WO2024183778A1 - Inhibiteur de méthionine adénosyltransférase 2a et son utilisation médicale - Google Patents

Inhibiteur de méthionine adénosyltransférase 2a et son utilisation médicale Download PDF

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WO2024183778A1
WO2024183778A1 PCT/CN2024/080417 CN2024080417W WO2024183778A1 WO 2024183778 A1 WO2024183778 A1 WO 2024183778A1 CN 2024080417 W CN2024080417 W CN 2024080417W WO 2024183778 A1 WO2024183778 A1 WO 2024183778A1
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alkyl
independently selected
membered
cycloalkyl
haloalkyl
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吴景卫
尹磊
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甘李药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention belongs to the technical field of drug synthesis, and relates to a methionine adenosyltransferase 2A inhibitor, a drug composition containing the inhibitor and pharmaceutical use thereof, in particular to the application of the inhibitor in the preparation of anti-tumor drugs.
  • Methionine adenosyltransferase also known as S-adenosylmethionine synthetase
  • SAM S-adenosylmethionine
  • ATP ATP-adenosylmethionine
  • SAM S-adenosylmethionine
  • ATP ATP-adenosylmethionine
  • SAM is the main methyl donor for the synthesis of polyamines and glutathione. Therefore, regulating the biosynthesis of SAM can affect cell growth, differentiation and function. Studies have shown that the proliferation and metastasis of tumor cells are abnormally dependent on methionine, and inhibiting the methionine cycle can significantly inhibit the proliferation and metastasis of stem cells.
  • MAT1 In mammalian tissues, the MAT gene mainly exists in two different isoenzymes, encoded by MAT1 and MAT2.
  • MAT1 is only expressed in the liver and is used to maintain the differentiation state of hepatocytes and bile duct epithelial cells;
  • MAT2 is commonly expressed in normal cells and cancer cells.
  • MAT2 contains two subunits, MAT2A and MAT2B, which serve as catalytic subunits and regulatory subunits, respectively.
  • MAT2A is a key enzyme in the SAM synthesis pathway. Studies have shown that upregulated expression of MAT2A exists in a variety of cancer cells, and knocking out the MAT2A gene can lead to the death of cancer cells. Therefore, MAT2A is an anti-tumor target.
  • MAT2A is a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deficient cancers.
  • MTAP methylthioadenosine phosphorylase
  • MTA methylthioadenosine phosphorylase
  • MTA 5-methylthioadenosine-1-phosphate
  • MTAP deletion is not only present in tissue culture cells, but also in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma and mesothelioma.
  • NSCLC non-small cell lung cancer
  • MTAP is a key enzyme in the methionine recycling pathway and is the only enzyme known to catalyze the degradation of MTA. The loss of MTAP is believed to lead to the accumulation of MTA in cancer cells.
  • MTA inhibits the activity of protein arginine methyltransferase 5 and increases the sensitivity of PRMT5 to further loss of SAM.
  • selective inhibition of MAT2A can reduce the proliferation activity of MTAP-deficient cancer cells.
  • the present invention provides a methionine adenosyltransferase 2A (MAT2A) inhibitor and a pharmaceutically acceptable salt thereof. Also disclosed herein are pharmaceutical compositions comprising such compounds and methods for treating diseases that can be treated by inhibiting MAT2A, such as cancer, including cancers characterized by reduced or inactive methylthioadenosine phosphorylase (MTAP) activity.
  • MAT2A methionine adenosyltransferase 2A
  • MTAP methylthioadenosine phosphorylase
  • a compound is provided, wherein the compound is a compound represented by formula (I-1), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
  • a 1 and B 1 are independently selected from the group consisting of formula (II), (III), (IV), (V), (VI), (VII) and (VIII):
  • R 1 is absent at each occurrence or is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, -SC 1-6 alkyl, -S(O)-C 1-6 alkyl, -S(O 2 )-C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, C 1-6 deuterated alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and -NR 1a R 1b , wherein R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 1-6 containing 1-3 heteroatoms independently selected from N, O, P and S R 1a and R 1
  • Each occurrence of Z is independently selected from C and N; when Z is selected from N, R 1 is absent;
  • R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkylamino, hydroxy, C 2-6 alkoxy, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
  • G1 and G2 are each independently selected from O, S, and NR2a ;
  • E0 , E1 , E2 , E3, E4 , E5 , E6 , E7 , E8 , E9 , M1 , M2 , M3 , M4 , M5 , M6 and E are each independently selected from N and CR2a , and E7 , E8 , and E9 are not CR2a at the same time;
  • R2a at each occurrence is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH2OCH2CH2Si ( CH3 ) 3 , C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-S-, -S(O) -C1-6 alkyl, -SO2 - C1-6 alkyl, -OC1-6 alkyl, -OC1-6 haloalkyl, -NR2bR2c , -C(O)R8c, -C(O)NR8aR8b, -C1-6 alkylene -C3-6 cycloalkyl, C3-6 cycloalkyl-NR2b-, 3-6 membered heterocycloalkyl-NR2b containing 1-3 heteroatoms independently selected from N , O , P and S -, 3-12 membered monocycloalkyl, 5-12 membered
  • R 2b and R 2c are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 2b and R 2c and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl containing 1, 2 , 3 or 4 heteroatoms independently selected from N, O, P and S , wherein the heterocycloalkyl is optionally substituted with 0,
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 8a and R 8b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted with 0, 1, 2
  • R 8c is independently selected at each occurrence from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 5-10 heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloal
  • X2 is selected from C1-6 alkylene and C2-6 alkenylene
  • R 8d is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl
  • J 1 and J 2 are independently selected from a single bond, O, S, C(O), S(O), S(O 2 ), C(R 1c R 1d ), C( ⁇ CR 1e R 1f ) and N(R 3 ), preferably, J 1 and J 2 are not single bonds at the same time;
  • R 1c , R 1d , R 1e and R 1f are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl, and C 5-10 heteroaryl are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic,
  • Linker C is the linker connecting A1 and B1, which is -L a -L b -L c -L d -L e -;
  • L a , L c , and L e at each occurrence are each independently selected from -(L) n -;
  • n is selected from 1, 2, 3, 4, 5 and 6;
  • L is independently selected at each occurrence from a single bond, -O-, -S-, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 haloalkylene, -N(R L6 )C(O)-, -N(R L6 )S(O)-, -N(R L6 )S(O 2 )-, -C(O)-, -OC(O)-, -NR L6 -, -S(O)-, -S(O 2 )-, -S(O 2 )NR L6 -, -CR L1 R L2 -, and C 1-6 alkylenehydroxyl, optionally wherein the C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, and C 1-6 haloalkylene
  • the 1-6 haloalkylene groups are each independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from
  • R L6 is independently selected at each occurrence from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl
  • the 5-10 heteroaryl group is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered
