WO2020006724A1 - Composé de dégradation ciblée de protéine fak et utilisation associée - Google Patents

Composé de dégradation ciblée de protéine fak et utilisation associée Download PDF

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WO2020006724A1
WO2020006724A1 PCT/CN2018/094594 CN2018094594W WO2020006724A1 WO 2020006724 A1 WO2020006724 A1 WO 2020006724A1 CN 2018094594 W CN2018094594 W CN 2018094594W WO 2020006724 A1 WO2020006724 A1 WO 2020006724A1
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independently
deuterium
ring atoms
alkyl
butyl
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PCT/CN2018/094594
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Chinese (zh)
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饶燏
周光飚
孙永汇
吴越
高红英
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清华大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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

Definitions

  • the present invention relates to the field of biomedicine, and in particular, the present invention relates to a compound for targeted degradation of FAK protein and its application.
  • FAK protein also known as PTK2
  • PTK2 is encoded by the PTK2 gene.
  • FAK kinases play an important role in cell adhesion, including the adhesion between cells and the interaction of cells with the surrounding environment, and FAK also plays an important role in the movement of cells to the surrounding environment. There is evidence that when FAK kinase function is blocked, breast cancer metastasis is greatly reduced.
  • FAK mRNA levels are highly expressed in about 37% of ovarian cancer cells and about 26% of breast cancer cells. Because FAK is involved in the regulation of a variety of tumors, currently inhibitors of FAK have also been developed. Including PF-228, PF-271, Y15 (1,2,4,5-benzenetetraamine tetrahydrochloride) and PND-1186, which were developed in 2012.
  • FAK inhibitors have entered clinical trials, including ATP competition inhibitors VS-6062, Defactinib and PND-1186.
  • Defactinib has entered phase II clinical trials for the treatment of KRAS-mutated non-small cell lung cancer.
  • ATP-dependent FAK small molecule inhibitors can interfere with the activity of the FAK catalytic region, which may affect multiple downstream signaling pathways, causing a wide range of side effects, while non-ATP-dependent FAK small molecule inhibitors such as allosteric FAK inhibitors can block Delay specific protein-protein interactions (such as the interaction of p53 with FAK), thereby inhibiting FAK activity. Therefore, although many FAK small molecule inhibitors have been developed for the above two types, due to the complexity and limitations of organisms, very few small molecule inhibitors are actually used in clinical practice.
  • the inventor proposed a new compound that uses a dual-target molecular structure.
  • the structure is shown in Figure 1.
  • One end of this type of molecule targets E3 ligase and the other end
  • the structure targets the FAK protein, and the structures at both ends are connected through a linker to form a complete compound molecule.
  • the compound ubiquitinates the target protein through E3 and guides the target protein into the degradation pathway, which specifically degrades the target protein. Strong.
  • the compound can specifically degrade FAK, so it has potential application value in the field of antitumor and reproductive system.
  • the present invention proposes a compound which is a compound represented by Formula I or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate , Solvates, metabolites, pharmaceutically acceptable salts or prodrugs:
  • X represents a ligand of FAK protein (Focal Adhesion Kinase-Related Nonkinase)
  • Z represents a ligand of E3 ligase
  • Y represents a chain connecting X and Z.
