·CH2Cl2(516.48mg,632.45μmol)，无水乙酸钾(1.24g,12.65mmol)和双联嚬哪醇硼酸酯(3.21g,12.65mmol)，100℃加热反应3小时。反应完成后，冷却至室温，减压浓缩。残余物用水(20mL)稀释，二氯甲烷(3×30mL)萃取，合并有机层，无水硫酸钠干燥。过滤，滤液浓缩，得到黑棕色胶状化合物28-2(5.7g,粗品)，直接用于下一步反应。LCMS[M+H]+440.1。
步骤3：氮气保护下，将化合物28-2(2.2g,5mmol,1.4eq)和化合物28.2(801.39mg,3.54mmol)加入到1,4-二氧六环(20mL)和水(2mL)的混合溶液中，然后加入Pd(dppf)Cl2·CH2Cl2(120.60mg,147.68μmol)和碳酸钾(816.39mg,5.91mmol)，80℃加热反应3小时。反应完成后，冷却至室温，减压浓缩。残余物用水(20mL)稀释，然后用二氯甲烷(3×30mL)萃取，合并有机层，无水硫酸钠干燥。过滤，滤液浓缩，得到粗品。粗品经柱层析分离纯化(DCM:MeOH＝100:1～40:1)，得化合物28-3(650mg,收率33.9％)，白色固体。LCMS[M+H]+541.3。
步骤4：将化合物28-3(600mg,1.10mmol)溶于二氯甲烷(10mL)，然后加入三氟乙酸(5.54mmol,410.84μL)，室温反应1小时。反应完成后，将反应液减压浓缩，得化合物Int-28(640mg,粗品)。黄色固体，直接用于下一步反应。LCMS[M+H]+385.2。
化合物Int-29的合成
步骤1：氮气保护下，将化合物29-1(400mg,1.84mmol)，异吲哚啉-1,3-二酮(270.83mg,1.84mmol)，三苯基膦(1.45g,5.52mmol)溶于无水四氢呋喃(20mL)中，降温至0℃后，向其中缓慢加入DIAD(5.52mmol,1.07mL)，滴完室温反应1小时。反应结束后，将反应混合物减压浓缩，得到粗品。粗品经柱层析分离纯化(PE：EA＝20:1～5:1)，得黄色油状化合物29-2(600mg,收率94.1％)。LCMS[M-Boc+H]+247.1。
步骤2：将化合物29-2(600mg,1.73mmol)和水合肼(3.46mmol,198.07μL,85％purity)溶于无 水乙醇(10mL)中，60℃加热反应1小时。反应结束后，冷却至室温，直接减压浓缩，得到粗品化合物29-3(370mg,收率98.8％)，直接用于下一步反应。
步骤3：氮气保护下，将化合物29-3(370mg,1.71mmol)，化合物4-1(472.46mg,1.71mmol)和DIPEA(442.12mg,3.42mmol)溶于二甲亚砜(10mL)，100℃加热反应3小时。反应完成后，冷却至室温，加入少量的饱和氯化铵水溶液和二氯甲烷萃取，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，得到粗品。粗品经柱层析分离纯化(PE：EA＝10:1～1:1)，得黄色油状化合物29-4(400mg,收率49.5％)。LCMS[M+Na]+495.4。
步骤4：将化合物29-4(50mg,105.81μmol)溶于二氯甲烷(10mL),加入三氟乙酸(121.0mg,1.06mmol)，室温反应1小时。反应结束后，将反应液减压浓缩，得到粗品化合物Int-29(60mg)，黄色油状物。LCMS[M+H]+373.3。
以下中间体的合成，采用与Int-29类似的方法制备。
化合物Int-31的合成
步骤1：将化合物31-1(500mg,2.17mmol)，邻苯二甲酸酐(321.51mg,2.17mmol)，DIPEA(420.81mg,3.26mmol)溶于无水甲苯(15mL)，110℃加热反应10小时。反应结束后，冷却至室温，加入饱和氯化铵水溶液，乙酸乙酯萃取，有机相用无水硫酸钠干燥。过滤，滤液经减压浓缩，得无色油状化合物31-2(700mg,收率89.5％)。LCMS[M+Na]+383.2。
步骤2～4参照化合物Int-29的合成步骤2～4，得到化合物Int-31，LCMS[M+H]+401.3。
以下中间体的合成，采用与Int-31类似的方法制备。

中间体33：化合物Int-33的合成
以化合物33-1为原料，参照化合物Int-29或Int-31的合成方法得到化合物Int-33，LCMS[M+H]+429.2。化合物Int-34的合成
步骤1：将化合物34-1(5.0g,28.98mmol)溶解在NMP(100mL)中，依次加入DIPEA(86.92mmol,15.14mL)和1-叔丁基-哌嗪(6.48g,34.77mmol)，130℃加热反应12小时。反应结束后，冷却至室温，加入水和乙酸乙酯进行萃取，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，得到粗品。粗品经柱层析分离纯化(PE：EA＝10:1-3:1)，得化合物34-2(3.3g,收率33.4％)，黄色固体。LCMS[M+H]+323.2。
步骤2：将化合物34-2(2.3g,7.13mmol)溶于无水甲醇(50mL)，氮气保护下，缓慢加入湿钯碳(1.5g,10％Pd)，室温反应2小时。反应结束后，过滤，滤液减压浓缩，得化合物34-3(4g,粗品)，棕色固体。LCMS[M-H]-291.3。
步骤3：将化合物34-3(4g,粗品)溶于无水乙醇(100mL)，加入3-乙氧基-3-亚氨基-丙酸乙酯盐酸盐(3.21g,16.42mmol)，60℃加热反应3小时。反应完成后，冷却至室温，将反应液减压浓缩，得到粗品。粗品经柱层析分离纯化(PE：EA＝10:1-0:1)，得化合物34-4(2.2g,5.66mmol)，黄色固体。LCMS[M+H]+389.2。
步骤4：将化合物34-4(2g,5.15mmol)和3-氨基-2-氰基噻吩(767.11mg,6.18mmol)溶解于无水 四氢呋喃(30mL)，0℃下，滴加二(三甲基硅)氨基锂的四氢呋喃溶液(1M,20.59mL)，滴完45℃加热反应2小时。反应完成后，加入饱和氯化铵溶液(20mL)淬灭，加水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥。过滤，减压浓缩，得到粗品。粗品经柱层析分离纯化(PE：EA＝10:1-1:1)，得化合物34-5(900mg,收率37.5％)，黄色固体。LCMS[M+H]+467.1。