  • R L1 and R L2 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -XL - OR L3 , -XL - NR L4LR L5 , C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, preferably R L1 and R L2 are each independently selected from hydrogen , deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -XL - OR L3 , -XL- NR L4LR L5 and C 3-10 cycloalkyl; or R L1 and R L2 and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered
  • XL at each occurrence is independently selected from C1-6 alkylene and C2 - C6 alkenylene;
  • RL3 is selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl
  • RL4 and RL5 are independently selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
  • L b , and L d are each independently selected from a single bond, a cycloalkylene group, a cycloalkenylene group, a heterocycloalkylene group, an arylene group, a heteroarylene group, and a fused heterocycloalkylene group, wherein the cycloalkylene group, the cycloalkenylene group, the heterocycloalkylene group, the arylene group, the heteroarylene group, and the fused heterocycloalkylene group may be optionally substituted with 0, 1, 2, 3, 4, 5 or 6 R 9 ; preferably, L b , L d d is independently selected from a single bond, phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 member
  • R 9 is independently selected from halogen, deuterium, alkyl, haloalkyl, cyano, cycloalkyl, heterocycloalkyl, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 is independently selected from halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, C 3 - 7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 is independently selected from F, Cl, Br, I, C 1-6 C 1-3 alkyl, and
  • R 9a , R 9b and R 9c are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl; preferably, R 9a , R 9b and R 9c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene
  • L b and L d are each independently a phenylene group, or a 5-membered heteroarylene group containing 1 or 2 heteroatoms selected from N and S, at least one of La and Le is not a single bond, or when La and Le are both single bonds, L c is selected from -S-, C 2-6 alkylene, C 2-6 alkyleneoxy, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 haloalkylene, -N(R L6 )S(O)-, -N(R L6 )S(O 2 )-, -OC(O)-, -S(O)-, -S(O 2 )-, -S(O 2 )NR L6 -, - and C 1-6 alkylenehydroxyl, optionally, the C 2-6 alkylene, C 2-6 alkyleneoxy, C 2-6 alkenylene, C 2-6 alkynylene, and C 1-6 haloalkylene 1-6 hal
  • Linker C is an aliphatic chain
  • Linker C is optionally substituted -C 8 H 16 -, preferably optionally substituted -(CH 2 ) 8 -, preferably -(CH 2 ) 8 -;
  • L b and L d are not simultaneously single bonds;
  • Linker C is selected from Formula (IX), (X), (XI) and (XII):
  • R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl;
  • X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence;
  • R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are connected form a 3-10 membered cycloalkyl;
  • R 7a and R 7b are each independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -XL - OR L3 , -XL - NR L4LR L5 , C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, preferably R L1 and R L2 are each independently selected from hydrogen , deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -XL - OR L3 , -XL- NR L4LR L5 and C 3-10 cycloalkyl; or R 7a and R R 7a and R 7b and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a
  • XL at each occurrence is independently selected from C1-6 alkylene and C2 - C6 alkenylene;
  • RL3 is selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl
  • RL4 and RL5 are independently selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
  • W is selected from the following groups:
  • Q ring and R ring are each independently selected at each occurrence from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene, said phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene optionally substituted with 0-6 R 9 ;
  • R 9a , R 9b and R 9c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene
  • T ring and U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene at each occurrence, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 0, 1, 2 or 3 substituents independently selected from cyano, halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, C 3-6 heterocycloalkyl, and C 3-6 cycloalkyl, preferably, optionally substituted with substituents selected from F, Cl, Br, I, C 1-3 alkyl, and C 1-3 haloalkyl;
  • L1 is selected from the following groups:
  • L2 is selected from the following groups:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are each independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C—, and a single bond;
  • L3 is selected from the following groups:
  • Y 8 , Y 9 , Y 10 , Y 11 and Y 12 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CR Y1 RY2 -, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C-, a single bond, phenylene, a 3-6 membered heterocycloalkylene group containing 1-4 heteroatoms independently selected from N, O, P and S, and a 5-6 membered heteroarylene group containing 1-4 heteroatoms independently selected from N, O, P and S;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1-6 alkyl at each occurrence, or R Y1 and R Y2 form a 3-6 membered cycloalkylene or 3-6 membered heterocycloalkylene to the C to which they are attached; and f, g, h, i and j are independently selected from 0, 1, 2 and 3. 3.
  • R 1 is absent at each occurrence or is independently selected from hydrogen, deuterium, F, Cl, Br, I, cyano, hydroxyl, amide, sulfonamide, C 1-3 alkyl, -SC 1-3 alkyl, -S(O)-C 1-3 alkyl, -S(O 2 )-C 1-3 alkyl, -OC 1-3 alkyl, -OC 1-3 haloalkyl, C 1-3 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and -NR 1a R 1b , wherein R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 deuterated alkyl
  • the present invention relates to a C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C3-6 monocyclic cycloalkyl, C3-6 mono
  • Z is independently selected from C and N at each occurrence; and when Z is N, R 1 is absent; and/or
  • R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 2-3 alkoxy, C 1-3 haloalkyl, 3-6 membered monocyclic cycloalkyl, 3-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, and 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, chlorine, fluorine, Br, C 1-3 alkyl, 3-6 membered monocyclic cycloalkyl, and 3-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S; and/or
  • R 5 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl and C 1-4 haloalkyl; optionally, the C 1-4 alkyl, C 3-6 cycloalkyl and C 1-4 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-4 alkyl, amino, hydroxyl and C 1-4 alkoxy; preferably, R 5 is selected from hydrogen, C 1-3 alkyl and C 3-6 cycloalkyl, optionally, the C 1-3 alkyl and C 3-6 cycloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-6 alkyl, amino and hydroxyl; more preferably, R 5 is selected from H and C 1-3 alkyl; and/or
  • G1 and G2 are each selected from O, S, and NR2a ; and/or
  • R 2a at each occurrence is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, -S(O)-C 1-3 alkyl, -SO 2 -C 1-3 alkyl, -OC 1-3 alkyl, -OC 1-3 haloalkyl, -NR 2b R 2c , -C 1-3 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl-NR 2b -, 3-6 membered heterocycloalkyl-NR 2b containing 1-3 heteroatoms independently selected from N, O, P and S -, 3-6 membered monocyclic alkyl, 3-6 membered monocyclic heterocyclic alkyl containing 1-3 heteroatoms independently selected
  • R 3 is -X 1 -R 8 , X 1 is selected from a single bond, -O-, -S-, C 1-3 alkyleneoxy, C 2-3 alkenylene and C 1-3 alkylene;
  • R 8 is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b , C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, and 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S.
