WO2023030453A1 - 一种降解Bcl-2家族蛋白的化合物及其在医药上的应用 - Google Patents
一种降解Bcl-2家族蛋白的化合物及其在医药上的应用 Download PDFInfo
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- WO2023030453A1 WO2023030453A1 PCT/CN2022/116529 CN2022116529W WO2023030453A1 WO 2023030453 A1 WO2023030453 A1 WO 2023030453A1 CN 2022116529 W CN2022116529 W CN 2022116529W WO 2023030453 A1 WO2023030453 A1 WO 2023030453A1
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
Definitions
- the present invention relates to a compound of general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and its intermediate and preparation method, and Use in Bcl-2 family proteins such as cancer diseases.
- Apoptosis is an autonomous and orderly death process regulated by genes at a certain developmental stage for most cells in an organism. It plays an important role in tissue evolution, organ development and maintenance of the body's own stability. In malignancy, anti-apoptotic effects are considered to be a key feature. Therefore, specifically targeting anti-apoptotic pathways has potential applications in cancer therapy.
- the Bcl-2 protein family consists of pro-apoptotic proteins and anti-apoptotic proteins, which can regulate the intrinsic apoptosis pathway of cancer cells.
- Bcl-2, Bcl-xL, and Mcl-1 members of the Bcl-2 protein family, have been identified as anti-tumor targets, and inhibition of these proteins can promote Bax/Bak oligomerization and eventually induce mitochondrial outer membrane permeabilization, which subsequently causes Release of cytochrome c and activation of caspases, thereby executing apoptosis of cancer cells.
- PROTAC proteolysis targeting chimera
- PROTAC proteolysis targeting chimera
- E3 ubiquitin ligases This type of compound can be recognized by the proteasome of the cell, causing the degradation of the targeting protein, and can effectively reduce the target protein. protein content in cells.
- the object of the present invention is to provide a compound with novel structure, good drug effect, high bioavailability, safer, capable of inhibiting and degrading Bcl-2 family proteins (such as Bcl-xL or Bcl-2), for the treatment of Bcl-2 family proteins (such as Bcl-xL or Bcl-2) related diseases such as cancer.
- Bcl-2 family proteins such as Bcl-xL or Bcl-2
- Bcl-2 family proteins such as Bcl-xL or Bcl-2 related diseases such as cancer.
- the present invention provides a compound or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from compounds represented by general formula (I),
- L is selected from a bond or -C 1-50 alkyl-, in which there are 0 to 20 methylene units optionally further replaced by -Ak-, -Cy-;
- L is selected from a bond or -C 1-20 alkyl-, in which there are 0 to 20 methylene units optionally further replaced by -Ak-, -Cy-;
- L is selected from a bond or -C 1-10 alkyl-, wherein there are 0 to 10 (eg, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 Or 10) the methylene unit is optionally further replaced by -Ak-, -Cy-;
- the chain does not contain a chemical bond selected from NO, OO or NS;
- the chain does not contain a chemical bond selected from NO, OO or NS;
- each -Ak- is independently selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9;
- each -Cy- is independently selected from Cy1, Cy2, Cy3, Cy4, or Cy5;
- each -Cy- is independently selected from a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring , 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aromatic
- L is selected from -Cyl-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cyl-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2 -Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-C
- L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5 -, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2 -Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -C
- L is selected from a bond or a group shown in Table B-1, and the left side of the group is connected to B;
- the -CH 2 - is optionally further selected from 0 to 2 (for example 0, 1 or 2) selected from H, halogen, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen Substituted C
- the -CH 2 - is optionally further replaced by 0 to 2 selected from H, F, Cl, Br, I, , OH, CN, NH 2 , CF 3 , hydroxymethyl, C 1-4 alkyl, C 1-4 Substituents of
- each R L is independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl;
- each R L is independently selected from H or C 1-6 alkyl
- each R L is independently selected from H or C 1-4 alkyl
- each RL is independently selected from H, methyl, or ethyl
- each of Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from one of the following groups which are bonded or substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, azacyclopentyl, aziridinyl, piperidinyl, morpholinyl, piperazinyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, Cyclopropylcyclopentyl, Cyclopropylcyclohexyl, Cyclobutylcyclobutyl, Cyclobutylcyclopentyl, Cyclobutylcyclohexyl, Cyclopentylcyclopentyl, Cyclopentyl And cyclohexyl, cyclohexyl and cyclohexyl, cyclopropylspirocyclopropyl,
- K is selected from
- K is selected from Indicates that the ring is selected from an aromatic ring or a non-aromatic ring;
- K is selected from
- each Q is independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q -, or 3- 12-membered heterocyclic group
- each Q is independently selected from -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q -, or 4-7 members
- the heterocyclic group contains 1 to 4 (such as 1, 2, 3, 4) selected Heteroatoms from O, S, N;
- R is selected from H or C 1-6 alkyl
- R is selected from H or C 1-4 alkyl
- Rq is selected from H, methyl, ethyl
- each E is independently selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, the heterocycle or heteroaryl Aryl contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
- each E is independently selected from C3-8 carbocycle, benzene ring, 4-7 membered heterocycle, 8-12 membered heterocycle, 7-12 membered heteroaryl or 5-6 membered heterocycle Aryl, the heterocyclic or heteroaryl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
- each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl, oxa Azolyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyl;
- each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl, or oxa Azolyl;
- each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl;
- each E is independently selected from a benzene ring or a pyridine ring;
- A is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, the heterocyclic or heteroaryl containing 1 to 4 (for example 1, 2, 3 or 4) heteroatoms selected from O, S, N;
- each of A, H1 or H2 is independently selected from C3-8 carbocycle, benzene ring, 4-7 membered heterocycle or 5-6 membered heteroaryl, and the heterocycle or heteroaryl Contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
- each of A, H1 or H2 is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, Thienyl or oxazolyl;
- A, H1 or H2 are each independently selected from phenyl or pyridyl;
- each F (F ring) is independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, said Heterocyclyl or heteroaryl contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
- each F is independently selected from 3-7 membered monocycloalkyl, 4-10 membered parallel cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 membered bridged cycloalkyl, 4 -7 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 aryl or 5-10 membered heteroaryl, said heteromono
- the ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaryl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
- each F is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopenta[ c] pyridyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, pyridine Base, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, benzimidazolyl, benzene Pyrazolyl, benzothiazolyl, benzothieny
- each R k2 is independently selected from a bond, -CO-, -SO 2 -, -SO-, or -C(R k3 ) 2 -;
- each R k2 is independently selected from -CO-, -SO 2 - or -C(R k3 ) 2 -;
- each R k4 is independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl, so
- each R k4 is independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;
- each R k5 is independently selected from CO, CH 2 , SO 2 or
- each R is independently selected from CO, CH, SO, SO 2 , CH 2 or N;
- each Rk7 is independently selected from CO, CH, N, CH2 , O, S, N( CH3 ) or NH;
- each Rk7 is independently selected from CH2 , O, N( CH3 ) or NH;
- each R is independently selected from C, N, or CH;
- each Rk9 is independently selected from CO, SO2 or CH2 ;
- the heteroaryl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
- M is selected from -NH- or -O-;
- K is selected from one of the structural fragments shown in Table K-a;
- K is selected from one of the following structural fragments:
- K is selected from
- B is selected from
- B is selected from
- B is selected from
- W is selected from W 1 , W 2 ;
- W 1 is selected from -CR w1 R w2 -, -(CR w1 R w2 ) 3 -, -(CR w1 R w2 ) 4 -, -CH 2 CR w3 R w4 -, -CR w3 R w4 CH 2 -, -CR w1 R w2 O-, -OCR w1 R w2 -, -CR w1 R w2 NR w5 -, -NR w5 CR w1 R w2 -;
- W 2 is selected from -(CR w1 R w2 ) 2 -;
- D is selected from C 1-4 alkylene
- D is selected from ethylene
- B and Z are each independently selected from the group consisting of azetidinyl, azepanyl, piperazinyl, piperidinyl, azepinyl, azepanyl, 1,4-diazepanyl, cyclobutylazetidinyl, cyclobutylazepanyl, cyclobutylazepanyl, cyclobutylpiperidinyl, cyclobutyl Pentylazetidinyl, Cyclopentylazetidinyl, Cyclopentylazetidinyl, Cyclopentylpiperidinyl, Cyclohexylazetidinyl, Cyclohexyl Azacyclopentyl, cyclohexylazetidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylazetidinyl, a
- B and Z are each independently selected from
- B and Z are each independently selected from
- B 2 , B 3 , B 4 , and B 5 are each independently selected from C 6-10 aryl, 5-10 membered heteroaryl, and said B 2 is optionally further replaced by 0 to 4 R B2 is substituted, said B3 is optionally further substituted with 0 to 5 R B3 , said B4 is optionally further substituted with 0 to 4 R B4 , said B5 is optionally further substituted with 0 to 5 R B5 Substitution, the heteroaryl group contains 1 to 3 heteroatoms selected from O, S, N;
- B 2 and B 4 are each independently selected from phenyl, 5-6 membered heteroaryl
- B 3 and B 5 are each independently selected from phenyl, naphthyl, 5-6 membered heteroaryl Base, benzo 5 to 6 membered heteroaryl
- said B 2 is optionally further substituted by 0 to 4 R B2
- said B 3 is optionally further substituted by 0 to 5 R B3
- said B 4 is optionally Further substituted by 0 to 4 RB4