步骤5：将化合物34-5(50mg,107.17μmol)溶于二氯甲烷(5mL)，加入三氟乙酸(13.51mmol,1mL)，室温搅拌2小时。反应结束后，将反应液减压浓缩，得化合物Int-34(50mg,粗品)，棕色固体。LCMS[M+H]+366.9。
化合物Int-35的合成
步骤1：将化合物Int-34(65.56mg,136.45μmol)溶于DMF(5mL)，缓慢加入溴乙酸叔丁酯(109.16μmol,16.13μL)和DIEA(409.34μmol,71.30μL)，0℃下反应3小时。反应结束后，加水(15mL)稀释，乙酸乙酯(3×10mL)萃取，有机相用无水硫酸钠干燥。过滤，减压浓缩，得到粗品化合物35-1(43mg,收率65.6％)，棕色油状物。LCMS[M+H]+481.2。
步骤2：将化合物35-1(43mg,89.47μmol)溶解于盐酸的1,4-二氧六环溶液(3mL)中，室温反应2小时。反应结束后，直接将反应液减压浓缩，得化合物Int-35(180mg,粗品)，棕色固体。LCMS[M+H]+425.2。
化合物Int-36的合成
以化合物36-1为原料，采用与Int-13相同的方法制备。LCMS[M+H]+242.0。
化合物Int-37的合成
以化合物Int-36为原料，采用与Int-14相同的方法制备。LCMS[M+H]+428.2。
化合物Int-38的合成
以化合物38-1和化合物8-2为原料，采用与Int-8相同的方法制备。LCMS[M+H]+420.2。
化合物Int-39的合成
步骤1：氮气保护下，将化合物39-1(378.63mg,1.75mmol)，化合物39-2(400.00mg,1.46mmol)，三苯基膦(1.15g,4.38mmol)溶于四氢呋喃(10mL)溶液中，将混合物降温到0℃，然后缓慢加入偶氮二甲酸二异丙酯(884.85mg,4.38mmol)，将混合物在0℃下搅拌反应5小时。反应结束后，将反应混合物直接减压浓缩得到粗品。粗品经反相柱层析纯化(甲酸体系)，得到化合物39-3(100mg,收率14.5％)，白色固体。LCMS[M+Na]+495.4。
步骤2：氮气保护下，将化合物39-3(100mg,211.63μmol)，三氟乙酸(3.08g,27.01mmol,2.00mL)溶于无水二氯甲烷(10ML)溶液中，将混合物在25℃下搅拌反应10小时。反应结束后，将反应混合物直接减压浓缩，得到化合物Int-39(80mg,收率90.8％)，黄色油状物。LCMS[M+H]+417.2。
实施例1：4-(2-(2-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)-1,2,3,4-四氢异喹啉-6-基)-5H-吡咯并[2,3-b]吡嗪-7-基)-N,N-二甲基苯甲酰胺(EX-1)合成
将化合物Int-3(50mg,139.15μmol)溶于DMF(2mL)中，依次向反应液中加入EDCI(53.35mg,278.29μmol)，DMAP(25.5mg,208.73μmol)和化合物Int-4(66.37mg,166.98μmol)，室温反应2小时。反应完成后，反应混合物经反相制备HPLC纯化，得化合物EX-1(30mg,收率29.0％)，黄色固体。LCMS[M+H]+739.2。
1H NMR(400MHz,DMSO-d6)δ12.42(d,J＝3.0Hz,1H),11.09(s,1H),8.91(s,1H),8.53(d,J＝3.0Hz,1H),8.38(d,J＝8.1Hz,2H),8.04(d,J＝8.2Hz,1H),8.01(s,1H),7.61–7.54(m,1H),7.51(d,J＝8.1Hz,2H),7.36(dd,J＝13.1,8.0Hz,1H),7.18(dd,J＝11.1,8.6Hz,1H),6.99(d,J＝7.0Hz,1H),6.69(brs,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.71(d,J＝12.3Hz,2H),3.80–3.69(m,2H),3.36(s,2H),3.01(s,6H),2.99–2.81(m,3H),2.61–2.45(m,4H),2.06–1.98(m,1H),1.91–1.80(m,2H)。
实施例2：化合物EX-2～EX-16的合成
化合物EX-2～EX-16的合成可采用与实施例1类似的方法和相应的原料。




实施例3：4-(2-(2-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己基)-1,2,3,4-四氢异喹啉-6-基)-5H-吡咯并[2,3-b]吡嗪-7-基)-N,N-二甲基苯甲酰胺(EX-17)的合成
在氮气保护下，将化合物Int-15(70mg,140.95μmol),化合物4-1(38.93mg,140.95μmol)和DIPEA(704.73μmol,122.75μL)溶于二甲亚砜(3mL)，100℃加热反应5小时。反应结束后，冷却至室温，反应混合物经反相制备HPLC纯化(盐酸体系)，得化合物EX-17盐酸盐(4.68mg,收率4.2％)，黄色固体。LCMS[M+H]+753.4。
1H NMR(400MHz,DMSO-d6)δ12.48(d,J＝3.0Hz,1H),11.10(s,1H),10.33(brs,1H),8.95(s,1H),8.55(d,J＝3.0Hz,1H),8.37(d,J＝8.2Hz,2H),8.13(d,J＝8.6Hz,1H),8.11(s,1H),7.60(dd,J＝8.6,7.1Hz,1H),7.51(d,J＝8.1Hz,2H),7.39(d,J＝8.1Hz,1H),7.12(d,J＝8.7Hz,1H),7.04(d,J＝7.0Hz,1H),6.56(t,J＝5.8Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.63(d,J＝15.7Hz,1H),4.36(dd,J＝15.8,8.0Hz,1H),3.83–3.73(m,1H),3.53–3.43(m,2H),3.28–3.15(m,5H),3.01(s,6H),2.94–2.82(m,1H),2.64–2.45(m,2H),2.08–1.98(m,1H),1.88–1.75(m,2H),1.67–1.58(m,2H),1.49–1.31(m,4H)。