  • each occurrence of the Q ring, the R ring, L b and L d is independently selected from the following groups:
  • the compound is selected from the following structures:
  • the compound is selected from the following structures:
  • Linker C is selected from the following structures:
  • a compound, wherein the compound is a compound represented by formula (I), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
  • ring A and ring B are independently selected from formula (II), (III) and (IV):
  • Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI) and (VII):
  • R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl and alkoxy; or R 1a and R R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10
  • R2 , R4 and R6 are independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 monoalkylamino, C2-6 dialkylamino, C1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1-6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
  • E, G, J and Z are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, C 1-6 alkyl-O-, C 1-6 haloalkyl-O-, -NR 2b R 2c , C 3-6 -membered cycloalkylamino, 3-6-membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12-membered monocyclic alkyl, 5-12-membered spirocycloalkyl and 4-12-membered bridged cycloalkyl, 3-12-membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently
  • R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl;
  • X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence;
  • R 7c is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 7d and R 7e are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are connected form a 3-10 membered cycloalkyl;
  • the R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c , -X 5 -NR 10b R 10c , -OR 10a and -X 5 -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 5 is selected from C 5 C 1-6 alkylene and C 2-6 alkeny
  • L1 is selected from the following groups:
  • L2 is selected from the following groups:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 -, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C—, and a single bond, wherein the hydrogen atom is optionally substituted with 0-2 substituents independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl;
  • R 11 are independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
  • R 1a and R 1b are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
  • R2 , R4 and R6 are independently selected from halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 monoalkylamino, C1-3 dialkylamino, C1-3 haloalkylamino, cycloalkyl containing 3-12 membered monocyclic ring, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1 - C6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5
  • R5 is selected from hydrogen, C1-3 alkyl and C1-3 haloalkyl
  • E, G, J and Z are independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, C 1 -C 3 alkyl-SO-, C 1-3 alkyl-SO 2 -, C 1-3 alkyl-O-, C 1-3 haloalkyl-O-, -NR 2b R 2c , C 3-6 membered cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membere
  • R3 is -X1 - R8 , X1 is selected from a chemical bond, C2 - C4 alkenylene and C1 - C4 alkylene;
  • R8 is selected from hydrogen, halogen, C1 - C3 alkyl, C1 - C3 haloalkyl, C6 - C10 aryl, -NR8aR8b , -C(O) R8c , -C(O) NR8aR8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S;
  • R8a and R8b are independently selected from hydrogen, deuterium, C1 - C3 alkyl, C1 - C3 haloalkyl and phenyl at each occurrence , the phenyl being optionally substituted with 0-2 groups selected from C1-4 alkyl, -OR8d and -X2 - R8d ;
  • R8c
  • R 1c and R 1d are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
  • R 7a and R 7b are each independently selected from hydrogen, halogen, C 1-4 alkyl and C 1-4 haloalkyl; or
  • the Q ring is optionally substituted with 1-2 R 9 , each of which is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, each of which is independently selected from N, O and S, -S(O 2 )R 9a , NR 9b R 9c and -OR 9a ; each of R 9a , R 9b and R 9c is independently selected from hydrogen, C 1-3 alkyl and C 1-3 haloalkyl at each occurrence; or
  • the R ring is a 5-6 membered heterocycloalkylene or 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c and -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl at each occurrence; or
  • the T ring and the U ring are independently selected from phenylene and pyridinylene, respectively, wherein the phenylene and pyridinylene are optionally substituted by 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C1-6 alkyl and C3-6 cycloalkyl.
  • R2 is selected from hydrogen, fluorine, chlorine, cyclopropyl, C1-3 alkyl and C1-3 haloalkyl; or
  • R3 is hydrogen
  • R 4 is selected from hydrogen, fluorine, chlorine, bromine and cyclopropyl
  • R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl
  • R5 is selected from hydrogen and methyl
  • R 1c and R 1d are independently selected from hydrogen and C 1 -C 3 alkyl; preferably, R 1c and R 1d are independently selected from hydrogen and methyl; or
  • the Q ring is selected from the following groups:
  • the R ring is selected from the following groups:
  • each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.
  • the Q ring, R ring, T ring, U ring, W ring, R 1a , R 1b , R 1c , R 1d , R 7a , R 7b , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in claim 1 , 2 or 3.
  • Ring A and Ring B are each independently selected from Formula (II-1), (IV-1) and (III-1):
  • R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 4 , R 5 and R 6 have the same definitions as in claim 1 , 2 or 3.
  • Qa ring is consistent with the definition of Q ring in claim 1, 2 or 3;
  • Ra ring is consistent with the definition of R ring in claim 1, 2 or 3;
  • R1a , R1b , R1c , R1d , R7a , R7b , E, G, J, Z, L2 , R2 and R6 are defined the same as in claim 1, 2 or 3.