  • the above compound may further include at least one of the following additional technical features:
  • X is a compound represented by Formula II-1 or II-2,
  • Cy 1 or Cy 2 are each independently a benzene ring, a C 6-12 aryl group, a heteroaryl group consisting of 5-12 ring atoms, a C 3-12 cycloalkyl group or a heterocyclic group consisting of 3-12 ring atoms ;
  • Each Cy 1 or Cy 2 is independently replaced by 1, 2 , 3, 4, 5, or 6 R h1 ;
  • Each L 1 is independently replaced by 1, 2, 3, 4, 5 or 6 R h2 ;
  • Each R h1 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, heterocyclic group consisting of 3-12 ring atoms, 5-12 ring atoms Composition of heteroaryl, R g- (CR m R w ) g -O- (CR m R w ) g- , R g- (CR m R w ) g -S- (CR m R w ) g- , R g- (CR m R w ) g -N (R 1a )-(CR m R w ) g- , R g- (CR m R w ) g- , R g
  • Each R h2 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, heterocyclic group consisting of 3-12 ring atoms, 5-12 ring atoms Composition of heteroaryl, R g- (CR m R w ) g -O- (CR m R w ) g- , R g- (CR m R w ) g -S- (CR m R w ) g- , R g- (CR m R w ) g -N (R 1a )-(CR m R w ) g- , R g- (CR m R w ) g- , R g
  • Each R h1 is independently replaced by 1, 2, 3, 4, 5 or 6 R h3 ;
  • Each R h2 is independently replaced by 1, 2, 3, 4, 5 or 6 R h4 ;
  • Each R g is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxygen, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms The composition of heteroaryl;
  • Each R g1 is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxygen, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms The composition of heteroaryl;
  • Each R 1a is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms The composition of heteroaryl;
  • Each R m or R w is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1 -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocycle consisting of 3-12 ring atoms, or 5-10 Heteroaryl consisting of two ring atoms;
  • n is independently 1, 2, 3 or 4;
  • Each g is independently 0, 1, 2, 3 or 4;
  • Each p is independently 1 or 2.
  • Cy 1 or Cy 2 are each independently a benzene ring, a C 6-10 aryl group, a heteroaryl group consisting of 5-10 ring atoms, a C 3-6 cycloalkyl group, or 3-12 A heterocyclic group consisting of ring atoms.
  • each R h1 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-4 alkyl, C 1-4 haloalkane , C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms , Heteroaryl consisting of 5-10 ring atoms, R g- (CR m R w ) g -O- (CR m R w ) g- , R g- (CR m R w ) g -S- (CR m R w ) g- , R g- (CR m R w ) g -N (R 1a )-(CR m R w ) g- , R g- (CR m R w )
  • Each R h2 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkane Oxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms, 5-10 ring atoms Composition of heteroaryl, R g- (CR m R w ) g -O- (CR m R w ) g- , R g- (CR m R w ) g -S- (CR m R w ) g- , R g- (CR m R w ) g -N (R 1a )-(CR m R w ) g- , R g- (CR m R w ) g- , R g
  • Each R h1 is independently replaced by 1, 2, 3, 4, 5 or 6 R h3 ;
  • Each R h2 is independently replaced by 1, 2, 3, 4, 5 or 6 R h4 ;
  • Each R g is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkane Oxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms The composition of heteroaryl;
  • Each R g1 is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkane Oxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms Composition of heteroaryl.
  • each R 1a is independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, amino, carboxyl, C 1-4 alkyl, C 1-4 haloalkyl , C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or Heteroaryl consisting of 5-10 ring atoms;
  • Each R m or R w is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1 -4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocycle consisting of 3-12 ring atoms or 5-10 A heteroaryl group consisting of two ring atoms.
  • Cy 1 or Cy 2 are each independently
  • each R h1 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, methyl, ethyl, n-propyl, isopropyl Group, n-butyl, isobutyl, tert-butyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 Br, -CHBr 2 ,- CBr 3 , -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCF 3 , -CF 2 CHF 2 , -CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CF 2 CHF 2 , R g- (CR m R w ) g -O- (CR
  • Each R h2 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl or tert-butyl;
  • Each R h1 is independently replaced by 1, 2, 3, 4, 5 or 6 R h3 ;
  • Each R h2 is independently replaced by 1, 2, 3, 4, 5 or 6 R h4 ;
  • Each R h4 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl or tert-butyl;
  • Each R g is independently
  • Each R g1 is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.