实施例4：4-(2-(2-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己基)-1,2,3,4-四氢异喹啉-6-基)-5H-吡咯并[2,3-b]吡嗪-7-基)-N,N-二甲基苯甲酰胺(EX-18)的合成
以化合物Int-3和Int-16为原料，参照EX-17的合成方法制得化合物EX-18，LCMS[M+H]+739.4。
1H NMR(400MHz,DMSO-d6)δ12.51(d,J＝3.0Hz,1H),11.14(brs,1H),11.02(s,1H),8.94(s,1H),8.54(d,J＝3.0Hz,1H),8.38(d,J＝8.3Hz,2H),8.11(dd,J＝8.1,1.8Hz,1H),8.08(s,1H),7.51(d,J＝8.3Hz,2H),7.41–7.32(m,2H),7.07(d,J＝7.5Hz,1H),6.93(d,J＝8.1Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.60(d,J＝15.6Hz,1H),4.40–4.19(m,3H),3.79–3.69(m,1H),3.46–3.28(m,2H),3.27–3.10(m,5H),3.00(s,6H),2.98–2.87(m,1H),2.66–2.58(m,1H),2.37–2.25(m,1H),2.09–1.99(m,1H),1.92–1.79(m,2H),1.72–1.61(m,2H),1.51–1.34(m,4H)。
实施例5：4-(2-(2-(2-((3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙基)氨基)-2-氧代乙基)-1,2,3,4-四氢异喹啉-6-基)-5H-吡咯并[2,3-b]吡嗪-7-基)-N,N-二甲基苯甲酰胺(EX-19)的合成
在氮气保护下，将化合物Int-23(50mg,101.63μmol),Int-24(43.51mg,97.91μmol)，EDCI(96.46mg,503.18μmol)和DMAP(30.74mg,251.59μmol)溶于DMF(2.5mL)，室温反应6小时。反应结束后，反应混合物经反相制备HPLC纯化，得化合物EX-19(10mg,收率11.6％)，黄色固体。LCMS[M+H]+768.7。
1H NMR(400MHz,DMSO-d6)δ12.50(d,J＝3.1Hz,1H),11.10(s,1H),10.73(brs,1H),8.94(s,1H),8.84(t,J＝5.7Hz,1H),8.54(d,J＝3.0Hz,1H),8.37(d,J＝8.4Hz,2H),8.15–8.08(m,2H),7.61(dd,J＝8.6,7.1Hz,1H),7.51(d,J＝8.4Hz,2H),7.40(d,J＝8.1Hz,1H),7.15(d,J＝8.6Hz,1H),7.05(d,J＝7.0Hz,1H),6.68(brs,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.69–4.57(m,1H),4.57–4.44(m,1H),4.14(s,2H),3.76–3.72(m,1H),3.55–3.51(m,1H),3.44–3.13(m,6H),3.00(s,6H),2.96–2.82(m,1H),2.64–2.46(m,2H),2.09–1.99(m,1H),1.78(p,J＝6.6Hz,2H)。
实施例6：化合物EX-20～EX-21的合成
化合物EX-20～EX-21的合成可采用与实施例5类似的方法和相应的原料。

实施例7：N-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙基)-N-甲基-4-(2-(2-甲基-1,2,3,4-四氢异喹啉-6-基)-5H-吡咯并[2,3-b]吡嗪-7-基)苯甲酰胺(EX-22)的合成
将化合物Int-28(50mg,100.31μmol)和Int-27(38.20mg,83.33μmol)加入到DMF(1mL)中，然后加入EDCI(28.84mg,150.47μmol)和DMAP(36.76mg,300.93μmol)，室温反应12小时。反应完成后，将反应混合物用水(5mL)稀释，乙酸乙酯(3×5mL)萃取，合并有机层，无水硫酸钠干燥。过滤，滤液浓缩，得到粗品。粗品经反相制备HPLC纯化(甲酸体系)，得化合物EX-22(11.2mg,收率18.9％)，黄色固体。LCMS[M+H]+711.4。
1H NMR(400MHz,DMSO-d6)δ12.18(brs,1H),10.82(brs,1H),8.85(s,1H),8.37(s,1H),8.30(d,J＝7.9Hz,2H),7.99–7.91(m,2H),7.57(t,J＝7.8Hz,1H),7.45(d,J＝7.9Hz,2H),7.23(d,J＝7.9Hz,1H),7.08(d,J＝8.6Hz,1H),6.97(d,J＝7.1Hz,1H),6.52(brs,1H),4.95(dd,J＝12.3,5.5Hz,1H),3.69(s,2H),3.53(t,J＝7.2Hz,2H),3.37–3.31(m,2H),3.04–2.97(m,5H),2.88–2.75(m,3H),2.60–2.48(m,2H),2.47(s,3H),2.00–1.90(m,3H)。
实施例8：化合物EX-23～EX-027的合成
化合物EX-23～EX-27的合成可采用与实施例7相同的方法和相应的原料。


实施例9：4-((6-(4-(2-(7-氨基-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1H-苯并[d]咪唑-6-)基)哌嗪-1-基)-6-氧代己基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(EX-28)的合成
以化合物Int-6和化合物Int-34为原料，参照EX-1的合成方法制得化合物EX-28,LCMS[M+H]+736.2。