  • ring A and ring B are the same or different, and ring A and ring B are independently selected from formula (II), (III) and (IV):
  • Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI), (VI-2) and (VII):
  • R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyalkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl and alkoxy; or R
  • R 2 , R 4 and R 6 are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkylamino , 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
  • E, G, J and Z are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, --NHCO-C 1-6 alkyl, -COHN 2 , -C 1-6 alkyl-COHN 2 , sulfonamido, -NHCONH 2 , -NH-CS-NH 2 , amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, C 1-6 alkyl-O-, C 1-6 haloalkyl-O-, -NR 2b R 2c , C 1-6 alkylamino, C 2-6 dialkylamino, -CONH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 3-6 cycloalkylamin
  • R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, -O-, -S-, alkoxy, C 2-6 alkenylene and C 1-6 alkylene;
  • R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S;
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, and the phenyl is optionally substituted with 0-2 groups selected from C 1-4 alkyl, halogen, hydroxy, cyano, amino, -OR 8d and -X 2 -R 8d ;
  • R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl;
  • X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence;
  • R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are attached form a 3-10 membered cycloalkyl;
  • W is selected from the following groups:
  • the Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted by 0-2 R 9 , R 9 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; R 9a , R 9b and R 9c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
  • the R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c , -X 5 -NR 10b R 10c , -OR 10a and -X 5 -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 5 is selected from C 5 C 1-6 alkylene and C 2-6 alkeny
  • the T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
  • L1 is selected from the following groups:
  • L2 is selected from the following groups:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C—, and a single bond, wherein the hydrogen atoms in said L 2 are each independently substituted with any substituent selected from deuterium, halogen, amino, alkylamino, aminoalkyl, —CONH 2 , —NHCO—C 1-6 alkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl;
  • a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
  • R11 are independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R11a, NR11bR11c, -X6- NR11bR11c , -OR11a and -X6-OR11a;
  • R11a, R11b and R11c are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R11a, NR11bR11c , -X6 - NR11bR11c , -OR11a and -X6 - OR11a ;
  • R 1a and R 1b are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
  • R2 , R4 and R6 are independently selected from halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, -NHC1-3 alkyl, -N( C1-3 alkyl) C1-3 alkyl, C1-3 haloalkylamino, cycloalkyl containing 3-12 membered monocyclic ring, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1 - C6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered
  • R5 is selected from hydrogen, C1-3 alkyl and C1-3 haloalkyl
  • E, G, J and Z are independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -NHCO-C 1-6 alkyl, -CONH 2 , -C 1-6 alkyl-CONH 2 , sulfonamido, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, C 1 -C 3 alkyl-SO-, C 1-3 alkyl-SO 2 -, C 1-3 alkyl-O-, C 1-3 haloalkyl-O-, -NR 2b R 2c , C 3-6 membered cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 hetero
  • R3 is -X1 - R8 , X1 is selected from a chemical bond, C2 - C4 alkenylene and C1 - C4 alkylene;
  • R8 is selected from hydrogen, halogen, C1 - C3 alkyl, C1 - C3 haloalkyl, C6 - C10 aryl, -NR8aR8b , -C(O) R8c , -C(O) NR8aR8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S;
  • R8a and R8b are independently selected from hydrogen, deuterium, C1 - C3 alkyl, C1 - C3 haloalkyl and phenyl at each occurrence , the phenyl being optionally substituted with 0-2 groups selected from C1-4 alkyl, -OR8d and -X2 - R8d ;
  • R8c
  • R 1c and R 1d are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
  • R 7a and R 7b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl and C 1-4 haloalkyl; or
  • the Q ring is optionally substituted with 1-2 R 9 , each of which is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, each of which is independently selected from N, O and S, -S(O 2 )R 9a , NR 9b R 9c and -OR 9a ; each of R 9a , R 9b and R 9c is independently selected from hydrogen, deuterium, C 1-3 alkyl and C 1-3 haloalkyl at each occurrence; or
  • the R ring is a 5-6 membered heterocycloalkylene or 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R10 , each occurrence of which is independently selected from halogen, C 1 -C 3 alkyl, hydroxy, amino, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c and -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, deuterium, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl at each occurrence; or
  • the T ring and the U ring are independently selected from a 5-6 membered heterocyclylene group containing 1, 2, or 3 N, O, or S atoms, a phenylene group, and a pyridylene group, wherein the phenylene group and the pyridylene group are optionally substituted by 1 to 3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, cyano, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl.
  • R3 is hydrogen
  • R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl
  • R5 is selected from hydrogen and methyl
  • R 1c and R 1d are independently selected from hydrogen and C 1 -C 3 alkyl; preferably, R 1c and R 1d are independently selected from hydrogen and methyl; or
  • the Q ring is selected from the following groups:
  • connection site on the left side of each Q ring group is independently connected to -CR 7a R 7b - in formula (V), and the connection site on the right side of each Q ring group is independently connected to the R ring in formula (V); or
  • the R ring is selected from the following groups:
  • each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.
  • Q ring, R ring, T ring, U ring, L 1 , L 2 , W, R 1a , R 1b , R 1c , R 1d , R 7a , R 7b , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in claim 2 , 3 or 4.
  • R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 4 , R 5 and R 6 have the same definitions as in claim 1 or 2 or 3 or 4;
  • the A ring and the B ring are identical.
  • Qa ring is consistent with the definition of Q ring in claim 2, 3 or 4;
  • Ra ring is consistent with the definition of R ring in claim 2, 3 or 4;
  • R1a , R1b , R1c , R1d , R7a , R7b , E, G, J, Z, L2 , R2 and R6 are defined the same as in claim 1, 2, 3 or 4.
  • the compound is a compound represented by formula (I), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
  • ring A and ring B are independently selected from formula (II), (III) and (IV):
  • Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI) and (VII):
  • R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl and alkoxy; or R 1a and R R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10
  • R2 , R4 and R6 are independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 monoalkylamino, C2-6 dialkylamino, C1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1-6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
  • E, G, J and Z are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, C 1-6 alkyl-O-, C 1-6 haloalkyl-O-, -NR 2b R 2c , C 3-6 -membered cycloalkylamino, 3-6-membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12-membered monocyclic alkyl, 5-12-membered spirocycloalkyl and 4-12-membered bridged cycloalkyl, 3-12-membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently
  • R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, C 2-6 alkenylene and C 1-6 alkylene;
  • R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S;
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, the phenyl being optionally substituted with 0-2 groups selected from C 1-4 alkyl, -OR 8d and -X 2 -R 8d ;
  • R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 amino
  • R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl;
  • X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence;
  • R 7c is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 7d and R 7e are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are connected form a 3-10 membered cycloalkyl;
  • the W ring is selected from the following groups:
  • the Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted by 0-2 R 9 , R 9 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; R 9a , R 9b and R 9c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
  • the R ring is a 5-6 membered heterocycloalkylene or 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , each occurrence of which is independently R 10a , R 10b and R 10c are each independently selected from the group consisting of hydrogen , C 1-6 alkyl and C 1-6 haloalkyl ; X 5 is selected from the group consisting of C 1-6 alkylene and C 2-6 alkenylene ;
  • the T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
  • L1 is selected from the following groups:
  • L2 is selected from the following groups:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 -, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C—, and a single bond, wherein the hydrogen atom is optionally substituted with 0-2 substituents independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl;
  • a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
  • R 11 are independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
  • Ring A and Ring B are independently selected from Formula (II), (III), (IV), (V), (VI), (VII) and (VIII):
  • Linker C is a linker connecting Ring A and Ring B, selected from Formula (IX), (X), (XI) and (XII):