- said B 5 is optionally further substituted by 0 to 5 RB5
- said heteroaryl contains 1 to 3 heteroatoms selected from O, S, N;
- B is selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo 5 to 6 membered heteroaryl, and said B is optionally further substituted with 0 to 5 R B3 ;
- B3 is selected from
- B3 is selected from
- B 2 and B 4 are each independently selected from phenyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrimidinyl, Azinyl, pyridazinyl, B 3 , B 5 are each independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzene Thienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, said B 2 is optionally further substituted by 0 to 4 R B 2 , said B 3 is optionally further substituted by 0 to 5 R B 3 , the B 4 is optionally further substituted by 0 to 4 RB4 ,
- R B1 , R Q , R B2 , R B3 , R B5 are each independently selected from halogen, oxo, OH, CN, C 1-4 alkyl or C 1-4 alkoxy, so The above-mentioned alkyl or alkoxy group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- R B1 , R Q , R B2 , R B3 , R B5 are each independently selected from F, Cl, Br, I, oxo, OH, CN, methyl, ethyl, methoxy, or Ethoxy, the methyl, ethyl, methoxy or ethoxy are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- each R B4 is independently selected from -SO 2 -C 1-4 alkyl, nitro, halogen, CN, OH, C 1-4 alkyl or C 1-4 alkoxy, so The above-mentioned alkyl or alkoxy group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- R B4 are each independently selected from -SO 2 -methyl, -SO 2 -ethyl, nitro, F, Cl, Br, I, OH, CN, methyl, ethyl, methyl Oxygen or ethoxy, the methyl, ethyl, methoxy or ethoxy are optionally further 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl replaced by
- each R B4 is independently selected from -SO 2 -CF 3 , nitro;
- each of R w1 , R w2 , and R w5 is independently selected from H, halogen, CN, OH, C 1-4 alkyl or C 1-4 alkoxy, and said alkyl or alk Oxygen is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- each of R w1 , R w2 , and R w5 is independently selected from H, F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy, or ethoxy, and the The methyl, ethyl, methoxy or ethoxy groups are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- R w1 and R w2 are directly connected to form a C 3-6 carbocycle or a 3-6 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, Halogen, OH, CN, C 1-4 alkyl substituents are substituted, and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
- Rw1 and Rw2 are directly linked to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azepanyl, azacyclohexyl, oxa Cyclobutyl, oxacyclopentyl, oxacyclohexyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, Oxetanyl, oxanyl, and oxanyl are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- R w1 and R w2 are selected from methyl, or R w1 and R w2 are directly connected to form a cyclopropyl group together with the carbon atom to which they are attached;
- R w3 and R w4 are directly connected to form a C 3-6 carbocycle or a 3-6 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, Halogen, OH, CN, C 1-4 alkyl substituents are substituted, and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
- Rw3 and Rw4 are directly linked to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azepanyl, azacyclohexyl, oxa Cyclobutyl, oxacyclopentyl, oxacyclohexyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, Oxetanyl, oxanyl, and oxanyl are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- R B1 and R B2 are directly connected to form a C 5-7 carbocycle or a 5-7 membered heterocycle, and the carbocycle or heterocycle is optionally further substituted by 0 to 3 R c , so Said heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
- Z is selected from
- compounds of general formula (I) have the following definitions:
- W 2 is selected from -(CR w1 R w2 ) 2 -, and R w1 and R w2 are each independently selected from F, methyl or methoxy, B satisfies at least one of the following conditions:
- B 1 is not piperazine
- R B1 and R B2 are directly connected to form a C 5-7 carbocycle or a 5-7 membered heterocycle, the carbocycle or heterocycle is optionally further substituted by 0 to 3 R c , and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
- compounds of general formula (I) have the following definitions:
- W 2 is selected from -(CR w1 R w2 ) 2 -, and R w1 and R w2 are each independently selected from F, methyl or methoxy, B satisfies at least one of the following conditions:
- B 1 is not piperazine
- B3 is selected from phenyl, phenyl is substituted by 1 R B3 , when R B3 is located at the para-position of phenyl, R B3 is not halogen, methyl or trifluoromethyl;
- R B1 and R B2 are directly connected to form a C 5-7 carbocycle or a 5-7 membered heterocycle, the carbocycle or heterocycle is optionally further substituted by 0 to 3 R c , and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
- B is selected from one of the structural fragments shown in Table B-a;
- each q is independently selected from 0, 1, 2, 3, 4, 5 or 6;
- each q is independently selected from 0, 1, 2, 3 or 4;
- each q is independently selected from 0, 1, 2 or 3;
- each q is independently selected from 0, 1 or 2;
- n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
- p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;
- p1 or p2 are each independently selected from 0, 1 or 2.
- L is selected from a bond or -C 1-50 hydrocarbon group-, in which there are 0 to 20 methylene units optionally further replaced by -Ak-, -Cy-;
- q are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
- RL are each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;
- Each -Cy- is independently selected from a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, a 3-7 membered monocyclic ring Alkyl, 4-10 membered and cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, the aryl, Heteroaryl, cycloalkyl, heteromonocyclic, heteroheterocyclic, heterospirocyclic or heterobridged rings are optionally further represented by 0 to 4 members selected from H, F, Cl, Br, I, OH, COOH, CN, NH 2.
- W is selected from W 1 , W 2 ;
- W 1 is selected from -CR w1 R w2 -, -(CR w1 R w2 ) 3 -, -(CR w1 R w2 ) 4 -, -CH 2 CR w3 R w4 -, -CR w3 R w4 CH 2 -, - CR w1 R w2 O-, -OCR w1 R w2 -, -CR w1 R w2 NR w5 -, -NR w5 CR w1 R w2 -;
- W 2 is selected from -(CR w1 R w2 ) 2 -;
- D is selected from C 1-4 alkylene
- B 2 , B 3 , B 4 , and B 5 are each independently selected from C 6-10 aryl, 5 to 10 membered heteroaryl, said B 2 is optionally further substituted by 0 to 4 R B2 , said B 3 is optionally further substituted by 0 to 5 R B3 , said B4 is optionally further substituted by 0 to 4 R B4 , said B5 is optionally further substituted by 0 to 5 R B5 , said heteroaryl
- the group contains 1 to 3 heteroatoms selected from O, S, N;
- R B1 , R Q , R B2 , R B3 , and R B5 are each independently selected from halogen, oxo, OH, CN, C 1-4 alkyl or C 1-4 alkoxy, and the alkyl or alkoxy The group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- R B4 are each independently selected from -SO 2 -C 1-4 alkyl, nitro, halogen, CN, OH, C 1-4 alkyl or C 1-4 alkoxy, the alkyl or alkoxy The group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- R w1 , R w2 , and R w5 are each independently selected from H, halogen, CN, OH, C 1-4 alkyl or C 1-4 alkoxy, and the alkyl or alkoxy is optionally further replaced by 0 Replaced by 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- R w1 and R w2 are directly connected to form a C 3-6 carbocycle or a 3-6 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, CN, C 1-4 alkyl substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
- R w3 and R w4 are directly connected to form a C 3-6 carbocycle or 3 to 6 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, CN, C Substituted by 1-4 alkyl substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
- R B1 and R B2 are directly connected to form a C 5-7 carbocycle or a 5-7 membered heterocycle, and the carbocycle or heterocycle is optionally further substituted by 0 to 3 R c , and the heterocycle Contains 1 to 3 heteroatoms selected from O, S, N;
- the condition is that when W 2 is selected from -(CR w1 R w2 ) 2 -, and R w1 and R w2 are each independently selected from F, methyl or methoxy, B satisfies at least one of the following conditions:
- B 1 is not piperazine
- B3 is selected from phenyl, phenyl is substituted by 1 R B3 , when R B3 is located at the para-position of phenyl, R B3 is not halogen, methyl or trifluoromethyl;
- R B1 and R B2 are directly connected to form a C 5-7 carbocycle or a 5-7 membered heterocycle, the carbocycle or heterocycle is optionally further substituted by 0 to 3 R c , and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
- Q is each independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or a 3-12 membered heterocyclic group, so
- R is selected from H or C 1-6 alkyl
- A is selected from C 3-10 carbocyclic group, C 6-10 aryl group, 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, and the heterocyclic ring or heteroaryl group contains 1 to 4 members selected from O , S, N heteroatoms;
- F is each independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclic group or 5-20 membered heteroaryl, and the heterocyclic group or heteroaryl contains 1 to 4 a heteroatom selected from O, S, N;
- Each R k2 is independently selected from a bond, -CO-, -SO 2 -, -SO- or -C(R k3 ) 2 -;
- R k4 are each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group, the alkyl, cycloalkane
- M 3 is selected from -NH- or -O-;
- n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
- p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
- L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-,
- Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, a 3- 7-membered monocycloalkyl, 4-10-membered cycloalkyl, 5-12-membered spirocycloalkyl, 7-10-membered bridged cycloalkyl, 5-10-membered heteroaryl or 6-10-membered aryl, all
- q are each independently selected from 0, 1, 2, 3 or 4;
- RL are each independently selected from H or C 1-6 alkyl
- RL are each independently selected from H or C 1-4 alkyl
- the ring is selected from an aromatic ring or a non-aromatic ring
- Each Q is independently selected from -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or 4-7 membered heterocyclic group, the
- R is selected from H or C 1-4 alkyl
- R k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-6-membered carbocycle or a 3-7-membered heterocycle
- the heterocycle contains 1 to 4 heteroatoms selected from O, S, N;
- R k4 are each independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;