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),11.10(s,1H),7.97(d,J＝5.3Hz,1H),7.62–7.54(m,2H),7.32(brs,1H),7.14–7.07(m,2H),7.02(d,J＝7.0Hz,1H),7.01(d,J＝5.3Hz,1H),6.55(brs,1H),5.05(dd,J＝12.9,5.4Hz,1H),3.68(brs,4H),3.31(t,J＝7.5Hz,2H),3.20(d,J＝18.2Hz,4H),2.96–2.81(m,1H),2.62–2.44(m,2H),2.39(t,J＝7.3Hz,2H),2.07–1.98(m,1H),1.66–1.52(m,4H),1.44–1.33(m,2H)。
实施例10：2-(4-(2-(7-氨基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1H-苯并[d]咪唑-6-基)哌嗪-1-基)-N-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙基)乙酰胺(EX-29)的合成
以化合物Int-35和化合物Int-24为原料，参照EX-1的合成方法制得化合物EX-29,LCMS[M+H]+737.5。1H NMR(500MHz,DMSO-d6)δ12.73(s,0.5H),12.72(s,0.5H),11.79(s,0.5H),11.09(s,0.5H),10.76–10.43(m,0.5H),7.97–7.91(m,2H),7.83(brs,0.5H),7.58(dd,J＝8.2,7.4Hz,1H),7.51(d,J＝8.7Hz,0.5H),7.44(d,J＝8.8Hz,0.5H),7.20(d,J＝2.0Hz,0.5H),7.11–7.07(m,1.5H),7.04–7.00(m,2H),6.92–6.87(m,1H),6.74(t,J＝5.9Hz,1H),5.04(dd,J＝12.7,5.5Hz,1H),3.32(q,J＝6.4Hz,2H),3.21(q,J＝6.4Hz,2H),3.18–3.13(m,4H),2.99(s,2H),2.92–2.83(m,1H),2.64–2.58(m,4H),2.57–2.47(m,2H),2.06–1.98(m,1H),1.72(p,J＝6.5Hz,2H)。
实施例11：4-(2-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)乙氧基)乙氧基)乙酰基)-1,2,3,4-四氢异吲哚啉-6-基)-5H-吡咯并[2,3-b]吡嗪-7-基)-N,N-二甲基苯甲酰胺(EX-30)的合成
以化合物Int-3和化合物Int-38为原料，参照EX-1的合成方法制得化合物EX-30。LCMS[M+H]+799.5。1H NMR(400MHz,DMSO-d6)δ12.40(brs,1H),11.04(brs,1H),8.90(s,1H),8.52(s,1H),8.37(d,J＝8.1Hz,2H),8.06–8.01(m,1H),8.00(s,1H),7.55–7.48(m,3H),7.41–7.29(m,1H),7.19(t,J＝7.0Hz,1H),7.02(s,1H),6.91–6.86(m,1H),5.01(dd,J＝13.0,5.4Hz,1H),4.68(s,2H),4.29(d,J＝4.4Hz,2H),3.76–3.57(m,8H),3.40–3.35(m,2H),3.00(s,6H),2.98–2.79(m,3H),2.59–2.52(m,1H),2.46–2.38(m,1H),2.02–1.91(m,1H)。
实施例12：4-(2-(2-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氧基)辛酰基)-1,2,3,4-四氢异吲哚啉-6-基)-5H-吡咯并[2,3-b]吡嗪-7-基)-N,N-二甲基苯甲酰胺(EX-31)的合成
以化合物Int-3和化合物Int-39为原料，参照EX-1的合成方法制得化合物EX-31。LCMS[M+H]+796.6。1H NMR(400MHz,DMSO-d6)δ12.42(brs,1H),11.11(brs,1H),8.90(d,J＝2.1Hz,1H),8.52(d,J＝4.5Hz,1H),8.37(dd,J＝8.3,3.1Hz,2H),8.07–8.00(m,2H),7.79(dd,J＝13.7,8.3Hz,1H),7.51(d,J＝8.1Hz,2H),7.43–7.27(m,3H),5.11(dd,J＝13.0,5.2Hz,1H),4.73(s,1H),4.67(s,1H),4.20–4.10(m,2H),3.73(t,J＝5.9Hz,2H),3.00(s,6H),2.99–2.96(m,1H),2.94–2.82(m,2H),2.63–2.52(m,2H),2.48–2.38(m,2H),2.08–2.00(m,1H),1.80–1.66(m,2H),1.62–1.50(m,2H),1.48–1.28(m,6H)。
实施例13：4-(2-(2-(8-((2-(2,6--二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)辛酰基)-8-甲氧基-1,2,3,4-四氢异吲哚啉-6-基)-5H-吡咯并[2,3-b]吡嗪-7-基)-N,N-二甲基苯甲酰胺(EX-32)的合成
以化合物Int-37和化合物Int-10为原料，参照EX-1的合成方法制得化合物EX-32。LCMS[M+H]+825.6。
1H NMR(400MHz,DMSO-d6)δ12.43(brs,1H),11.09(brs,1H),8.96(s,1H),8.53(s,1H),8.39(d,J＝8.1Hz,2H),7.73–7.61(m,2H),7.60–7.53(m,1H),7.51(d,J＝8.0Hz,2H),7.11–7.03(m,1H),7.00(t,J＝6.5Hz,1H),6.56–6.45(m,1H),5.04(dd,J＝13.0,5.4Hz,1H),4.55(d,J＝7.2Hz,2H),4.03– 3.93(m,3H),3.75–3.66(m,2H),3.32–3.21(m,2H),3.00(s,6H),2.98–2.79(m,3H),2.62–2.54(m,2H),2.46–2.37(m,2H),2.08–1.97(m,1H),1.64–1.48(m,4H),1.42–1.26(m,6H)。