  • R 1 is selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, C 1-6 haloalkyl, -SC 1-6 alkyl, -S(O)-C 1-6 alkyl, -S(O 2 )-C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, C 1-6 deuterated alkyl and -NR 1a R 1b , wherein R 1a and R 1b are independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N,
  • R 1a and R 1b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, hydroxy, alkylamino, aminoalkyl, and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, hydroxy , alkylamino , aminoalkyl, and alkoxy. Substituted with 1-6 deuterated alkyl, cyano, C 1-6 aminoalkyl and hydroxyl;
  • Z is selected from C and N; when Z is selected from N, R 1 is absent;
  • R2 , R4 and R6 are independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl , C1-6 alkoxy, C1-6 haloalkyl, -NHC1-6 alkyl, -N( C1-6 alkyl) C1-6 alkyl, C1-6 haloalkoxy, C1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, -SC1-6 alkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
  • G1 and G2 are selected from O, S, and NR2a ;
  • M 1-6 and E are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl -S-, -SO-C 1-6 alkyl, -SO 2 -C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, -NR 2b R 2c , -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, -C(O)R 8c , -C(O)NR 8a R 8b , -C 1-6 alkylene-C 1-6 cycloalkyl, C 3-6 -membered cycloalkylamino, 3-6-membered heterocycloalkylamino containing 1-3 heteroatoms
  • J1 and J2 are independently selected from a single bond, O, S, C(O), S(O), S( O2 ), C( R1cR1d ), C( ⁇ CR1eR1f ) and N( R3 ); wherein R1c , R1d , R1e and R1f are independently selected from hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C3-12 monocyclic, spirocyclic or bridged cycloalkyl, C3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl and C5-10 heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-12 monocyclic, spirocyclic or bridged cycloalkyl, C3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P
  • 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl, and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-6 alkyl, amino, hydroxy, C 1-6 alkylamino, C 1-6 aminoalkyl, and C 1-6 alkoxy; or R 1c and R 1d and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; or R 1e and R 1f and the carbon atom to which they are commonly attached form a 3-10 member
  • R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, -O-, -S-, alkoxy, C 2-6 alkenylene and C 1-6 alkylene;
  • R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S;
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, and the phenyl is optionally substituted with 0-2 groups selected from C 1-4 alkyl, halogen, cyano, amino, -OR 8d and -X 2 -R 8d ;
  • R 8c
  • R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl;
  • X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence;
  • R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are attached form a 3-10 membered cycloalkyl;
  • W is selected from the following groups:
  • the Q ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted with 0-6 R 9 , and each occurrence of R 9 is independently selected from halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, C 3-7 heterocycloal
  • the R ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted with 0-6 R10 , and each occurrence of R10 is independently selected from halogen, deuterium, C1-6 alkyl, hydroxyl, amino, C1-6 haloalkyl, cyano,
  • the T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 0-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
  • L1 is selected from the following groups:
  • L2 is selected from the following groups:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C—, and a single bond;
  • a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
  • L 1 and L 2 are optionally substituted by 0-5 R 11 , R 11 are independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
  • a pharmaceutical composition characterized in that it comprises a therapeutically effective dose of the compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.
  • a method for treating a MAT2A-related disease in a patient comprising administering to the patient a therapeutically effective amount of one or more compounds according to any one of claims 1-11 or the pharmaceutical composition according to claim 12; preferably, the MAT2A-related disease is cancer or tumor.
  • MAT2A-related disease preferably, the MAT2A-related disease is cancer or tumor.
  • Alkyl refers to a straight-chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. Those skilled in the art will recognize that the term “alkyl” may include “alkylene” groups.
  • alkylene refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkenyl refers to a straight chain monovalent hydrocarbon radical having 2 to 6 carbon atoms or a 3 to 6 carbon atom A branched monovalent hydrocarbon group, such as propenyl, butenyl, etc.
  • alkynyl group refers to a linear monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched monovalent hydrocarbon group having 3 to 6 carbon atoms containing a triple bond, for example, ethynyl, propynyl, butynyl and the like.
  • Alkoxy refers to a -OR group where R is alkyl as defined above, for example methoxy, ethoxy, propoxy or 2-propoxy, n-, iso- or tert-butoxy and the like.
  • Amino refers to -NH2 .
  • Alkylamino refers to an -NHR group where R is alkyl as defined above, for example, methylamino, ethylamino, propylamino or 2-propylamino, and the like.
  • Aryl refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 3 to 12 ring atoms, for example, phenyl or naphthyl.
  • Alkyl refers to an -(alkylene)-R group where R is aryl as defined above, eg, benzyl, phenethyl, and the like.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Haloalkyl refers to an alkyl group as defined above substituted by 1 to 5 halogen atoms, such as fluorine atoms or chlorine atoms, including groups substituted by different halogens, such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc.
  • halogen atoms such as fluorine atoms or chlorine atoms
  • groups substituted by different halogens such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc.
  • Hydroalkyl refers to a linear monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical having 3-6 carbon atoms substituted by one or two hydroxyl groups, provided that if two hydroxyl groups are present, they are not simultaneously on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl.
  • salts are meant to include salts of active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (either neat or in a suitable inert solvent).
  • salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include salts derived from the following inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from the following relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid,
  • inorganic acids such as hydrochlor
  • salts of amino acids such as arginine salts
  • salts of the following organic acids such as glucuronic acid or galacturonic acid, and the like
  • Certain specific compounds of the present invention contain both basic and acidic functional groups, which allows the compounds to be converted into base addition salts or acid addition salts.
  • the neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties (e.g., solubility in polar solvents), but for the purposes of the present invention, these salts are equivalent to the parent form of the compound.
  • the present invention also includes protected derivatives of the compounds disclosed herein.
  • a group such as a hydroxyl group, a carboxyl group, a thiol group or any group containing one or more nitrogen atoms
  • these groups may be protected by suitable protecting groups.
  • suitable protecting groups can be found in TW Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, Inc (2014), the disclosure of which is incorporated herein by reference in its entirety.
  • Protected derivatives of the compounds of the present disclosure can be prepared by methods well known in the art.
  • the present invention also includes prodrugs of the compounds, or pharmaceutically acceptable salts thereof.
  • Prodrugs of the compounds described herein are those compounds that are susceptible to chemical changes under physiological conditions to provide compounds of the present invention.
  • An example of a prodrug, not limited to, is a compound ("prodrug") administered as an ester, which is then metabolically hydrolyzed to a carboxylic acid, i.e., an active entity.
  • the prodrug can be converted into a compound of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when the prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, it can be slowly converted into a compound of the present invention.
  • the compounds disclosed in the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present invention.
  • Certain formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-J), (I-K), (I-L), (I-M), (I-N), (I-O), (I-P), (I-Q), (I-R), (I-S), (I-T), (I-U), (I-V), (I-W), (I-X), (I-Y) and (I-Z) compounds may exist in a variety of crystalline or amorphous forms. Generally, all physical forms such as polymorphs are equivalent for the intended use of the present disclosure and are intended to fall within the scope of the present disclosure.
  • the compounds disclosed in the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) are all intended to be included in the isomer range of the compounds of the present invention.
  • stereochemical descriptions refers to compounds in which one isomer is present and substantially free of another isomer.
  • substantially free of another isomer means that the ratio of the two isomers is at least 80/20, more preferably 90/10, or 95/5 or higher.
  • one of the isomers will be present in an amount of at least 99%.