- Each R k5 is independently selected from CO, CH 2 , SO 2 or
- R K6 are each independently selected from CO, CH, SO, SO 2 , CH 2 or N;
- Each R k7 is independently selected from CO, CH, N, CH 2 , O, S, N(CH 3 ) or NH;
- Each R K8 is independently selected from C, N or CH;
- R K9 are each independently selected from CO, CH 2 or SO 2 ;
- A, H1 or H2 are each independently selected from C 3-8 carbocycles, benzene rings, 4-7 membered heterocycles or 5-6 membered heteroaryls, and the heterocycles or heteroaryls contain 1 to 4 members selected from Heteroatoms of O, S, N;
- E are each independently selected from C 3-8 carbocyclic ring, benzene ring, 4-7 membered heterocyclic ring, 8-12 membered heterocyclic ring, 7-12 membered heteroaryl group or 5-6 membered heteroaryl group, the heterocyclic ring Or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N;
- F is independently selected from 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 bridged cycloalkyl, 4-7 membered heteromonocyclic, 4-10 membered heterocyclic ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 aryl or 5-10 membered heteroaryl, the heteromonocyclic, heterocyclic, heterocyclic
- the spiro ring, heterobridged ring or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N;
- RL is selected from H, methyl or ethyl
- q are each independently selected from 0, 1, 2 or 3;
- Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups that are bonded or substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, nitrogen Heterocyclopentyl, aziridinyl, piperidinyl, morpholinyl, piperazine, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, Cyclopropyl cyclohexyl, cyclobutyl cyclobutyl, cyclobutyl cyclopentyl, cyclobutyl cyclohexyl, cyclopentyl cyclopentyl, cyclopentyl cyclohexyl, cyclohexyl Cyclohexyl, cyclopropylspirocyclopropy
- D is selected from ethylene
- B 1 and Z are each independently selected from azetidinyl, azepanyl, piperazinyl, piperidinyl, aziridinyl, azepanyl, 1,4-diazepine Cycloheptyl, Cyclobutylazetidinyl, Cyclobutylazetidinyl, Cyclobutylazetidinyl, Cyclobutylpiperidinyl, Cyclopentylazetidinyl base, cyclopentyl azacyclopentyl, cyclopentyl azacyclohexyl, cyclopentyl piperidinyl, cyclohexyl azetidinyl, cyclohexyl azacyclopentyl, Cyclohexyl azetidinyl, cyclohexyl piperidinyl, azetidinyl azetidinyl, azacyclopentyl aze
- B 2 and B 4 are each independently selected from phenyl, 5-6 membered heteroaryl
- B 3 and B 5 are each independently selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo5-6 Member heteroaryl
- said B 2 is optionally further substituted by 0 to 4 R B 2
- said B 3 is optionally further substituted by 0 to 5 R B 3
- said B 4 is optionally further substituted by 0 to 4 R B4 is substituted
- the B5 is optionally further substituted by 0 to 5 R B5
- the heteroaryl group contains 1 to 3 heteroatoms selected from O, S, N;
- R B1 , R Q , R B2 , R B3 , and R B5 are each independently selected from F, Cl, Br, I, oxo, OH, CN, methyl, ethyl, methoxy or ethoxy, and the Methyl, ethyl, methoxy or ethoxy are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- R B4 are each independently selected from -SO 2 -methyl, -SO 2 -ethyl, nitro, F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy or ethoxy,
- the methyl, ethyl, methoxy or ethoxy groups are optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- R w1 , R w2 , and R w5 are each independently selected from H, F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, Methoxy or ethoxy is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CN, C 1-4 alkyl;
- R w1 and R w2 are directly connected to form a C 3-6 carbocycle or a 3-6 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, CN, C 1-4 alkyl substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
- R w3 and R w4 are directly connected to form a C 3-6 carbocycle or 3 to 6 membered heterocycle, and the carbocycle or heterocycle is optionally further replaced by 0 to 4 members selected from H, halogen, OH, CN, C Substituted by 1-4 alkyl substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S, N;
- R B1 and R B2 are directly connected to form a C 5-7 carbocycle or a 5-7 membered heterocycle, and the carbocycle or heterocycle is optionally further substituted by 0 to 3 R c , and the heterocycle Contains 1 to 3 heteroatoms selected from O, S, N;
- ring E is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl;
- A is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl;
- F is each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6,7-dihydro-5H-cyclopenta [c] pyridyl, 2, 3-Dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazine Base, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzo Thiazolyl, benzothienyl, benzofuryl
- R k7 are each independently selected from CH 2 , O, N(CH 3 ) or NH;
- p1 or p2 are each independently selected from 0, 1 or 2;
- L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2- Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, - Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak
- L is selected from a bond or a group shown in Table B-1, wherein the left side of the group is connected to B;
- the compound represented by the above general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, K is selected from From one of the following structural fragments:
- the compound represented by the above general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal the general formula
- the compound shown in (I) is selected from the compound shown in general formula (Ia)
- q1 is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
- R w1 and R w2 are selected from methyl
- R w1 and R w2 are directly connected to form a cyclopropyl group together with the carbon atom to which they are connected;
- the compound represented by the above general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal the general formula
- the compound shown in (I) is selected from the compound shown in general formula (Ib),
- q1 is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
- R w1 and R w2 are selected from methyl
- R w1 and R w2 are directly connected to form a cyclopropyl group together with the carbon atom to which they are connected;
- R d each independently selected from H or deuterium
- the compound represented by general formula (Ib) has at least one deuterium.
- the present invention relates to a compound or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structures shown in Table P-1 one:
- the present invention relates to a pharmaceutical composition, comprising the above-mentioned compounds of the present invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and pharmaceutically acceptable carrier.
- the present invention relates to a kind of above-mentioned compound of the present invention or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal used in the preparation of therapeutic and Bcl-2 family protein activity Or the application in the medicine of expression related diseases.
- the present invention relates to a compound or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal of the above-mentioned compound of the present invention for the preparation of treatment and inhibition or degradation of Bcl-2 Application in the medicine of family protein-related diseases.
- the present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, deuteriums, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and the disease is selected from cancer.
- the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite , a pharmaceutically acceptable salt or co-crystal and a pharmaceutically acceptable excipient.
- the pharmaceutical composition may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
- the present invention also provides a method for treating a disease in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, Metabolites, pharmaceutically acceptable salts or co-crystals or pharmaceutical compositions.
- the mammals of the present invention include humans.
- Effective amount or “therapeutically effective amount” as used in the present application refers to the administration of a sufficient amount of the compound disclosed in the present application, which will alleviate to some extent one or more of the diseases or conditions (such as cancer) to be treated. symptoms. In some embodiments, the result is reduction and/or alleviation of signs, symptoms or causes of disease, or any other desired alteration of a biological system.
- an "effective amount” for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
- therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6 -600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg , 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50 -500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-
- the pharmaceutical composition includes but is not limited to 1-1500mg, 1-1000mg, 20-800mg, 40-800mg, 40-400mg, 25-200mg, 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg, 320mg, 400mg, 480mg, 500mg, 600mg, 640mg, 840mg, 1000mg of the compound of the present invention or its stereoisomer, deuter
- a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably cancer.
- a method for treating a disease in a mammal comprises, the compound of the present invention or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal with A daily dose of 1-1500 mg/day is administered to the subject, and the daily dose can be a single dose or divided doses.
- the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10 -800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg /day, in some embodiments, daily doses include but are not limited to 10mg/day, 20mg/day, 25mg/day, 50mg/day, 80mg/day, 100mg/day, 125mg/day, 150mg/day, 160mg/day , 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day, 1500mg/day.
- the present invention relates to a kit, which may comprise a composition in single or multi-dose form, the kit comprising a compound of the present invention or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutical acceptable salt or co-crystal, the amount of the compound of the present invention or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is the same as that in the above-mentioned pharmaceutical composition same amount.
- the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
- the isotopes of carbon include 12 C, 13 C and 14
- Halogen means F, Cl, Br or I.
- Halogen substituted refers to F, Cl, Br or I substitution, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 substituents selected from F, Cl, Br Or substituted by a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I.
- Halo-substituted is simply referred to as "halo”.