药理学活性及应用
本发明化合物的活性可以使用以下分析方法来证明。
HPK1 HiBiT蛋白标签检测方法
稳定表达HPK1-HiBiT标记蛋白的人急性T淋巴细胞白血病细胞Jurkat培养在培养皿中，培养基为含10％胎牛血清(FBS,Gibco，产品号10099141)，0.1％青霉素/链霉素溶液(P/S)的RPMI 1640(Gibco，产品号11875093)，置于温度37℃，相对湿度95％，5％CO2的无菌培养箱中培养。取指数生长期的细胞，以20000个细胞/孔的密度接种到96孔板(Corning，产品号3903)中，每孔加入100μL培养基。24小时后，将本文披露的、不同浓度的化合物加入到已接种细胞的孔中(每个化合物设置10个浓度梯度，最高检测浓度为10μM，4倍梯度稀释)，DMSO终浓度为0.1％。24小时后，加入50μLHiBiT萤光素酶检测试剂(Progema，产品号N3040)，使用Envision读取荧光信号。采用GraphPad prisim 8将数据拟合为剂量响应曲线，从而得到测试化合物的IC50值。
表2本发明部分化合物对HPK1-HiBiT信号的IC50值
A:<100nM；B:100-500nM；C:500-5000nM；D:>5000nM
其中，HC90-51(参见WO 2020/227325)为阳性对照化合物，结构式如下所示：
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (12)

  1. 通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，
    HPK1 Ligands——LIN——EL (I)
    其中，HPK1 Ligands为与HPK1结合的配体，如HPK1的抑制剂，表示为通式(II)和通式(II‘)：
    为单键或双键；
    为HPK1 Ligands与LIN的连接点；
    L’连接至X1所在的环，L连接至Z4所在的环，或L’连接Z4所在的环，L连接至X1所在的环，或L’、L同时连接至X1所在的环；
    X1、X2、X3、X4各自独立的选自N或CRX；
    RX相同或不同，且Rx各自独立的为：-(CR’2)S-R#-(CR* 2)t-R1；
    R’相同或不同，R*相同或不同，R’、R*、R1各自独立的为氢、氘、NRaRb、羟基、卤素、氰基、CORd、C(O)NRaRb、NRNC(O)Rd、NRNC(O)NRaRb、C(O)ORd、OC(O)Rd、S(O)1-2Rd、S(O)1-2NRaRb、NRNS(O)1- 2Rd、S(O)1-2ORd、OS(O)1-2Rd、P(＝O)RaRb、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，两个R’或两个R*与其相连的C原子一起形成C3-8环烷基或4-12元杂环基；所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R”所取代；
    R#为化学键、O、S、NRN、C(O)、C(O)NRN、NRNC(O)、C(O)O、OC(O)、S(O)1-2、S(O)1-2NRN、NRNS(O)1-2、S(O)1-2O、OS(O)1-2、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基；所述C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基任选的被1、2、3或4个R”所取代；
    Z1为O、S、N或C原子，其任选的被一或两个RZ1所取代；
    Z2为O、S、N或C原子，其任选的被一或两个RZ2所取代；
    Z3为O、S、N或C原子，其任选的被一或两个RZ3所取代；
    Z4为O、S、N或C原子，其任选的被一或两个RZ4所取代；
    或，Z1不存在，Z2连接至与Z1相连的C原子上；
    RZ1、RZ2、RZ3、RZ4各自独立的为不存在、氢、氘、NRaRb、羟基、卤素、氰基、C(O)NRaRb、CORd、-(C(R4)2)1-6-R4’、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-O-C3-8环烷基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，Z1与两个RZ1一起形成C＝O、C3-8环烷基或4-12元杂环基；或，Z2与两个RZ2一起形成C＝O、C3-8环烷基或4-12元杂环基；或，Z3与两个RZ3一起形成C＝O、C3-8环烷基或4-12元杂环基；或，Z4与两个RZ4一起形成C＝O、C3-8环烷基或4-12元杂环基； 所述C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R”取代；
    R4、R4’各自独立的选自氢、氘、NRaRb、羟基、卤素、C(O)NRaRb、CORd、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；所述C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R”取代；或两个R4与其相连的C原子一起形成C3-8环烷基或4-12元杂环基；
    L、L’各自独立的为化学键或-(CR2 2)p-RL-(CR3 2)q-；
    R2、R3各自独立的选自氢、氘、NRN、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或两个R2或两个R3与相连的C一起形成C3-8环烷基或4-12元杂环基；所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R##取代；
    RL选自O、S、NRN、C(O)、C(O)O、OC(O)、C(O)NRN、NRNC(O)、NRNC(O)NRN、S(O)1-2、S(O)1- 2O、OS(O)1-2、S(O)1-2NRN、NRNS(O)1-2、NRNS(O)1-2NRN、C1-6亚烷基、卤代C1-6亚烷基、C1-6亚烷氧基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基；所述C1-6亚烷基、卤代C1-6亚烷基、C1-6亚烷氧基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基任选的被1、2、3或4个R##所取代；