  • the compounds disclosed herein may also contain unnatural amounts of isotopes at one or more atoms constituting such compounds.
  • An unnatural amount of an isotope may be defined as an amount ranging from the amount found in nature to 100% of the atom in question. It differs only when one or more isotopically enriched atoms are present.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H , 3H , 11C , 13C , 14C , 13N , 15N , 15O , 17O, 18O , 32P , 33P , 35S , 18F , 36Cl , 123I , and 125I , respectively .
  • Isotopically labeled compounds e.g., those labeled with 3H and 14C ) are useful in compound or substrate tissue distribution assays.
  • Tritium (i.e., 3H ) and carbon-14 (i.e., 14C ) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H ) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • one or more hydrogen atoms are replaced by 2H or 3 H substitution, or one or more carbon atoms are substituted with 13 C- or 14 C-enriched carbon.
  • Positron emitting isotopes eg, 15 O, 13 N, 11 C, and 15 F
  • PET positron emission tomography
  • Isotopically labeled compounds can generally be prepared by following steps similar to those disclosed in the Examples of the present invention, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • “Pharmaceutically acceptable carrier or excipient” refers to a carrier or excipient that can be used to prepare a pharmaceutical composition, is generally safe, non-toxic and not biologically or otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes one or more such excipients.
  • disease is intended to be generally synonymous with the terms “disorder,””condition,” and “condition” (as in medical condition) and are used interchangeably because they all reflect an abnormal condition of the human or animal body or a part thereof that impairs the normal functioning, usually manifests itself as distinctive signs and symptoms, and results in a shortened life span or reduced quality of life in the human or animal.
  • Patient is often synonymous with the term "subject” and, as used herein, includes all mammals, including humans. Examples of patients include humans, livestock (e.g., cattle, goats, sheep, pigs, and rabbits), and companion animals (e.g., dogs, cats, rabbits, and horses). Preferably, the patient is a human.
  • livestock e.g., cattle, goats, sheep, pigs, and rabbits
  • companion animals e.g., dogs, cats, rabbits, and horses.
  • the patient is a human.
  • in need of treatment refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from treatment. This judgment is based on a variety of factors within the physician's or caregiver's expertise.
  • administering when used for example in patients, cells, tissues, organs or biological fluids, refers to contacting the compounds disclosed herein, pharmaceutical compositions or diagnostic agents containing the same with subjects, cells, tissues, organs or biological fluids.
  • administration includes contact of the agent with the cell (e.g., in vitro or ex vivo), and contact of the agent with the fluid, wherein the fluid is in contact with the cell.
  • therapeutically effective amount refers to, for example, a compound disclosed herein or an embodiment described herein, when administered alone or as part of a pharmaceutical composition and in a single dose or as part of a series of doses to a patient treating a disease, an amount sufficient to affect the treatment of such disease.
  • the "therapeutically effective amount” will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.
  • the therapeutically effective amount can be determined by measuring the relevant physiological effects, and the therapeutically effective amount can be adjusted in combination with the dosing regimen and diagnostic analysis of the subject's condition, etc. For example, measuring the serum level of a compound disclosed herein (or its metabolite) at a specific time after administration can indicate whether a therapeutically effective amount has been used.
  • Treatment or “treatment” of a disease includes:
  • a disease that is, causing clinical symptoms of a disease to not develop in a mammal that may be exposed to or susceptible to the disease but does not yet experience or show symptoms of the disease;
  • “Inhibition”, “reduction” or any variation of these terms with respect to MAT2A includes any measurable reduction or complete inhibition to achieve the desired result.
  • the reduction in MAT2A activity can be reduced by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any derivable range thereof.
  • the synthesis of compound 1-9 refers to the synthesis of compound 1-5, except that p-vinylaniline in step 1 is replaced by p-bromoaniline.
  • reaction solution is dried over anhydrous sodium sulfate, and the organic phase after drying is evaporated on a rotary evaporator to remove the solvent.
  • the obtained residue is purified by column chromatography to obtain compound 3-4 (1.1g, 36%), which is a white solid.
  • methyl isonicotinate 1.0 g, 7.3 mmol
  • 50 mL of methanol 50 mL
  • 0.2 mL of concentrated sulfuric acid was added, and the temperature was raised to 65°C.
  • ammonium persulfate 15 g, 65.79 mmol
  • 25 mL of water 25 mL
  • TLC monitored the reaction to be complete, concentrated to remove a large amount of methanol, and extracted with 50 mL of water and 150 mL of ethyl acetate, which was repeated three times.
  • 3-iodoaniline (3.0 g, 13.70 mmol) and 1H-imidazole-4-carbonitrile (1.3 g, 13.70 mmol) were dissolved in N, N-dimethylformamide (30 mL) at room temperature, and cuprous iodide (260 mg, 1.37 mmol), trans-N, N-dimethyl-1,2-cyclohexanediamine (200 mg, 1.37 mmol) and cesium carbonate (13.4 g, 41.07 mmol) were added, and the mixture was heated to 100 ° C and stirred for 18 hours under nitrogen protection.
  • Oxalyl chloride (2.0 g, 15.96 mmol) was added dropwise to dichloroethane DCE (10 mL) of compound 32-3 (1.2 g, 7.98 mmol) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After the excess oxalyl chloride was removed by rotary evaporation under reduced pressure, it was diluted with DCE (8 mL) and added dropwise to the DCE/DMF (1.5 mL/0.5 mL) system of compound 2 (500 mg, 2.65 mmol). The reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the slurry, and the solid after filtration was compound 32-4, 1.35 g, white solid, with a yield of 93%. LC-MS (ESI) m/z: 547 [M+H] + .
  • Phosphorus oxychloride (0.8 mL) was added to a solution of compound 5 (80 mg, 0.16 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. Methylethylamine (47 mg, 0.79 mmol) was dissolved in tetrahydrofuran THF (5 mL) and added dropwise to the reaction system to remove phosphorus oxychloride, and stirred at room temperature for 30 minutes. LC-MS detected complete reaction.
  • compound 34-1 (900 mg, 4 mmol) was dissolved in 5 mL of anhydrous ethanol, p-toluenesulfonyl hydrazide (755 mg, 4 mmol) was added, and the mixture was stirred at room temperature overnight. TLC monitored that compound 34-1 reacted completely and new spots were generated. Then 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)indigo (1.4 g, 4 mmol) and potassium carbonate (1.11 g, 4 mmol) were added, and the temperature was raised to 80 ° C and stirred for 45 minutes.
  • n-Nitrophenyl borate (2.12 g, 12.8 mmol) and 4-bromothiophene-2-carbonitrile (2.0 g, 10.6 mmol) were dissolved in a mixture of dioxane (30 mL) and DMF (4 mL), and an aqueous solution (13 mL) of sodium carbonate (3.38 g, 31.8 mmol) was added.