  • each R 1a is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
  • Each R m , R w or R g is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • X is a compound represented by formula III-1, III-2, III-3, III-4, III-5, or III-6,
  • Z is a compound represented by Formula IV,
  • Q is N or CR 2 ;
  • M is C (R e R f ), N (R 1b ), O or S;
  • W, K are independently C (R e R f ), N (R 1b ), O or S;
  • R 2 is hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
  • Each R 2a and R 2b is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, oxo, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, heterocyclic group consisting of 3-12 ring atoms or Heteroaryl consisting of 5-12 ring atoms;
  • Each R 2c is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-12 ring atoms The composition of heteroaryl;
  • Each R e and R f are independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1 -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocycle consisting of 3-12 ring atoms, or 5-10 Heteroaryl consisting of two ring atoms;
  • Each R 1b is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-12 ring atoms The composition of heteroaryl;
  • n 1 and n 2 are independently 0, 1 , 2 or 3;
  • n 3 is 0, 1, 2, 3, 4 or 5.
  • R 2 is hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-4 alkyl, C 1-4 haloalkyl, C 1 -4 alkoxy, C 2-4 alkenyl or C 2-4 alkynyl.
  • each of R 2a and R 2b is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, oxo, C 1-4 alkyl , C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-12 rings Atomic heterocyclyl or heteroaryl consisting of 5-10 ring atoms;
  • Each R 2c is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkane Oxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms Composition of heteroaryl.
  • each of R e and R f is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-4 alkyl, C 1 -4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-12 ring atoms Heterocyclyl or heteroaryl consisting of 5-10 ring atoms;
  • Each R 1b is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkane Oxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms Composition of heteroaryl.
  • R 2 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • each of R 2a and R 2b is independently hydrogen, deuterium, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
  • Each R 2c is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • each of R e and R f is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
  • Each R 1b is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • Z is a compound represented by formula V-1, V-2, V-3, V-4, or V-5,
  • the Y is a group containing 1 to 30 atoms, and the atom includes at least one selected from a carbon atom, a sulfur atom, an oxygen atom, a nitrogen atom, and a selenium atom.
  • the Y is a C 1-20 alkyl group, a C 1-20 haloalkyl group, a C 1-20 alkoxy group, a C 2-20 alkenyl group, a C 2-20 alkynyl group, and C 3- A group consisting of at least one of a 12- cycloalkyl group, a C 6-12 aryl group, a heterocyclic group consisting of 3-12 ring atoms, or a heteroaryl group consisting of 5-12 ring atoms.
  • Y is Among them, x 1 -x 23 are each independently a key,
  • R 1d is H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl or C 1-4 alkyl.
  • Y is a compound represented by Formula VI-1 or VI-2,
  • Each r is an integer between 0 and 12 independently;
  • Each k is an integer between 0 and 12 independently;
  • Each j is independently an integer between 0 and 12;
  • Each t 1 or t 3 is independently a bond
  • Each t 2 or t 4 is independently a bond
  • t 5 is the key or
  • R 1d is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the present invention provides a compound which is a compound represented by any one of Formulas 1 to 38 or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, Hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the invention proposes a pharmaceutical composition.
  • the pharmaceutical composition includes a compound according to any one of the above.
  • the above pharmaceutical composition may further include at least one of the following additional technical features:
  • the pharmaceutical composition further includes an excipient.
  • the pharmaceutical composition further includes a medicament for contraception or another medicament for treating or preventing a disease related to a tumor or a reproductive system.
  • the tumor or reproductive system-related diseases include at least one selected from breast cancer, ovarian cancer, cervical cancer, lung cancer, liver cancer, gastric cancer, colorectal cancer, skin cancer, brain cancer, and osteosarcoma. .
  • the other medicament for treating or preventing a tumor or reproductive system-related disease includes at least one selected from the group consisting of fetinib, afatinib, cetuximab, Gamendazole, and testosterone.
  • the present invention provides the use of the compound according to any one of the above or the pharmaceutical composition according to any one of the above to prepare a medicament, which is used to degrade FAK protein.
  • the present invention provides the use of the compound according to any one of the above or the pharmaceutical composition according to any one of the above to prepare a medicament for treating or preventing a tumor or a reproductive system Related diseases.
  • the tumor or reproductive system-related diseases include at least one selected from breast cancer, ovarian cancer, cervical cancer, lung cancer, liver cancer, stomach cancer, colorectal cancer, skin cancer, brain cancer, and osteosarcoma.