    Y1为N或C原子，且其任选地被一或两个RY1所取代；
    Y2为N或C原子，且其任选地被一或两个RY2所取代；或，Y2不存在，Y1与Y3连接；
    Y3为N或C原子，且其任选地被一或两个RY3所取代；
    Y4为N或C原子，且其任选地被一或两个RY4所取代；
    Y5为N或C原子，且其任选地被一或两个RY5所取代；
    Y6为N或C原子，且其任选地被一或两个RY6所取代；
    RY1、RY2、RY3、RY4、RY5、RY6各自独立的表示为：-(CRe 2)n1-R#1-(CRf 2)n2-R#2；
    Re相同或不同，Rf相同或不同，Re、Rf、R#2各自独立的为氢、氘、NRaRb、羟基、卤素、氰基、C(O)Rd、C(O)ORd、OC(O)Rd、C(O)NRaRb、NRNC(O)Rd、S(O)1-2Rd、S(O)1-2NRaRb、NRNS(O)1-2Rd、S(O)1-2ORd、OS(O)1-2Rd、P(＝O)RaRb、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，两个Re或两个Rf与其相连的C原子一起形成C3-8环烷基或4-12元杂环基；所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R##所取代；
    R#1为化学键、O、S、NRN、C(O)、C(O)NRN、NRNC(O)、NRNC(O)NRN、C(O)O、OC(O)、S(O)1-2、S(O)1-2NRN、NRNS(O)1-2、NRNS(O)1-2NRN、S(O)1-2O、OS(O)1-2、C1-6亚烷基、C1-6亚烷氧基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基；或，两个RY2与Y2一起形成羰基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，L与Y1、Y2、Y3、Y4之一连接，Y5、Y6与其相连的取代基一起形成C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，Y2不存在，L与Y1、Y3、Y4、Y5、Y6之一连接，剩余的环原子中相邻两环原子与其相连的取代基一起形成C3- 8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；所述C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、C3-8 亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基为未取代的或任选的被1、2、3或4个R##所取代；
    R0选自：C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基；所述C3-8亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基任选的被1、2、3、4或更多个R##所取代；
    V1、V2、V3各自独立的选自N或CRV；V4为N、O、S或C原子，其任选的被1或2个RV所取代；
    环V为C6-10芳基或5-16元杂芳基，且其任选的被1、2、3或4个RV所取代；
    RV相同或不同，RV、RV1、RV1’、RV2、RV2’、RV3、R31、R32各自独立的选自-O-(CR5R5’)m1-RV’、-(CR5R5’)m1-RV’或-NRN-(CR5R5’)m1-RV’；
    RV’、R5、R5’各自独立的选自氢、氘、卤素、NRaRb、羟基、氰基、C(O)NRaRb、-NRNCORd、-NRNCONRaRb、-CORd、-COORd、-OCORd、S(O)1-2Rd、S(O)1-2NRaRb、NRNS(O)1-2Rd、NRNS(O)1-2NRaRb、S(O)1-2ORd、OS(O)1-2Rd、P(＝O)RaRb、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或R5、R5’或R31、R32与其相连的C原子一起形成C3-8环烷基或4-12元杂环基；所述C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3、4或更多个R##所取代；
    LIN表示为-L1-L2-L3-……-Lr-,
    L1、L2、L3……Lr各自独立的选自化学键、O、S、NRN、-(CR6R6’)m2-、C(O)、C(O)NRN、NRNC(O)、NRNC(O)NRN、C(O)O、OC(O)、OC(O)O、S(O)1-2、S(O)1-2O、OS(O)1-2、S(O)1-2NRN、NRNS(O)1-2、NRNS(O)1-2NRN、-OC1-10亚烷基、C2-10亚烯基、C2-10亚炔基、C3-16亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基；所述C1-10亚烷基、C2-10亚烯基、C2-10亚炔基、C3-16亚环烷基、4-12元亚杂环基、C6-10亚芳基或5-16元亚杂芳基任选的被1、2、3、4或更多个R##所取代；
    R6、R6’各自独立的选自氢、氘、NRaRb、卤素、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，R6、R6’与相连的C一起形成C＝O、C3-8环烷基或4-12元亚杂环基；所述C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3、4或更多个R##所取代；
    s、t、p、q、n1、n2、m1、m2、u各自独立的为0、1、2、3、4、5、6、7或8；
    t1、t2各自独立的为0、1或2；
    r为4-20的正整数；
    EL表示为通式(III)：
    其中，G1、G2、G3、G4各自独立的为N或CRg；G1、G2、G3、G4不同时为N；