  • 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex 500 mg, 0.05 mmol was added in a N2 atmosphere, and the mixture was heated to 100°C and reacted overnight.
  • compound 44-1 (1.5 g, 6.944 mmol) was dissolved in ammonia methanol solution (20 mL, 7N), 2 mL of water-sealed Raney nickel was taken, the supernatant was removed after precipitation, methanol was added to wash twice, the supernatant was removed after standing and precipitation, and then the precipitate was diluted with methanol and added to the reaction system, and the hydrogen was replaced three times and kept at room temperature for 4 hours. LC-MS monitored the complete reaction.
  • compound 47-1 (650 mg, 6.944 mmol) was dissolved in ammonia methanol solution (7N, 20 mL), 2 mL of water-sealed Raney nickel was taken, the supernatant was removed after precipitation, methanol was added to wash twice, the supernatant was removed after standing and precipitation, and then the precipitate was diluted with methanol and added to the reaction system, and the hydrogen was replaced three times and kept at room temperature for 4 hours. LC-MS monitored the complete reaction.
  • m-Nitrophenylboronic acid 500 mg, 4.5 mmol
  • compound 50-1 470 mg, 2.5 mmol
  • a mixture of dioxane 5 mL
  • DMF 1 mL
  • an aqueous solution 2 mL
  • sodium carbonate 795 mg, 7.5 mmol
  • 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex 100 mg, 0.125 mmol was added in a N2 atmosphere, and the mixture was heated to 100°C and reacted overnight.
  • m-Nitrophenyl borate (1.86 g, 11.1 mmol) and compound 55-3 (2.79 g, 9.3 mmol) were dissolved in a mixture of dioxane (25 mL) and DMF (4 mL), and an aqueous solution (7 mL) of sodium carbonate (2.96 g, 27.9 mmol) was added.
  • 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (380 mg, 0.46 mmol) was added in a N2 atmosphere, and the mixture was heated to 50°C and reacted overnight.
  • compound 57-1 (2.0 g, 9.90 mmol) was dissolved in ammonia methanol solution (7N, 20 mL), 2 mL of water-sealed Raney nickel was taken, the supernatant was removed after precipitation, methanol was added to wash twice, the supernatant was removed after standing and precipitation, and then the precipitate was diluted with methanol and added to the reaction system, and the hydrogen was replaced three times and kept at room temperature for 4 hours. LC-MS monitored the complete reaction.
  • compound 57-4 (100 mg, 0.18 mmol) was dissolved in 3 mL of anhydrous acetonitrile, cooled to 0 ° C, DIEA (100 mg, 0.78 mmol) and phosphorus oxychloride (130 mg, 0.85 mmol) were added, slowly heated to room temperature and then heated to 80 ° C and stirred for 6 hours.
  • the reaction solution was concentrated to remove a large amount of phosphorus oxychloride, and then a THF solution of dimethylamine (2 mL, 2.5 N) was added and stirred at room temperature for 30 minutes.
  • LC-MS monitored the reaction to be complete.
  • compound 60-2 500 mg, 2.01 mmol was dissolved in tetrahydrofuran (5 mL), cooled to 0 ° C, and a solution of lithium aluminum tetrahydride in tetrahydrofuran (2.5 mL) was added dropwise. Under nitrogen protection, the temperature was raised to 70 ° C and stirred for 2 hours. TLC monitored the complete reaction, and the reaction system was quenched with water (10 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Oxalyl chloride (555 mg, 4.37 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (380 mg, 2.18 mmol) in dichloroethane (DCE) (5 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing the excess oxalyl chloride by vacuum rotary evaporation, it was diluted with DCE (2 mL) and then added dropwise to the DCE (3 mL) system of compound 60-3 (146 mg, 0.71 mmol), and the reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the reaction system for slurrying, and the solid after filtration was compound 60-4, 248 mg, yield 58%, white solid. LC-MS (ESI) m/z: 604 [M + H] + .
  • Phosphorus oxychloride (0.8 mL) was added to a solution of compound 5 (70 mg, 0.12 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. A tetrahydrofuran solution of dimethylamine (4 mL) was added dropwise to the reaction system where phosphorus oxychloride was removed, and stirred at room temperature for 30 minutes. LC-MS detected the complete reaction.
  • 2-amino-6-bromopyridine (1g, 5.8mmol), 1-H-4-cyanoimidazole (540mg, 5.8mmol), cuprous iodide (110mg, 0.6mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (90mg, 0.6mmol) and cesium carbonate (5.6g, 17.2mmol) were dissolved in 20mL anhydrous DMF, nitrogen was replaced three times, and the temperature was raised to 100°C oil bath for 16 hours. LC-MS monitored the reaction to be complete.
  • compound 62-1 500 mg, 2.7 mmol was dissolved in ammonia methanol solution (7N, 10 mL ), take 2mL of water-sealed Raney nickel, remove the supernatant after precipitation, add methanol to wash twice, remove the supernatant after standing precipitation, then dilute the precipitate with methanol and add it to the reaction system, replace hydrogen three times and keep the reaction at room temperature for 4 hours.
  • LC-MS monitors the reaction to be complete. Add 50mL DCM and 10mL methanol to dilute the reaction solution and filter it with diatomaceous earth.
  • Oxalyl chloride (460 mg, 4.06 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (320 mg, 2.03 mmol) in dichloroethane (5 mL) at 0 ° C. Under nitrogen protection, the reaction mixture was stirred at 70 ° C overnight, and the excess oxalyl chloride was removed by vacuum rotary evaporation. After dilution with DCE (2 mL), it was added dropwise to the DCE (3 mL) system of compound 68-5 (140 mg, 0.67 mmol), and the reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the reaction system for slurrying, and the solid after filtration was compound 68-6, 299 mg, yield 74%, white solid. LC-MS (ESI) m/z: 604 [M + H] + .
  • Phosphorus oxychloride (0.8 mL) was added to a solution of compound 68-7 (60 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. A tetrahydrofuran solution of dimethylamine (4 mL) was added dropwise to the reaction system where phosphorus oxychloride was removed, and stirred at room temperature for 30 minutes. LC-MS detected the complete reaction.
  • Oxalyl chloride (5.9 g, 52.14 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (4.1 g, 26.07 mmol) in dichloroethane (DCE) (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride under reduced pressure, it was diluted with DCE (20 mL) and then added dropwise to the DCE (20 mL) system of compound 72-5 (1.8 g, 8.69 mmol), and the reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction.