- Alkyl refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to an alkyl group of 1 to 20 carbon atoms, an alkyl group of 1 to 8 carbon atoms, an alkyl group of 1 to 6 An alkyl group of carbon atoms, an alkyl group of 1 to 4 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched chain isomers; Alkyl group appearing in this article, its definition is consistent with this definition. Alkyl groups can be monovalent, divalent, trivalent or tetravalent.
- Hydrocarbyl refers to a substituted or unsubstituted, linear or branched, saturated or unsaturated group composed of carbon and hydrogen atoms. Hydrocarbyl groups may be monovalent, divalent, trivalent or tetravalent.
- Heteroalkyl refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) replace.
- Non-limiting examples include -X(CH 2 )vX(CH 2 )vX(CH 2 )vH (v is an integer from 1 to 5, each of X is independently selected from a bond or a heteroatom, and the heteroatom includes but is not limited to N , O or S, and at least one X is selected from heteroatoms, and N or S in heteroatoms can be oxidized into various oxidation states).
- Heteroalkyl groups can be monovalent, divalent, trivalent or tetravalent.
- Alkylene refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10), examples of alkylene include but not Limited to methylene, ethylene, propylene and butylene, etc.
- Heteroalkylene means a substituted or unsubstituted alkylene group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) substitutions.
- Non-limiting examples include -X(CH 2 )vX(CH 2 )vX(CH 2 )v-, v is an integer from 1 to 5, each of X is independently selected from a bond, N, O or S, and at least 1 X is selected from N, O or S.
- Cycloalkyl means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclo Heptyl etc. As used herein, cycloalkyl is as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.
- Heterocycloalkyl refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 atoms selected from N, O or
- the heteroatoms of S, the selectively substituted N and S in the ring of heterocycloalkyl can be oxidized into various oxidation states.
- the heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring or a spiro ring.
- Non-limiting examples include ring Oxyethyl, aziridyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl.
- a heterocycloalkyl group can be monovalent, divalent, trivalent or tetravalent.
- alkenyl means a substituted or unsubstituted straight and branched unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain including but not limited to 2 to 10 1, 2 to 6, or 2 to 4 carbon atoms
- alkenyl examples include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-but Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octen
- Alkynyl means a substituted or unsubstituted straight and branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to Including 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1 -Butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butyne Base, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- Hexynyl, 1-methyl-1-pentynyl,
- Alkoxy means a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl Oxygen and Cyclobutoxy.
- Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring
- the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered Bicyclic or 10- to 15-membered tricyclic ring system
- the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring
- the aromatic ring or non-aromatic ring is optionally a monocyclic, bridged or spiro ring.
- Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,
- a "carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
- Heterocyclic group refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered A bicyclic ring or a 10- to 15-membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, and the ring of the heterocyclyl group is selected from sexually substituted N and S can be oxidized into various oxidation states.
- the heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring.
- Non-limiting examples include oxirane , aziridyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyryl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorph Linyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl Base, benzimidazolyl, benzo
- Spiro ring or “spirocyclic group” refers to a polycyclic group that shares one atom (called spiro atom) between substituted or unsubstituted monocyclic rings.
- a “spirocycle” or “spirocyclyl” can be monovalent, divalent, trivalent or tetravalent.
- the number of ring atoms in the double ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:
- Alkyl or “alkyl” may be monovalent, divalent, trivalent or tetravalent.
- the number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12 or 5 to 10.
- Non-limiting examples include
- a "bridged ring” or “bridged ring group” may be monovalent, divalent, trivalent or tetravalent.
- Carbospiro refers to a “spirocycle” whose ring system consists only of carbon atoms.
- the definitions of “carbospirocycle”, “spirocyclic carbocyclyl”, “spirocarbocyclyl” or “carbospirocyclyl” appearing herein are consistent with spirocycle.
- Carbocyclic “paracyclic carbocyclyl”, “paracarbocyclyl” or “carbocyclyl” refers to a “carbocyclyl” whose ring system consists only of carbon atoms.
- the definition of “carbocyclyl”, “paracyclic carbocyclyl”, “paracarbocyclyl” or “carbocyclyl” used herein is consistent with that of paracyclyl.
- Carbobridged ring refers to a “bridged ring” whose ring system consists only of carbon atoms.
- the definitions of "carbon bridged ring”, “bridged ring carbocyclyl”, “bridged carbocyclyl” or “carbobridged ring” appearing in this article are consistent with those of bridged ring.
- Heterocyclic group refers to the “heterocyclic group” or “heterocyclic group” of a monocyclic ring system, and the heterocyclic group, "monocyclic heterocyclic group” appearing herein group” or “heteromonocyclic group”, the definition of which is consistent with that of heterocycle.
- Heterocyclyl refers to “heterocycles” that contain heteroatoms.
- the definition of heterocyclic ring, “heterocyclic group”, “heterocyclic heterocyclic group” or “heterocyclic group” used herein is consistent with that of parallel ring.
- Heterospiro refers to a “spirocycle” that contains heteroatoms.
- heterospirocycle refers to a “spirocycle” that contains heteroatoms.
- heterospirocycle refers to a “spirocycle” that contains heteroatoms.
- heterospirocycle refers to a “spirocycle” that contains heteroatoms.
- heterospirocycle refers to a “spirocycle” that contains heteroatoms.
- heterospirocycle refers to a "heterospirocyclyl” that contains heteroatoms.
- Heterobridged ring refers to a “bridged ring” that contains heteroatoms.
- the definition of heterobridged ring, “heterobridged ring group”, “bridged ring heterocyclyl group” or “heterobridged ring group” used herein is consistent with bridged ring.
- Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group with a single ring or a condensed ring, and the number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10 carbon atoms.
- the aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples include benzene, naphthalene, "Aryl” or “aromatic ring” may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
- heteroaryl examples include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
- the heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples include Where heteroaryl appears herein, its definition is consistent with this definition.
- Heteroaryl groups can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the heteroaryl ring.
- 5-membered ring and 5-membered heteroaromatic ring refers to a 5-membered condensed heteroaromatic ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N), the entire group is aromatic, and non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolopyrrole ring, pyrazolofuran ring, pyrrolothiophene ring, pyrazolothiophene ring.
- 5 and 6-membered heteroaryl ring refers to a 5-6 membered fused heteroaryl ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N) , the entire group is aromatic, non-limiting examples include benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl.
- Constants 1 to 5 heteroatoms selected from O, S, N means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.
- Substituted by 0 to X substituents selected from refers to being substituted by 0, 1, 2, 3...X substituents selected from..., and X is selected from any integer between 1 and 10.
- substituted by 0 to 4 substituents selected from ! refers to being substituted by 0, 1, 2, 3 or 4 substituents selected from ....
- substituted by 0 to 5 substituents selected from ! refers to being substituted by 0, 1, 2, 3, 4 or 5 substituents selected from ....
- the heterobridged ring is optionally further substituted by 0 to 4 substituents selected from H or F means that the heterobridged ring is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H or F base replaced.
- X-Y-membered rings (X is selected from an integer less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) includes X+1, X+2, X+3, X+4....Y-membered rings ring.
- Rings include heterocycles, carbocycles, aryls, aryls, heteroaryls, cycloalkyls, heteromonocycles, heteroheterocycles, heterospirocycles or heterobridged rings.
- 4--7 membered heteromonocyclic ring refers to 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring
- 5--10-membered heterocyclic ring refers to 5-, 6-, 7-, and 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
- Alkyl optionally substituted by F means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
- “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention maintains the biological effectiveness and characteristics of free acid or free base, and the free acid is mixed with a non-toxic inorganic base or Organic base, the salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.
- “Pharmaceutical composition” refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of co-crystals and other chemical components, wherein “other chemical components” refer to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
- Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
- Carrier refers to a material that does not produce significant irritation to an organism and that does not abrogate the biological activity and properties of the administered compound.
- Animal is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
- Stepoisomer refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
- Tautomer refers to a functional group isomer produced by a certain atom in a molecule moving rapidly at two positions, such as keto-enol isomerization and amide-imino alcohol isomerization.
- IC50 is the concentration of drug or inhibitor required to inhibit a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.) by half.
- Fig. 1 is the inhibitory result of compound 6 to the growth of MOLT-4 nude mouse xenograft tumor model; Wherein, compared with vehicle control group, ****P ⁇ 0.0001, two-way ANOVA (two-way ANOVA) first, then carry out Dunnnett's test (Dunnnett's test).
- the compounds used in the reactions described herein were prepared according to organic synthesis techniques known to those skilled in the art starting from commercially available chemicals and/or compounds described in the chemical literature "commercially available Chemicals” were obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai ) Chemical Industry Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.
- references books and monographs in the field detail the synthesis of reactants useful in the preparation of the compounds described herein, or are provided by reference to articles describing such preparations. These reference books and monographs include: “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S.R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H.O. House, “Modern Synthetic Reactions", 2nd Ed., W.A.Benjamin, Inc.
- the compounds used in the reactions described herein are prepared according to techniques of organic synthesis known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature.