    Rg相同或不同且各自独立的选自：氢、氘、NRaRb、羟基、卤素、氰基、C(O)NRaRb、C1-6烷基、卤代 C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；所述C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R00取代；
    K1选自O、S、C或N，其任选的被一个或两个RK1所取代；K2选自O、S、C或N，其任选的被一个或两个RK2所取代；K3选自O、S、C或N，其任选的被一个或两个RK3所取代；或K1、K2不存在，K4与K3连接，与K1相连的芳环上的C原子与RK连接；或，K1、K2、K3均不存在，K4连接至与K1或K3相连的芳环的C原子之一，芳环上的另一C原子与RK连接；
    K4为N或CRK4；
    RK1、RK2、RK3各自独立的为不存在、氢、氘、NRaRb、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1- 6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；
    或者，K1与两个RK1一起形成C＝O、C3-8环烷基或4-12元杂环基；或者，K2与两个RK2一起形成C＝O、C3-8环烷基或4-12元杂环基；或者，K3与两个RK3一起形成C＝O、C3-8环烷基或4-12元杂环基；
    RK、RK4、R7、R7’、R8、R8’各自独立的选自氢、氘、卤素、氰基、NRaRb、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或羟代C1-6烷基；
    Ra、Rb、Rd、RN各自独立的选自氢、氘、卤素、＝NH、NRe1Rf1、羟基、羟氨基、-C1-6亚烷基NRe1Rf1、CONRe1Rf1、乙酰基、C1-6烷基、卤代C1-6烷基、羟代C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，Ra、Rb与相连的N原子共同形成4-12元杂环基；所述C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个R00取代；
    R00、R”、R##各自独立的选自氢、氘、＝O、卤素、羟基、羟氨基、＝NH、NRe1Rf1、CONRe1Rf1、COR01、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、-(CR** 2)1-6-R01、-O-(CR** 2)1-6-R01、-S-R01、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；
    Re1、Rf1、R**、R01各自独立的选自氢、氘、氨基、＝NH、羟基、羟氨基、乙酰基、酰胺基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基；或，Re1、Rf1与相连的N原子共同形成4-12元杂环基；或两个R**与其相连的C原子一起形成C3-6环烷基或4-12元杂环基；所述C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、4-12元杂环基、C6-10芳基或5-14元杂芳基任选的被1、2、3或4个选自氢、氘、氨基、＝NH、羟基、羟氨基、乙酰基、酰胺基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1- 6烷基、C2-6烯基或C2-6炔基的取代基所取代；
    条件是，
    (1)式(II)中，当Z1不存在时：
    a)Z2、Z3、Z4为C或N，且Z3与Z2不同时为N，或Z3与Z4不同时为N,
    且当为时，X1、X2、X3、X4中至少两者为N；
    且当为时，L与R0中或L与L’中至少一者不为亚苯基或取代的亚苯基；或b) Z2或Z4为C＝O；
    c)当Z2、Z3、Z4中一者为S时，L、L’不同时与X1所在的环连接；
    (2)式(II’)中，L’不为
    (3)式(II)中，当Z1、Z2、Z3、Z4均存在时，L’与X1所在芳环的C原子连接，且L不为化学键。
  2. 如权利要求1所述通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，
    进一步选自：
    其中，Ra’、Rb’各自独立的选自氢、氘、甲基、乙基、丙基、异丙基(优选氢)。
  3. 如权利要求1所述通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，进一步选自：
    Y7为N或＝CRY；Y9为N或＝CRY；Y8为O或S；
    RY1、RY2、RY3、RY4、RY各自独立的选自：氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、NRaRb、CONRaRb、C3-8环烷基、-O-(CH2)0-4-C3-8环烷基、4-7元杂环基、苯基或5-14元杂芳基。
  4. 如权利要求1所述通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，R0表示为：
    为R0与L’的连接点，为R0与LIN的连接点；
    Z5、Z6、Z7各自独立的选自N或CRZ’；
    Z8、Z9、Z10各自独立的为C、N、O或S原子，且Z8、Z9、Z10任选的被1或2个RZ’所取代；或Z8、Z9与其相连的取代基一起形成4-7元环烷基或5-7元杂环基，而LIN与Z8、Z9形成的环连接；优选的，Z8、Z9、Z10各自独立的为NRN、O或CH2；
    RZ’相同或不同，RZ’各自独立的选自氢、氘、氟、氯、溴、氨基、乙酰基、羟基、氰基、-NRaRb、-CONRaRb、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、C3-6环烷基、-O-C3-6环烷基、4-7元杂环基、苯或5-14元杂芳基；
    或，两个RZ’与其相连的C原子一起形成C＝O；
    优选的，RZ’选自：C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基；优选RZ’为氢、卤素、氰基、氨基或酰胺基；