  • DCE dichloroethane
  • Phosphorus oxychloride (0.8 mL) was added to a solution of compound 72-7 (60 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 h, and the excess phosphorus oxychloride was removed under reduced pressure. A tetrahydrofuran solution of deuterated dimethylamine (4 mL) was added dropwise to the reaction system in which phosphorus oxychloride was removed, and stirred at room temperature for 30 min. LC-MS detected the complete reaction.
  • compound 79-2 (2.0 g, 10.58 mmol) was dissolved in 20 mL of N, N-dimethylformamide, 3-tert-butyloxycarbonylaminopiperidine (2.3 g, 11.64 mmol) and potassium carbonate (4.4 g, 31.74 mmol) were added thereto, and stirred at room temperature for 16 h.
  • TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (50 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Oxalyl chloride (6.1 g, 47.88 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (4.1 g, 23.94 mmol) in dichloroethane (DCE) (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride by vacuum rotary evaporation, it was diluted with DCE (20 mL) and then added dropwise to the DCE (30 mL) system of compound 79-5 (1.7 g, 7.98 mmol), and the reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction.
  • DCE dichloroethane
  • Phosphorus oxychloride (0.8 mL) was added to a solution of compound 79-7 (60 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 h, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. After 4 mL of tetrahydrofuran solution of N-ethylmethylamine was dropped into the reaction system, it was stirred at room temperature for 30 min. LC-MS detected the complete reaction.
  • Embodiment 84 is a diagrammatic representation of Embodiment 84.
  • Phosphorus oxychloride (1.0 mL) was added to a solution of compound 72-7 (80 mg, 0.14 mmol) and N,N-diisopropylethylamine (1.0 mL) in acetonitrile CAN (5 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 h, and the excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure. After 4 mL of water was dropped into the reaction system, it was stirred at room temperature for 30 min. LC-MS detected the complete reaction.
  • 2,4,7-Trichloroquinazoline (5.0 g, 21.44 mmol) was dissolved in 50 mL of tetrahydrofuran (THF) at room temperature, 15 mL (31.12 mmol) of a tetrahydrofuran solution of N-ethylmethylamine (2M) was added thereto, and the mixture was stirred at room temperature for 16 h.
  • the reaction was completely monitored by TLC, and the compound 101-1 (3.7 g, white solid) was obtained after vacuum rotary evaporation and concentration, which was directly used in the next step without purification, with a yield of 68%.
  • compound 101-2 (1.0 g, 4.20 mmol) was dissolved in 10 mL of N, N-dimethylformamide, 2-bromo-5-bromomethylthiazole (1.3 g, 5.04 mmol) and potassium carbonate (1.8 g, 12.61 mmol) were added thereto, and stirred at room temperature for 16 h.
  • TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Oxalyl chloride (5.5 g, 43.01 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (3.7 g, 21.51 mmol) in dichloroethane (50 mL) at 0 ° C. Under nitrogen protection, the reaction mixture was stirred at 70 ° C overnight. After removing excess oxalyl chloride under reduced pressure, it was diluted with DCE (20 mL) and then added dropwise to 1-Boc-3-aminopyrrolidine (2.0 g, 10.75 mmol) in DCE (30 mL) system. The reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction.
  • Oxalyl chloride (5.5 g, 43.01 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (3.7 g, 21.51 mmol) in dichloroethane (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride under reduced pressure, it was diluted with DCE (20 mL) and then added dropwise to a DCE (30 mL) system of 1-tert-butyloxycarbonyl-3-aminopiperidine (2.0 g, 9.98 mmol), and the reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction.
  • Embodiment 107 is a diagrammatic representation of Embodiment 107.
  • Compound 79 was resolved by SFC to give single-configuration compounds 109 (79-P1) and 110 (79-P2).
  • Compound 80 was resolved by SFC to give single-configuration compounds 111 and 112.
  • Step 3 Synthesis of compounds 113 & 114
  • the synthesis method of compound 116 is similar to that of Example 102, except that dimethylamine in step 3 is replaced by azetidine, and 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one.

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Abstract

La présente invention concerne un composé qui est un composé tel que représenté par la formule (I), ou un isomère, un dérivé isotopique, un polymorphe, un promédicament, et un sel pharmaceutiquement acceptable ou un solvate (I) de celui-ci, les définitions de A, B et C étant telles que définies dans la description. L'invention concerne en outre une composition pharmaceutique et un composé de formule (I), ainsi qu'un procédé associé pour traiter des maladies associées au moyen de l'inhibition de MAT2A, les maladies comprenant certains cancers dans lesquels le gène codant pour la méthylthioadénosine phosphorylase (MTAP) est supprimé et/ou n'est pas entièrement fonctionnel.
PCT/CN2024/080417 2023-03-06 2024-03-07 Inhibiteur de méthionine adénosyltransférase 2a et son utilisation médicale WO2024183778A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107056771A (zh) * 2017-01-23 2017-08-18 中国药科大学 Bromodomain蛋白二价抑制剂及其制备方法和应用
CN111936499A (zh) * 2018-03-30 2020-11-13 安吉奥斯医药品有限公司 Mat2a的杂二环抑制剂和用于治疗癌症的方法
CN113454085A (zh) * 2018-12-27 2021-09-28 法国施维雅药厂 Mat2a的aza杂双环抑制剂和用于治疗癌症的方法
CN113474347A (zh) * 2018-12-27 2021-10-01 法国施维雅药厂 Mat2a的aza杂双环抑制剂和用于治疗癌症的方法
CN113999232A (zh) * 2020-07-28 2022-02-01 南京正大天晴制药有限公司 Mat2a抑制剂
WO2023196985A1 (fr) * 2022-04-08 2023-10-12 Ideaya Biosciences, Inc. Inhibiteurs de méthionine adénosyltransférase 2a

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107056771A (zh) * 2017-01-23 2017-08-18 中国药科大学 Bromodomain蛋白二价抑制剂及其制备方法和应用
CN111936499A (zh) * 2018-03-30 2020-11-13 安吉奥斯医药品有限公司 Mat2a的杂二环抑制剂和用于治疗癌症的方法
CN113454085A (zh) * 2018-12-27 2021-09-28 法国施维雅药厂 Mat2a的aza杂双环抑制剂和用于治疗癌症的方法
CN113474347A (zh) * 2018-12-27 2021-10-01 法国施维雅药厂 Mat2a的aza杂双环抑制剂和用于治疗癌症的方法
CN113999232A (zh) * 2020-07-28 2022-02-01 南京正大天晴制药有限公司 Mat2a抑制剂
WO2023196985A1 (fr) * 2022-04-08 2023-10-12 Ideaya Biosciences, Inc. Inhibiteurs de méthionine adénosyltransférase 2a

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