  • breast cancer ovarian cancer
  • cervical cancer lung cancer
  • liver cancer stomach cancer
  • colorectal cancer skin cancer
  • brain cancer and osteosarcoma.
  • the present invention provides a method for degrading FAK protein.
  • the method comprises: contacting a FAK protein with the compound according to any one of the above or the pharmaceutical composition with any one of the above.
  • the present invention provides a method for treating or preventing a tumor or reproductive system-related disease.
  • the method includes administering to a patient the compound according to any one of the above or any one of the above.
  • the tumor or reproductive system-related diseases include at least one selected from breast cancer, ovarian cancer, cervical cancer, lung cancer, liver cancer, stomach cancer, colorectal cancer, skin cancer, brain cancer, and osteosarcoma.
  • breast cancer ovarian cancer
  • cervical cancer lung cancer
  • liver cancer stomach cancer
  • colorectal cancer skin cancer
  • brain cancer and osteosarcoma.
  • FIG. 1 is a schematic diagram of a basic technical route of PROTACs (proteolytic targeting chimeras) according to an embodiment of the present invention
  • FIG. 2 is a schematic diagram of a compound of the present invention prepared by click chemistry according to an embodiment of the present invention
  • FIG. 3 is a schematic diagram of a synthetic route of a PF-562271 terminal derivative and a structure of PF-562271 according to an embodiment of the present invention
  • FIG. 4 is a schematic diagram of the degradation of FAK by the compound represented by Formula 1 to Formula 4 according to an embodiment of the present invention
  • FIG. 5 is a schematic diagram of the degradation of FAK by the compound represented by Formula 5 to Formula 10 according to an embodiment of the present invention
  • FIG. 6 is a schematic diagram showing a half degradation rate of a compound represented by Formula 2 on FAK in different tumor cell lines according to an embodiment of the present invention
  • FIG. 7 is a schematic diagram of degradation of FAK in mouse ovary and testis-related cell lines by the compound represented by Formula 2 according to an embodiment of the present invention.
  • 8-1 is a schematic diagram of the degradation effect of the compound represented by Formula 2 on FAK in mouse testis primary support cells according to an embodiment of the present invention.
  • 8-2 is a schematic diagram showing the results of degradation of FAK in mouse testis primary support cells by the compound of formula 2 according to an embodiment of the present invention.
  • the term "administers to a patient a compound or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable "Salt or prodrug or pharmaceutical composition as described above” refers to the introduction of a predetermined amount of a substance into a patient in a suitable manner.
  • the compound of formula I, formula II, formula III, formula IV, formula V or formula VI or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate of the present invention , Metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions can be administered by any common route as long as it can reach the intended tissue.
  • Various modes of administration are contemplated, including peritoneal, intravenous, intramuscular, subcutaneous, cortical, oral, topical, nasal, lung and rectal, but the invention is not limited to these exemplary modes of administration.
  • the frequency and dosage of the pharmaceutical composition of the present invention can be determined by a number of related factors, including the type of disease to be treated, the route of administration, the age, sex, weight and severity of the disease, and the active ingredient Type of medication.
  • treatment is used to refer to obtaining the desired pharmacological and / or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms, and / or may be therapeutic in terms of partially or completely curing the disease and / or adverse effects caused by the disease.
  • Treatment encompasses the treatment of diseases in mammals, particularly humans, including: (a) preventing the occurrence of a disease or disorder in an individual who is susceptible to the disease but has not yet been diagnosed; (b) inhibiting the disease; or (c) Relieve disease, such as reducing symptoms associated with the disease.
  • Treatment encompasses any medication that administers a drug or compound to an individual to treat, cure, alleviate, ameliorate, alleviate or inhibit the disease of the individual, including but not limited to those containing Formula I to Formula VI or Formula 1 to 18 Compounds or pharmaceutical compositions are administered to individuals in need.
  • the excipients include pharmaceutically acceptable excipients, lubricants, fillers, diluents, disintegrants, stabilizers, preservatives, emulsifiers, solubilizers, and colorants, which are well known in the formulation field. , Sweeteners, made into tablets, pills, capsules, injections and other different dosage forms.