    优选的，RZ’选自：氢、氘、甲基、乙基、丙基、异丙基、正丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、二氟甲基、三氟乙基、羟代甲基、羟代乙基、环丙基、环丁基、
  5. 如权利要求1所述通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，HPK1 Ligands进一步表示为：
    Z11、Z12各自独立的表示为N或CRZ’，Q1、Q2、Q3各自独立的表示为N或CRQ；
    RZ’、RQ各自独立的选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟代C1-6烷基、NRaRb、CONRaRb、C3-6环烷基、-O-(CH2)0-4-C3-6环烷基或4或5元杂环基；
    RZ”选自C1-6亚烷基、C1-6亚烷氧基、O、S、NRN、CONRN、SO1-2NRN、CO或C3-6亚环烷基；
    通式(II-f)中，L与Y1所在的环连接，或与Y7所在的环连接。
  6. 如权利要求1所述的通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，EL进一步表示为：
    RN、R7、R7’、R8、R8’、RK各自独立的选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基(优选氢、甲基或乙基)；
    K4为CH或N，K3为NRK3、CH2或CO；
    RK3选自氢、氘、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基(优选氢、甲基或乙基)；
    Rg选自氢、氘、卤素、氰基、氨基、酰胺基、二甲氨基、二甲酰胺基、C1-6烷基、C1-6烷氧基、卤代C1- 6烷基或羟代C1-6烷基；Rg优选氢、C1-6烷基和卤代C1-6烷基，进一步优选氢、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、三氟甲基、三氟乙基或氰基。
  7. 权利要求1所述的通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其进一步表示为：



  8. 如权利要求1所述通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、 外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，
    LIN表示为：-L1-L2-L3-L4-L5-L6-L7-,L7与EL连接；
    L1选自：化学键、O、S、NRN、CH2、C(CH3)2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、OCH2CH2、CH2CH2O、CO、CONRN、NRNCO、NRNCONRN、SO1-2、SO1-2NRN、NRNSO1-2、NRNSO1-2NRN、亚乙烯基、亚乙炔基、亚苯基、亚吡啶基、亚嘧啶基、亚吡嗪基、亚哒嗪基、亚哌嗪基、亚哌啶基、亚三氮唑基、亚四氮唑基、亚吡唑基、亚咪唑基、C3-6亚环烷基、4-12元亚杂环基、
    L2各自独立的选自：化学键、O、S、NRN、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、C(CH3)2、CO、CONRN、NRNCO、OCH2CH2、CH2CH2O、亚乙烯基、亚乙炔基、亚苯基、亚吡啶基、亚嘧啶基、亚哌嗪基、亚三氮唑基、亚四氮唑基、亚吡唑基、亚咪唑基、C3-6亚环烷基或4-12元亚杂环基；
    L3、L4各自独立的选自：化学键、O、S、NRN、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CO、CONRN、NRNCO、OCH2CH2、CH2CH2O、亚乙烯基、亚乙炔基、亚苯基、亚吡啶基、亚嘧啶基、亚哌嗪基、亚三氮唑基、亚四氮唑基、亚吡唑基、亚咪唑基；
    L5、L6各自独立的选自：化学键、O、S、NRN、CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CO、CONRN、NRNCO、OCH2CH2、CH2CH2O、亚乙烯基、亚乙炔基、亚苯基、亚吡啶基、亚嘧啶基、亚哌嗪基、亚三氮唑基、亚四氮唑基、亚吡唑基、亚咪唑基；
    L7选自：O、S、NH、N(甲基)、CH2、亚乙烯基、亚乙炔基、CONRN、NRNCO、NRNCONRN、SO1- 2、SO1-2NRN、NRNSO1-2或NRNSO1-2NRN；
    RN选自氢或甲基；上述任一亚甲基的氢任选的被1或2个R##所取代；
    所述C3-6亚环烷基、4-12元亚杂环基任选的被1或2个选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或羟代C1-6烷基的取代基所取代。
  9. 如权利要求1所述通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其选自表1。
  10. 药物组合物，其含有权利要求1-9中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及他们的混合物，和药学上可接受的赋形剂；优选地，其还含有其它治疗剂。
  11. 权利要求1-9中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及他们的混合物在制备用于治疗和/或预防癌症的药物中的用途。
  12. 权利要求11的用途，其中所述癌症选自膀胱癌,乳腺癌,结直肠癌,胃癌,头颈鳞状细胞癌,霍奇金淋巴瘤,梅尔克尔-细胞癌,间皮瘤,黑素瘤,非小细胞肺癌,卵巢癌,子宫癌,食道癌,肝癌,胰腺癌,前列腺癌,肾细胞癌,甲状腺癌,小细胞肺癌,过渡性细胞癌,尿路上皮癌,对靶向药物耐药的肿瘤；或依赖HPK1突变蛋白的肿瘤或疾病。
PCT/CN2023/074831 2022-02-08 2023-02-07 杂环化合物、包含其的药物组合物及其抗肿瘤应用 WO2023151559A1 (zh)

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