- “Commercially available chemicals” are obtained from formal commercial sources, suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec and Bailingwei Technology, etc. company.
- NMR nuclear magnetic resonance
- MS mass spectroscopy
- HPLC HPLC-based high pressure liquid chromatography
- the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
- the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. -0.5mm;
- the crude product 1b (1.5g) was added to 50mL 2mol/L hydrochloric acid ethyl acetate solution, and reacted at room temperature for 3h. Filter the reaction system, add 50 mL of dichloromethane to the filter cake, add 50 mL of saturated sodium bicarbonate solution and stir until the solids are completely dissolved, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product 1c (0.9 g) .
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.1% TFA).
- Gradient elution method 60% of acetonitrile was eluted with a gradient of 5% (elution time 15min).
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.1% TFA).
- Gradient elution method 60% of acetonitrile was eluted with a gradient of 5% (elution time 15min).
- Dissolve 3b (0.40g, 0.88mmol) in 10mL of methanol, add 1mL of water and sodium hydroxide (0.15g, 3.75mmol), and react at 80°C for 10h. Cool to room temperature, concentrate the reaction system under reduced pressure, dissolve it with 10 mL of water, wash with 20 mL of methyl tert-butyl ether, separate the water phase, adjust the pH to 6 with 1 mol/L hydrochloric acid, and extract with ethyl acetate (100 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 3c (0.20 g).
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.1% TFA).
- Gradient elution method 60% of acetonitrile was eluted with a gradient of 5% (elution time 15min).
- Dissolve 4c (0.55g, 1.20mmol) in 20mL of methanol, add 2mL of water, add sodium hydroxide (0.24g, 6.0mmol), stir at 80°C for 10h. Cool the reaction solution to room temperature, concentrate under reduced pressure, add 10 mL of water to dissolve, extract impurities with 20 mL of methyl tert-butyl ether, separate the water phase, adjust the pH to 6 with 1 mol/L hydrochloric acid, and extract with ethyl acetate (100 mL ⁇ 2 ), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (0.35 g).
- the fourth step the preparation of the trifluoroacetic acid salt of compound 4
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.1% TFA).
- Gradient elution method acetonitrile was eluted from 5% gradient to 60% (elution time 15 min), and lyophilized to obtain the trifluoroacetic acid salt of compound 4 (20 mg).
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.1% TFA).
- Gradient elution method 60% of acetonitrile was eluted with a gradient of 5% (elution time 15min).
- Embodiment 6 is a diagrammatic representation of Embodiment 6
- 6a (see WO2020041406 for the synthesis method) (2g, 9.85mmol) and (4-chlorophenyl)boronic acid (2.47g, 15.80mmol) were dissolved in 20mL of dioxane and 2mL of water in turn, and potassium acetate was added in turn (3.11g, 31.69mmol) and Pd(dppf)Cl 2 (0.2g, 0.27mmol) were reacted at 90°C for 4h.
- the fourth step the preparation of the trifluoroacetic acid salt of compound 6
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.1% TFA).
- Gradient elution method acetonitrile was eluted from 5% gradient to 60% (elution time 15 min), and lyophilized to obtain the trifluoroacetic acid salt of compound 6 (20 mg).
- Embodiment 7 is a diagrammatic representation of Embodiment 7:
- Dissolve 7b (0.320g, 0.68mmol) in 10mL of methanol, add 1mL of water and sodium hydroxide (0.11g, 2.75mmol), and react at 80°C for 10h. Cool to room temperature, concentrate the reaction system under reduced pressure, dissolve with 10 mL of water, extract impurities with 20 mL of methyl tert-butyl ether, adjust the pH to 6 with 1 mol/L hydrochloric acid, extract with ethyl acetate (100 mL ⁇ 2), anhydrous Dry over sodium sulfate and concentrate under reduced pressure to obtain a crude product (0.23 g).
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.1% TFA).
- Gradient elution method 60% of acetonitrile was eluted by a gradient of 5% (elution time 15min), 100mL DCM and 60mL saturated sodium bicarbonate solution were added to the preparation solution and stirred for 1h, the organic phase was separated, dried over anhydrous sodium sulfate, and reduced pressure Concentration gave compound 7 (60 mg, yield: 17%).
- Embodiment 8 is a diagrammatic representation of Embodiment 8
- Dissolve 8a (1.88g, 8.86mmol) in 10mL of dichloromethane, add triethylamine (0.98g, 9.68mmol), cool to 0°C, and slowly add 2,2,2-trichloroethyl chloroformate dropwise (2.06g, 9.72mmol), and then slowly warmed to room temperature for 2h.
- Dissolve 8b (0.7 g, 1.81 mmol) in 2 mL of dichloromethane, add 1 mL of trifluoroacetic acid, and react at room temperature for 3 h.
- the reaction solution was concentrated under reduced pressure, 20 mL of dichloromethane and 10 mL of water were added to the residue, the pH was adjusted to 9 with saturated sodium bicarbonate solution, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 8c ( 0.5g).
- the fourth step the preparation of the trifluoroacetic acid salt of 8e
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.1% TFA).
- Gradient elution method acetonitrile was eluted 60% by 5% gradient (elution time 15min), the preparation solution was lyophilized, 2mL ethyl acetate and 1mL saturated sodium bicarbonate solution were added to the lyophilized solid and stirred for 1min, and the organic phase, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8 (18 mg, yield: 10%).
- Embodiment 9 is a diagrammatic representation of Embodiment 9:
- the above crude product 9b (8.00 g) was dissolved in 60 mL of dichloromethane, 20 mL of trifluoroacetic acid was added, and reacted at room temperature for 3 h. Concentrate the reaction solution under reduced pressure, dissolve the residue in 50 mL of dichloromethane, adjust the pH to 8 with saturated aqueous sodium bicarbonate solution, separate the layers, extract the aqueous phase twice with 100 mL of dichloromethane, combine the organic phases, and dry over anhydrous sodium sulfate , filter the reaction system, add 50mL dichloromethane to the filter cake, add 50mL saturated sodium bicarbonate solution and stir until the solids are completely dissolved, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product 9c (3.50g ).
- the seventh step the preparation of the trifluoroacetic acid salt of compound 9
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.1% TFA).
- Gradient elution method acetonitrile was eluted from 5% gradient to 60% (elution time 15 min), and lyophilized to obtain the trifluoroacetic acid salt of compound 9 (0.02 g).
- Dissolve 10a (1.90g, 9.58mmol) in 10mL of dichloromethane, add triethylamine (1.07g, 10.57mmol), cool to 0°C, and slowly add 2,2,2-trichloroethyl chloroformate dropwise (2.24g, 10.57mmol), and then slowly rise to room temperature for 3h. After the reaction was completed, 15 mL of water was added to quench, and the layers were separated. The aqueous phase was extracted with 15 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 10b (3.25 g).
- the above crude product 10b (3.25 g) was dissolved in 20 mL of DCM, 7 mL of trifluoroacetic acid was added, and reacted at room temperature for 3 h.
- the reaction solution was concentrated under reduced pressure, the residue was dissolved in 50 mL of DCM, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, the liquids were separated, the aqueous phase was extracted twice with 100 mL of DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure , the crude product 10c (2.30 g) was obtained.
- the seventh step the preparation of compound 10
- 12a (see WO2021066873 for the synthesis method) (2 g, 9.21 mmol) and (4-chloro-2-fluorophenyl) boronic acid (2.41 g, 13.82 mmol) were dissolved in 20 mL of dioxane and 2 mL of water, followed by Potassium acetate (2.71g, 27.61mmol) and Pd(dppf)Cl 2 (0.2g, 0.27mmol) were added and reacted at 90°C for 4h.
- Dissolve 12b (2.4g, 9.0mmol) in 15mL DCE, add ethyl 4-(piperazin-1-yl)benzoate (2.10g, 9.0mmol) and 5mL tetraisopropyl titanate successively, and stir at room temperature for 3h Afterwards, sodium triacetoxyborohydride (3.81 g, 17.98 mmol) was added and reacted at room temperature for 16 h.
- Dissolve 12c (1.4g, 2.89mmol) in 10mL of methanol, add 1mL of water and sodium hydroxide (0.35g, 8.75mmol), and react at 80°C for 10h.
- the reaction solution was cooled to room temperature, concentrated under reduced pressure, dissolved in 10 mL of water, washed with 20 mL of methyl tert-butyl ether, separated from the water phase, adjusted to pH 6 with 1 mol/L hydrochloric acid, and extracted with ethyl acetate (100 mL ⁇ 2) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (0.8 g).
- the fourth step the preparation of the trifluoroacetic acid salt of 13e
- Dissolve 12c (1.4g, 2.89mmol) in 10mL of methanol, add 1mL of water and sodium hydroxide (0.35g, 8.75mmol), and react at 80°C for 10h.
- the reaction solution was cooled to room temperature, concentrated under reduced pressure, dissolved in 10 mL of water, washed with 20 mL of methyl tert-butyl ether, separated from the water phase, adjusted to pH 6 with 1 mol/L hydrochloric acid, and extracted with ethyl acetate (100 mL ⁇ 2) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (0.8 g).