  • Stereoisomers refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotomers), geometric isomers (cis / trans) isomers, atropisomers, etc. .
  • Chiral is a molecule that cannot overlap with its mirror image; “Achiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomers refer to two isomers of a compound that cannot overlap but mirror image each other.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical operations such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of a molecule with respect to its one or more chiral centers.
  • the prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by a compound, where (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are right-handed.
  • a specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, and this can occur when there is no stereoselection or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R, S) -configuration presence.
  • each asymmetric atom has at least a 50% enantiomeric excess in the (R)-or (S) -configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the present invention may be in one of the possible isomers or mixtures thereof, such as racemic and diastereomeric mixtures (depending on the number of asymmetric carbon atoms) ).
  • Optically active (R)-or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, based on differences in the physicochemical properties of the components. And / or fractional crystallization.
  • racemates of any of the resulting end products or intermediates can be resolved into optical enantiomers by methods known to those skilled in the art using known methods, for example, by subjecting the diastereomeric salts obtained Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis ( 2nd Ed. Robert E.
  • tautomers or “tautomeric forms” refers to structural isomers with different energies that can be converted to each other through a low energy barrier. If tautomerization is possible (eg in solution), the chemical equilibrium of the tautomers can be reached.
  • protontautomers also known as prototropic tautomers
  • Valence tautomers include interconversions through the reorganization of some bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-keto tautomerism.
  • a specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or like the specific examples, subclasses in the examples, and the compounds included in the present invention.
  • substituents such as the compounds of the general formula above, or like the specific examples, subclasses in the examples, and the compounds included in the present invention.
  • substituents such as the compounds of the general formula above, or like the specific examples, subclasses in the examples, and the compounds included in the present invention.
  • a class of compounds is understood that the term “optionally substituted” is used interchangeably with the term “substituted or unsubstituted”.
  • substituted means that one or more hydrogen atoms in a given structure are replaced with a specific substituent.
  • an optional substituent group may be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be
  • a ring system in which a substituent R 'is connected to a central ring by a bond represents that the substituent R' may be substituted at any substitutable position on the ring.
  • formula a represents any position that may be substituted on the B 'ring may be substituted by R', as shown in formula b, formula c and formula d.
  • attachment points on the ring It can be attached to the rest of the molecule at any connectable position on the loop.
  • formula i represents any position on the B ′ ring that may be connected can be used as the connection point, as shown in formulas d, e, and f.
  • two attachment points on the same ring It can be connected to the other two parts of the molecule at any two connectable positions on the ring, and the connection modes of the two ends can be interchanged.
  • formula j represents that two different positions on the D ring that may be connected can be used as connection points to connect with the other two parts of the molecule, as shown in formulas g, h, and k.
  • connection modes at both ends can be interchanged.
  • connection modes of p -N (R 1a )-(CR m R w ) g- are interchangeable.
  • C 1 - 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • an integer between 0 and 12 includes endpoints 0 and 12, and any integer between 0 and 12, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood as the linking group.
  • the “alkyl” or “aryl” represents a linked An alkylene group or an arylene group.
  • alkyl examples include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Isopropyl (i-Pr, -CH (CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH (CH 3 ) CH 2 CH 3 ), tert-butyl (t-Bu, -C (CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH (CH 3 ) CH 2 CH 2 CH 3 ), 3-pentyl (-CH (CH 2 CH 3 ) 2 ), 2-methyl-2 -Butyl (-C (CH 3 ) 2
  • alkyl and its prefix “alkane” are used herein and include both straight and branched saturated carbon chains.
  • alkylene is used herein to denote a saturated divalent hydrocarbon group obtained by eliminating two hydrogen atoms from a straight or branched chain saturated hydrocarbon. Examples of this include, but are not limited to, methylene, ethene , Isopropyl, and so on.
  • alkenyl refers to a straight-chain or branched monovalent hydrocarbon group containing 2-15 carbon atoms, which has at least one site of unsaturation, that is, a carbon-carbon sp 2 double bond, wherein the alkenyl group A group may be optionally substituted with one or more substituents described herein, including the positioning of "cis” and “tans", or the positioning of "E” and "Z".
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • alkynyl means a straight or branched monovalent hydrocarbon group containing 2-15 carbon atoms, which has at least one site of unsaturation, that is, a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more substituents described herein.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like .
  • cycloalkyl refers to monovalent or polyvalent, non-aromatic, saturated or partially unsaturated And does not contain heteroatoms, including monocyclic 3-12 carbon atoms or bicyclic 7-12 carbon atoms.
  • a bicyclic carbocyclic ring having 7-12 atoms may be a bicyclic [4,5], [5,5], [5,6], or [6,6] system, and a bicyclic carbocyclic ring having 9 or 10 atoms at the same time It can be a bicyclic [5,6] or [6,6] system.
  • Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • Examples of cyclic aliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1- Cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl Radical, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • heterocyclic refers to monocyclic, bicyclic or tricyclic systems in which one or more of the rings
  • the carbon atom is independently and optionally substituted with a heteroatom, which has the meaning as described herein, and the ring may be fully saturated or contain one or more degrees of unsaturation, but is by no means aromatic, and There are one or more junctions connected to other parts of the molecule.
  • Hydrogen atoms on one or more rings are independently and optionally substituted with one or more substituents described herein.
  • heterocyclic is a monocyclic ring of 3 to 7 members (1-6 carbon atoms and selected from N, 1-3 heteroatoms O, P, S, and replaced with S or P is optionally substituted by one or more oxygen atoms obtained e.g.
  • SO, SO 2, PO, PO 2 group when the When the ring is a three-membered ring, there is only one heteroatom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms, obtained e.g. SO, SO 2, PO, PO 2 group).
  • heterocyclic group may be a carbon group or a heteroatom group.
  • Heterocyclyl also includes groups formed by the combination of a heterocyclic group and a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothioranyl, piperidinyl, Morpholinyl, thiomorpholinyl, thiaxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thiocyclobutyl , Homopiperidinyl, epoxypropyl, azaheptyl, oxepanyl, thietyl, 4-
  • heterocyclic group also include 1,1-dioxothiomorpholinyl and a group in which two carbon atoms on the ring are replaced with an oxygen atom such as a pyrimidinedione group.
  • heteroatom means one or more O, S, N, P, and Si atoms, including any oxidation state of N, S, and P; forms of primary, secondary, tertiary amines, and quaternary ammonium salts; or in a heterocyclic ring A substituted form of hydrogen on a nitrogen atom, for example, N (e.g., N in 3,4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl), or NR (e.g., N-substituted pyrrole) NR in alkyl).
  • N e.g., N in 3,4-dihydro-2H-pyrrolyl
  • NH e.g., NH in pyrrolidinyl
  • NR e.g., N-substituted pyrrole
  • aryl can be used alone or as a major part of “aralkyl”, “aralkoxy” or “aryloxyalkyl”, meaning monocyclic, bicyclic and tricyclic containing 6-14 membered rings in total
  • a carbocyclic ring system in which at least one ring system is aromatic, wherein each ring system contains a 3-7 membered ring and has one or more attachment points connected to the rest of the molecule.
  • aryl may be used interchangeably with the term “aromatic ring”.
  • the aromatic ring may include phenyl, naphthyl and anthracenyl.
  • heteroaryl can be used alone or as a major part of “heteroarylalkyl” or “heteroarylalkoxy”, meaning monocyclic, bicyclic and tricyclic systems containing a total of 5-14 membered rings, Wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein the heteroatom has the meaning described in the present invention, wherein each ring system contains a 3-7 membered ring and has one or Multiple attachment points are connected to the rest of the molecule.
  • heteroaryl may be used interchangeably with the term “aromatic heterocycle” or "heteroaromatic compound”.
  • the aromatic heterocycle includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-Isoxazolyl, 4-Isoxazolyl, 5-Isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazolyl- 5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, pyrimid-5-yl, Pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazo)
  • prodrug used in the present invention represents a compound converted into a compound represented by Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI in vivo. Such transformations are influenced by the prodrug's hydrolysis in the blood or the enzyme's conversion into the parent structure in the blood or tissues.