- Pre-HPLC Instrument and preparative column: use SHIMADZU LC-20AP to prepare the liquid phase, prepare The column type is Phenomenex C18).
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.05% NH 4 HCO 3 ).
- Gradient elution method acetonitrile was eluted from 60% gradient to 90% (elution time 15 min), and lyophilized to obtain compound 15 (35 mg, yield: 7%).
- Pre-HPLC Instrument and preparative column: use SHIMADZU LC-20AP to prepare the liquid phase, prepare The column type is Phenomenex C18).
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.05% NH 4 HCO 3 ).
- Gradient elution method acetonitrile was eluted from 60% gradient to 90% (elution time 15 min), and lyophilized to obtain compound 16 (85 mg, yield: 16%).
- the above crude product (120mg) was dissolved in 15mL DCM, 0.17mL triethylamine, intermediate 1 (70mg, 0.12mmol) and HATU (68mg, 0.18mmol) were added successively, and reacted at room temperature for 2h.
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.05% NH 4 HCO 3 ).
- Gradient elution method acetonitrile was eluted from 50% gradient to 80% (elution time 15 min), and lyophilized to obtain compound 19 (40 mg, yield: 18%).
- the first step preparation of 20a
- Dissolve 12c (1.4g, 2.89mmol) in 10mL of methanol, add 1mL of water and sodium hydroxide (0.35g, 8.75mmol), and react at 80°C for 10h.
- the reaction solution was cooled to room temperature, concentrated under reduced pressure, dissolved in 10 mL of water, washed with 20 mL of methyl tert-butyl ether, separated from the water phase, adjusted to pH 6 with 1 mol/L hydrochloric acid, and extracted with ethyl acetate (100 mL ⁇ 2) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (0.8 g).
- Dissolve 21a (1.00g, 5.86mmol) and (4-chloro-2-fluorophenyl)boronic acid (1.02g, 5.85mmol) in 30mL of dioxane and 3mL of water, and replace nitrogen three times , Potassium acetate (1.73g, 17.63mmol) and Pd(dppf)Cl 2 (0.13g, 0.18mmol) were added under nitrogen protection, and reacted at 90°C for 7h.
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.05% NH 4 HCO 3 ).
- Gradient elution method acetonitrile was eluted from 20% gradient to 50% (elution time 15 min), and lyophilized to obtain compound 24 (221 mg, yield: 18%).
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water (containing 0.05% NH 4 HCO 3 ).
- Gradient elution method acetonitrile was eluted from 50% gradient to 80% (elution time 15 min), and lyophilized to obtain compound 25 (97 mg, yield: 14%).
- the fourth step the preparation of the trifluoroacetic acid salt of 26e
- 26f (0.87g, 1.11mmol) was added to 10mL DCM, and 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1 ,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (0.49g, 1.11mmol), DMAP (0.27g, 2.21mmol) and EDCI (0.43g, 2.25mmol), Reaction at room temperature for 12h.
- Preparation method Dissolve the crude product in methanol and dimethyl sulfoxide, and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
- Mobile phase system acetonitrile/water.
- Gradient elution method acetonitrile was eluted from 59% to 89% (elution time 15 min), and lyophilized to obtain compound 26 (80 mg, yield: 24%).
- Mobile phase system acetonitrile/water (containing 0.05% NH 4 HCO 3 ).
- Gradient elution method acetonitrile was eluted from 50% gradient to 80% (elution time 15 min), and lyophilized to obtain compound 27 (0.10 g, yield: 44%).
- 29a (0.35g, 0.30mmol) was added into 3mL of tetrahydrofuran and 15mL of methanol, zinc powder (1.57g, 24.15mmol) and ammonium chloride (0.48g, 8.97mmol) were added successively, and stirred at 27°C for 12h.
- 29a (0.35g, 0.30mmol) was added into 3mL of tetrahydrofuran and 15mL of methanol, zinc powder (1.57g, 24.15mmol) and ammonium chloride (0.48g, 8.97mmol) were added successively, and stirred at 27°C for 12h.
- the first step preparation of 31a
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Abstract
Description
序号 | 化合物编号 | DC 50(nM) |
1 | 对照化合物 | >20 |
2 | 化合物6 | 8.4 |
3 | 化合物8 | 8.8 |
5 | 化合物10 | 3.7 |
6 | 化合物11 | 5.3 |
9 | 化合物14 | 8.1 |
10 | 化合物15 | 3.6 |
12 | 化合物19 | 10.7 |
序号 | 化合物编号 | IC 50(nM) |
1 | 化合物2 | A |
2 | 化合物4的三氟乙酸盐 | A |
3 | 化合物5 | A |
4 | 化合物6的三氟乙酸盐 | A |
5 | 化合物7 | A |
6 | 化合物8 | A |
7 | 化合物9的三氟乙酸盐 | A |
8 | 化合物10 | A |
9 | 化合物11 | A |
10 | 化合物12 | A |
11 | 化合物13 | A |
12 | 化合物14 | A |
13 | 化合物15 | A |
14 | 化合物16 | A |
15 | 化合物17 | A |
16 | 化合物18 | A |
17 | 化合物19 | A |
18 | 化合物20 | A |
19 | 化合物21 | A |
20 | 化合物22 | A |
21 | 化合物23 | A |
22 | 化合物24 | A |
23 | 化合物25 | A |
24 | 化合物26 | A |
25 | 化合物27 | A |
26 | 化合物28 | A |
27 | 化合物29 | A |
28 | 化合物30 | A |
29 | 化合物31 | A |
30 | 化合物32 | A |
31 | 化合物33 | A |
32 | 化合物34 | A |
33 | 化合物35 | A |
34 | 化合物36 | A |
35 | 化合物37 | A |
36 | 化合物38 | A |
37 | 化合物39 | A |
38 | 化合物40 | A |
39 | 化合物41 | A |
40 | 化合物42 | A |
41 | 化合物43 | A |
42 | 化合物44 | A |
43 | 化合物45 | A |
检测时间点 | 化合物6(♂) | 化合物6(♀) | 对照化合物(♂) | 对照化合物(♀) |
给药剂量 | 60mg/kg | 60mg/kg | 60mg/kg | 60mg/kg |
D8 | ↓17% | ↓53% | ↓73% | ↓87% |
Claims (16)
- 一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,化合物选自通式(I)所示的化合物,B-L-K(I);L选自键或-C 1-50烃基-,所述烃基中有0至20个亚甲基单元任选进一步被-Ak-、-Cy-替换;每个-Ak-各自独立地选自-(CH 2) q-、-(CH 2) q-O-、-O-(CH 2) q-、-(CH 2) q-NR L-、-NR L-(CH 2) q-、-(CH 2) q-NR LC(=O)-、-NR L(CH 2) qC(=O)-、-(CH 2) q-C(=O)NR L-、-C(=O)-、-C(=O)-(CH 2) q-NR L-、-(C≡C) q-、-CH=CH-、-Si(R L) 2-、-Si(OH)(R L)-、-Si(OH) 2-、-P(=O)(OR L)-、-P(=O)(R L)-、-S-、-S(=O)-、-S(=O) 2-或者键,所述的-CH 2-任选进一步被0至2个选自H、卤素、OH、CN、NH 2、C 1-6烷基、C 1-6烷氧基、卤素取代的C 1-6烷基、羟基取代的C 1-6烷基、氰基取代的C 1-6烷基的取代基所取代;q各自独立的选自0、1、2、3、4、5或6;R L各自独立的选自H、C 1-6烷基、3-7元杂环基、3-7元环烷基、苯基或5-6元杂芳基;每个-Cy-各自独立地选自键、4-8元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基,所述芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH 2、=O、C 1-4烷基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代,所述的杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S或N的杂原子,当杂原子选自S时,任选进一步被0、1或2个=O取代;W选自W 1或W 2;W 1选自-CR w1R w2-、-(CR w1R w2) 3-、-(CR w1R w2) 4-、-CH 2CR w3R w4-、-CR w3R w4CH 2-、-CR w1R w2O-、-OCR w1R w2-、-CR w1R w2NR w5-或-NR