  • the prodrug compound of the present invention may be an ester.
  • esters can be used as prodrugs such as phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters, such as these phosphate ester compounds are obtained by phosphorylation of the hydroxy group on the parent.
  • prodrugs refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • Methodabolite refers to a product obtained by metabolizing a specific compound or a salt thereof in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention.
  • Such a product can be obtained by administering a compound through oxidation, reduction, hydrolysis, amidolation, deamidation, esterification, degreasing, enzymatic cleavage and the like.
  • the invention includes metabolites of a compound, including metabolites produced by sufficient contact of a compound of the invention with a mammal for a period of time.
  • salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in the literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, and camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glyceryl phosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pipate, pectate, persulfate, 3 -Phen
  • Salts obtained by appropriate bases include salts of alkali metals, alkaline earth metals, ammonium and N + (C 1-4 alkyl) 4 .
  • the present invention also contemplates the formation of quaternary ammonium salts of any compound containing N groups.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • the pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations formed by anti- counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -8 sulfonates and aromatic sulfonates.
  • solvate of the present invention means an association formed by one or more solvent molecules and a compound of the present invention.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association formed by the solvent molecules being water.
  • any disease or disorder as used herein in some embodiments refers to ameliorating the disease or disorder (ie, slowing or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by the patient. In other embodiments, “treating” refers to modulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., parameters that stabilize the body) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / Carbonate, bisulfate / sulfate, camphor sulfonate, chloride / hydrochloride, chlorotheophylline, citrate, ethanesulfonate, fumarate, glucoheptanoate, glucose Gluconate, glucuronide, hippurate, hydroiodate / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate Acid salt, malonate, mandelate, mesylate, methyl sulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, stearate, oleate, oxalic acid Salt, palm
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , Ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table.
  • the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine .
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, a basic or acidic moiety using conventional chemical methods.
  • such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K, or by These compounds are prepared by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of both.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
  • the compounds disclosed in the present invention can also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) for their crystallization.
  • solvents e.g., ethanol, DMSO, etc.
  • the compounds disclosed herein may form solvates inherently or by design with pharmaceutically acceptable solvents, including water; therefore, the invention is intended to include both solvated and unsolvated forms.
  • any structural formula given in the present invention is also intended to represent the isotopically enriched form of these compounds and the isotopically enriched form.
  • Isotopically enriched compounds have the structure depicted by the general formula given in the present invention, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds described herein include isotopically enriched compounds as defined in the invention, for example, those compounds in which radioisotopes are present, such as 3 H, 14 C, and 18 F, or in which non-radioactive isotopes are present, such as 2 H and 13 C.
  • This class of isotopically enriched compounds can be used in metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET), or including drugs or Single-photon emission computed tomography (SPECT) for the determination of substrate tissue distribution may be used in radiotherapy for patients.
  • 18 F-enriched compounds are particularly desirable for PET or SPECT studies.
  • Isotopically enriched compounds represented by Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI can use appropriate isotopes as described by conventional techniques familiar to those skilled in the art or as described in the examples and preparation procedures of the present invention. Labeled reagents are prepared in place of previously unlabeled reagents.
  • the substitution of heavier isotopes, especially deuterium can provide certain therapeutic advantages that result from higher metabolic stability. For example, increased half-life in the body or reduced dose requirements or improved therapeutic index. Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, especially deuterium.
  • the compound has at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation) for each specified deuterium atom, At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) isotope enrichment factors.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D 2 O, acetone-d 6 , DMSO-d 6 .
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable carrier, an excipient, a diluent, an adjuvant, a vehicle, or a combination thereof.
  • the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.
  • the small molecule compounds according to the embodiment of the present invention can be formed by a click chemistry (click reaction) between a Pomalidomide end or a Lenalidomide end derivative and a PF-562271 end derivative, as shown in FIG.
  • the preparation method of the terminal derivative can refer to the literatures Chemistry & Biology 22,755-763 (2015) and J. Med. Chem. 61,462-481 (2016).