w5CR w1R w2-;W 2选自-(CR w1R w2) 2-;D选自C 1-4亚烷基;B 1、Z各自独立的选自4-7元杂单环、5-12元杂并环、6-12元杂螺环或7-12元杂桥环,所述B 1任选进一步被0至4个R B1取代,所述Z任选进一步被0至4个R Q取代,所述的杂并环、杂螺环、杂桥环含有1至3个选自O、S或N的杂原子,当杂原子选自S时,任选进一步被0、1或2个=O取代;B 2、B 3、B 4、B 5各自独立的选自C 6-10芳基或5至10元杂芳基,所述B 2任选进一步被0至4个R B2取代,所述B 3任选进一步被0至5个R B3取代,所述B 4任选进一步被0至4个R B4取代,所述B 5任选进一步被0至5个R B5取代,所述的杂芳基含有1至3个选自O、S或N的杂原子;R B1、R Q、R B2、R B3、R B5各自独立的选自卤素、OH、oxo、CN、C 1-4烷基或C 1-4烷氧基,所 述的烷基或者烷氧基任选进一步被0至4个选自H、卤素、OH、CN或C 1-4烷基的取代基所取代;R B4各自独立的选自-SO 2-C 1-4烷基、硝基、卤素、CN、OH、C 1-4烷基或C 1-4烷氧基,所述的烷基或者烷氧基任选进一步被0至4个选自H、卤素、OH、CN或C 1-4烷基的取代基所取代;R w1、R w2、R w5各自独立的选自H、卤素、CN、OH、C 1-4烷基或C 1-4烷氧基,所述的烷基或者烷氧基任选进一步被0至4个选自H、卤素、OH、CN或C 1-4烷基的取代基所取代;作为选择,R w1、R w2直接连接,形成C 3-6碳环或3至6元杂环,所述的碳环或杂环任选进一步被0至4个选自H、卤素、OH、CN或C 1-4烷基的取代基所取代,所述的杂环含有1至3个选自O、S或N的杂原子;R w3、R w4直接连接,形成C 3-6碳环或3至6元杂环,所述的碳环或杂环任选进一步被0至4个选自H、卤素、OH、CN或C 1-4烷基的取代基所取代,所述的杂环含有1至3个选自O、S或N的杂原子;作为选择,R B1、R B2直接连接形成C 5-7碳环或5-7元杂环,所述的碳环或杂环任选进一步被0至3个R c取代,所述的杂环含有1至3个选自O、S或N的杂原子;R c各自独立的选自卤素、OH、CN、=O、C 1-4烷基、C 1-4烷氧基、C 3-6碳环或3至7元杂环,所述的烷基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至7元杂环烷基的取代基所取代,所述的杂环或杂环烷基含有1至3个选自O、S或N的杂原子;条件是当W 2选自-(CR w1R w2) 2-,且R w1、R w2各自独立地选自F、甲基或甲氧基时,B至少满足以下任意条件之一:1)B 1不为哌嗪;3)B 3选自苯基,苯基被1个R B3取代,R B3位于苯基对位时,R B3不为卤素、甲基或三氟甲基;4)B 2选自苯基时,所述苯基被1至4个R B2取代;5)R B1、R B2直接连接形成C 5-7碳环或5-7元杂环,所述的碳环或杂环任选进一步被0至3个R c取代,所述的杂环含有1至3个选自O、S、N的杂原子;6)B 5选自苯基时,所述苯基被1至4个R B5取代;Q各自独立地选自键、-O-、-S-、-CH 2-、-NR q-、-CO-、-NR qCO-、-CONR q-或3-12元杂环基,所述的杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代,所述杂环基含有1至4个选自O、S或N的杂原子;R q选自H或C 1-6烷基;A选自C 3-10碳环基、C 6-10芳基、3-10元杂环基或5-10元杂芳基,所述杂环或杂芳基含有1至4个选自O、S或N的杂原子;F各自独立地选自C 3-20碳环基、C 6-20芳基、3-20元杂环基或5-20元杂芳基,所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子;R k2各自独立地选自键、-CO-、-SO 2-、-SO-或-C(R k3) 2-;R k1各自独立地选自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-6烷基或C 1-6烷氧基,所述的烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;R k3各自独立地选自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或3-8元杂环基,所述的烷基、烷氧基、环烷基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代,所述杂环基含有1至4个选自O、S或N的杂原子;或者两个R k3和与二者直接相连的碳原子或环骨架共同形成3-8元碳环或3-8元杂环,所述碳环或杂环任选进一步被0至4个选自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代,所述杂环含有1至4个选自O、S或N的杂原子;R k4各自独立地选自H、OH、NH 2、CN、CONH 2、C 1-6烷基、C 3-8环烷基或3-8元杂环基,所述的烷基、环烷基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代,所述杂环基含有1至4个选自O、S或N的杂原子;M 1选自键、-C(=O)NH-、-NHC(=O)-、-CH 2-C(=O)NH-、-C(=O)CH 2NH-或5-6元杂芳基,所 述的杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、=O、CF 3、NH 2、CN、C 1-4烷基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代,所述的杂芳基含有含有1至4个选自O、S或N的杂原子;M 2选自-NHC(=O)-C 1-6烷基、-NHC(=O)-C 3-6环烷基或4-10元杂环基,所述的烷基、环烷基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代,所述杂环基含有1至4个选自O、S或N的杂原子;M 3选自-NH-或-O-;R k10选自C 1-6烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、=O、OH、C 1-6烷基或C 3-6环烷基的取代基所取代;R k11各自独立的选自H、F、Cl、Br、I、=O、OH、SH、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基或-O-C(=O)-C 1-6烷基,所述的烷基、烷氧基或烷硫基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代;R k12、R k13各自独立的选自H、C 1-6烷基或C 3-6环烷基,所述的烷基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;R k14选自5-6元杂芳基,所述的杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、=O、CF 3、CN、C 1-4烷基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代,所述杂芳基含有1至4个选自N、O或S的杂原子;G选自6-10元芳基或5-10元杂芳基,所述的芳基或者杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、=O、CF 3、CN、C 1-4烷基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代,所述杂芳基含有1至4个选自N、O或S的杂原子;任选地,通式(I)所示的化合物中的1至20个H被1至20个氘替换;n1、n2、n3各自独立的选自0、1、2或3;p1或p2各自独立的选自0、1、2、3、4或5。
- 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,L选自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、 -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9;Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH 2) q-、-(CH 2) q-O-、-O-(CH 2) q-、-(CH 2) q-NR L-、-NR L-(CH 2) q-、-(CH 2)q-NR LC(=O)-、-(CH 2) q-C(=O)NR L-、-C(=O)-、-C(=O)-(CH 2) q-NR L-、-(C≡C) q-或者键,所述的-CH 2-任选进一步被0至2个选自H、卤素、OH、CN、NH 2、C 1-4烷基、C 1-4烷氧基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基或氰基取代的C 1-4烷基的取代基所取代;Cy1、Cy2、Cy3、Cy4或Cy5各自独立地选自键、4-7元杂单环、4-10元杂并环、5-12元杂螺环、7-10元杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基,所述芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH 2、=O、C 1-4烷基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代,所述的杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S或N的杂原子,当杂原子选自S时,任选进一步被0、1或2个=O取代;q各自独立的选自0、1、2、3或4;R L各自独立的选自H或C 1-6烷基。
- 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH 2) q-、-(CH 2) q-O-、-O-(CH 2) q-、-(CH 2) q-NR L-、-NR L-(CH 2) q-、-(CH 2)q-NR LC(=O)-、-(CH 2) q-C(=O)NR L-、-C(=O)-、-C(=O)-(CH 2) q-NR L-、-(C≡C) q-或者键,所述的-CH 2-任选进一步被0至2个选自H、F、Cl、Br、I、OH、CN、NH 2、CF 3、羟甲基、C 1-4烷基、C 1-4烷氧基的取代基所取代;Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键、4-7元含氮杂单环、4-10元含氮杂并环、5-12元含氮杂螺环、7-10元含氮杂桥环、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基,所述杂单环、杂并环、杂桥环、杂螺环、环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH 2、=O、C 1-4烷基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代,所述的杂单环、杂并环、杂桥环、杂螺环或杂芳基含有1至4个选自O、S或N的杂原子,当杂原子选自 S时,任选进一步被0、1或2个=O取代;R L各自独立的选自H或C 1-4烷基;M 2选自-NHC(=O)-C 1-4烷基、-NHC(=O)-C 3-6环烷基或4-10元杂环基,所述的烷基、环烷基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代,所述杂环基含有1至4个选自O、S或N的杂原子;R k10选自C 1-4烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、=O、OH、C 1-4烷基或C 3-6环烷基的取代基所取代;R k11各自独立的选自H、F、Cl、Br、I、=O、OH、SH、C 1-4烷基、C 1-4烷氧基或C 1-4烷硫基 或-O-C(=O)-C 1-4烷基,所述的烷基、烷氧基或烷硫基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代;R k12、R k13各自独立的选自H、C 1-4烷基或C 3-6环烷基,所述的烷基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;Q各自独立地选自-O-、-S-、-CH 2-、-NR q-、-CO-、-NR qCO-、-CONR q-或4-7元杂环基,所述的杂环基任选进一步被0至4个选自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代,所述杂环基含有1至4个选自O、S或N的杂原子;R q选自H或C 1-4烷基;R k1、R k3各自独立的选自H、F、Cl、Br、I、OH、=O、NH 2、CF 3、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基,所述烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH或NH 2的取代基所取代;或者两个R k3和与二者直接相连的碳原子或环骨架共同形成3-6元碳环或3-7元杂环,所述碳环或杂环任选进一步被0至4个选自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代,所述杂环含有1至4个选自O、S或N的杂原子;R k4各自独立的选自H、OH、NH 2、CF 3、CN或C 1-4烷基;R k6各自独立地选自CO、CH、SO、SO 2、CH 2或N;R k7各自独立地选自CO、CH、N、CH 2、O、S、N(CH 3)或NH;R k8各自独立地选自C、N或CH;R k9各自独立地选自CO、CH 2或SO 2;A、H1或H2各自独立地选自C 3-8碳环、苯环、4-7元杂环或5-6元杂芳基,所述杂环或杂芳基含有1至4个选自O、S或N的杂原子;E各自独立地选自C 3-8碳环、苯环、4-7元杂环、8-12元杂环、7-12元杂芳基或5-6元杂芳基,所述杂环或杂芳基含有1至4个选自O、S或N的杂原子;F各自独立地选自3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、4-7元杂单环、4-10元杂并环、5-12元杂螺环、5-10元杂桥环、C 6-14芳基或5-10元杂芳基,所述杂单环、杂并环、杂螺环、杂桥环或杂芳基含有1至4个选自O、S或N的杂原子。
- 根据权利要求3所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自-(CH 2) q-、-(CH 2) q-O-、-O-(CH 2) q-、-(CH 2) q-NR L-、-NR L-(CH 2) q-、-(CH 2)q-NR LC(=O)-、-(CH 2) q-C(=O)NR L-、-C(=O)-、-C(=O)-(CH 2) q-NR L-、-(C≡C) q-或者键,所述的-CH 2-任选进一步被0至2个选自H、F、Cl、Br、I、OH、CN、NH 2、CF 3、羟甲基、甲基、乙基、甲氧基或乙氧基的取代基所取代;R L选自H、甲基或乙基;q各自独立的选自0、1、2、3;Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一:环丙 基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、苯基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环已基、环戊基并环戊基、环戊基并环已基、环已基并环已基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环已基、环已基螺环已基、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶基、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶基、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶基、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶基、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶基、环戊基螺哌啶基、环己基螺哌啶基、氮杂环丁基螺哌啶基、氮杂环戊基螺哌啶基、氮杂环己基螺哌啶基、 当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、COOH、CN、=O、C 1-4烷基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代;D选自亚乙基;B 1和Z各自独立的选自氮杂环丁基、氮杂环戊基、哌嗪基、哌啶基、氮杂环己烯基、氮杂环庚烷基、1,4-二氮杂环庚烷基、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环己基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊 基并哌啶基、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶基、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶基、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环己基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环己基、环己基螺氮杂环丁基、环己基螺氮杂环戊基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶基、环戊基螺哌啶基、环己基螺哌啶基、氮杂环丁基螺哌啶基、氮杂环戊基螺哌啶基、氮杂环己基螺哌啶基、 所述B 1任选进一步被0至4个R B1取代,所述Z任选进一步被0至4个R Q取代;B 2、B 4各自独立的选自苯基或5-6元杂芳基,B 3、B 5各自独立的选自苯基、萘基、5-6元杂芳基或苯并5至6元杂芳基,所述B 2任选进一步被0至4个R B2取代,所述B 3任选进一步被0至5个R B3取代,所述B 4任选进一步被0至4个R B4取代,所述B 5任选进一步被0至5个R B5取代,所述的杂芳基含有1至3个选自O、S或N的杂原子;R B1、R Q、R B2、R B3、R B5各自独立的选自F、Cl、Br、I、oxo、OH、CN、甲基、乙基、甲氧基或乙氧基,所述的甲基、乙基、甲氧基或乙氧基任选进一步被0至4个选自H、卤素、OH、CN或C 1-4烷基的取代基所取代;R B4各自独立的选自-SO 2-甲基、-SO 2-乙基、硝基、F、Cl、Br、I、OH、CN、甲基、乙基、甲氧基或乙氧基,所述的甲基、乙基、甲氧基或乙氧基任选进一步被0至4个选自H、卤素、OH、CN或C 1-4烷基的取代基所取代;R w1、R w2、R w5各自独立的选自H、F、Cl、Br、I、OH、CN、甲基、乙基、甲氧基或乙氧基,所述的甲基、乙基、甲氧基或乙氧基任选进一步被0至4个选自H、卤素、OH、CN或C 1-4烷基的取代基所取代;作为选择,R w1、R w2直接连接,形成C 3-6碳环或3至6元杂环,所述的碳环或杂环任选进一步被0至4个选自H、卤素、OH、CN或C 1-4烷基的取代基所取代,所述的杂环含有1至3个选自O、S或N的杂原子;R w3、R w4直接连接,形成C 3-6碳环或3至6元杂环,所述的碳环或杂环任选进一步被0至4个选自H、卤素、OH、CN或C 1-4烷基的取代基所取代,所述的杂环含有1至3个选自O、S或N的杂原子;作为选择,R B1、R B2直接连接形成C 5-7碳环或5-7元杂环,所述的碳环或杂环任选进一步被0至3个R c取代,所述的杂环含有1至3个选自O、S或N的杂原子;R c各自独立的选自F、Cl、Br、I、OH、CN、=O、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、吗啉基、哌嗪基,所述的甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、吗啉基、哌嗪基任选进一步被0至4个选自H、卤素、OH、CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3至7元杂环烷基的取代基所取代,所述的杂环烷基含有1至3个选自O、S或N的杂原子;M 1选自键、-C(=O)NH-、-CH 2-C(=O)NH-、-C(=O)CH 2NH-、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、异噁唑基、呋喃基、噻吩基或噻唑基;M 2选自-NHC(=O)-CH 3、-NHC(=O)-环丙基、-NHC(=O)-环丁基、氮杂环丁基、氮杂环戊基、 苯并氮杂环戊基或苯并氮杂环己基,所述的环丙基、环丁基、氮杂环丁基、氮杂环戊基、苯并氮杂环戊基或苯并氮杂环己基任选进一步被0至4个选自H、F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;R k10选自甲基、乙基、异丙基、丙基或叔丁基,所述的甲基、乙基、异丙基、丙基、叔丁基任选进一步被0至4个选自H、F、Cl、Br、I、=O、OH、C 1-4烷基或C 3-6环烷基的取代基所取代;R k11各自独立的选自H、F、Cl、Br、I、=O、OH、SH、甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、甲硫基、乙硫基、丙硫基或-O-C(=O)-CH 3,所述的甲基、乙基、异丙基、丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、甲硫基、乙硫基、丙硫基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代;R k12、R k13各自独立的选自H、甲基、乙基、异丙基、丙基、环丙基或环丁基,所述的甲基、乙基、异丙基、丙基、环丙基或环丁基任选进一步被0至4个选自H、F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;E各自独立地选自苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、呋喃基、噻吩基或噁唑基;A各自独立地选自苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、呋喃基、噻吩基或噁唑基;F各自独立地选自环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊烷基、6,7-二氢-5H-环戊[c]吡啶基、2,3-二氢-1H-茚基、苯基、萘基、蒽基、菲基、氮杂环丁基、氮杂环戊基、哌啶基、吗啉基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并吡啶基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基、吡咯并吡咯基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡嗪基、吡啶并哒嗪基、哒嗪并哒嗪基、哒嗪并吡嗪基或吡嗪并吡嗪基;R k7各自独立地选自CH 2、O、N(CH 3)或NH;p1或p2各自独立的选自0、1或2。
- 根据权利要求4所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9各自独立的选自键、-O-、-OCH 2-、-CH 2O-、-OCH 2CH 2-、-CH 2CH 2O-、-C≡C-、-C(CH 3) 2-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-N(CH 3)-、-NH-、-CH 2N(CH 3)-、-CH 2NH-、-NHCH 2-、-CH 2CH 2N(CH 3)-、-CH 2CH 2NH-、-NHCH 2CH 2-、-C(=O)-、-C(=O)CH 2NH-、-CH 2C(=O)NH-、-C(=O)NH-或-NHC(=O)-;B选自表B-a所示结构片段之一;K选自表K-a所示结构片段之一。
- 根据权利要求5所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,L选自键、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、 -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-。
- 根据权利要求1-6任一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,L选自键或表B-1所示的基团,其中基团左侧与B连接。
- 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中该化合物选自表P-1所示结构之一。
- 一种药物组合物,包括权利要求1-11任意一项所述的化合物或者其立体异构体、氘代物、 溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及药学上可接受的载体,优选地,所述的药物组合物中含有1~1500mg权利要求1-11任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。
- 权利要求1-11任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与Bcl-2家族蛋白活性或表达量相关疾病的药物中的应用。
- 权利要求1-11任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与抑制或降解Bcl-2家族蛋白相关疾病的药物中的应用。
- 根据权利要求13或14所述的应用,所述的疾病选自癌症。
- 一种用于治疗哺乳动物的疾病的方法,所述方法包括给予受试者治疗有效量的权利要求1-11任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,治疗有效量优选1-1500mg,所述的疾病优选癌症。
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WO2024067818A1 (zh) * | 2022-09-30 | 2024-04-04 | 江苏恒瑞医药股份有限公司 | 一种用于bcl-2蛋白靶向降解的嵌合体化合物、其制备方法及其在医药上的应用 |
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Publication number | Priority date | Publication date | Assignee | Title |
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