  • the PF-562271 (structure shown below) terminal derivative used in the following examples was prepared according to the following method, and the reaction equation is shown in Figure 3: Firstly, one terminal amino group of p-phenylenediamine is formed into an amide bond with the corresponding alkyne acid; secondly, The fluorine atom of cyanofluoropyridine is substituted with the nitrogen atom of the sulfonamide analog, and the benzylamine analog is obtained after reducing the cyano group; finally, the 2,4-dichloro-5-trifluoromethyl is replaced with the above benzylamine analog. A pyrimidine 4-position chlorine atom is substituted with the above-mentioned p-phenylenediamine derivative amino group at the 2-position chlorine atom to obtain a PF-562271 terminal derivative.
  • the specific preparation process is as follows:
  • the compounds represented by the formulae 2 to 38 were prepared according to the above preparation method.
  • the compound of the present invention has a strong degradation activity on FAK, and a small molecule compound represented by Formula 1 to 10 is used as an example for testing.
  • PA1 cells with a cell fusion degree of 90% were digested with 0.25% trypsin at 37 ° C for 1 minute, and Mycos'5A medium containing 10% FBS was added to terminate the digestion and pipetted into a single cell suspension.
  • 15 ml centrifuge tube Collect single cells, centrifuge at 800 rpm for 3 minutes, resuspend the cells with fresh medium, and count the number of cells on a cell counting plate. Cells were seeded in a 24-well plate at 800k cells per well.
  • test small molecule compound 1000x
  • incubate for 8 hours at 37 ° C in a 5% CO 2 incubator.
  • cells were collected, and proteins were extracted for Western blot analysis.
  • Discard the upper layer of the treated cells wash the cells twice with PBS, add cell lysate, add 100 ⁇ l RIPA lysate to each well, and incubate on ice for 20 minutes. Use a cell scraper to scrape off the cells and collect them with 1.5 Centrifuge in a milliliter Eppendorf tube at 4 ° C for 10 minutes at 2,000 rpm. Take 90 ⁇ l of the supernatant into a new 1.5 ml Eppendorf tube. Another 2 microliters of supernatant was used for quantitative analysis of protein concentration. Add 30 microliters of 4 ⁇ Loading Buffer to the remaining 90 microliters of protein extract, heat and boil at 95 degrees Celsius for 10 minutes, and store at -20 degrees Celsius or use it directly for Westernblot detection.
  • the composition of the RIPA buffer is: Tris-HCl at a final concentration of 50 mM, pH 8.0, 150 mM NaCl, 2 mM MgCl 2 , 0.1% SDS, 1.5% Nonidet-P40, 0.5% sodium deoxycholate. It also contains Pepstatin A at a concentration of 5 ⁇ g / ml, Leupeptin at 10 ⁇ g / mL, MG-132 at 5 ⁇ M, PMSF at 1 mM, and DTT at 0.25 mM.
  • the components of 4 ⁇ Loading Buffer are: SDS at a final concentration of 1%, ⁇ -mercaptoethanol, 6%, glycerol, and an appropriate amount of bromophenol blue.
  • Sample preparation Prepare protein samples according to experimental requirements. Take samples that have been denatured at 95 ° C for 10 minutes, centrifuge, mix and load them in SDS-PAGE gel. According to the results of protein quantitative analysis, adjust the appropriate sample loading volume. Usually, the loading volume of each well is 10 microliters.
  • Electrophoresis Turn on the power, the voltage of the protein sample in the concentrated gel is 80 volts. When the protein sample enters the separation gel, we adjust the voltage to 125 volts and continue electrophoresis. After the protein markers of the target band are completely separated, stop the electrophoresis.
  • the degradation activity of the small molecule compound of the present invention on FAK is as follows:
  • the compounds of the present invention have strong degradation activity against FAK.
  • the compound of the present invention has a strong degradation effect on FAK proteins of tumor cell lines of different origins.
  • the small molecule compound represented by Formula 2 is used as an example for testing below.
  • Different tumor cell lines Experimentally selected human ovarian cancer cell lines PA1, SKOV3; human cervical cancer cell line HeLa; human breast cancer cell lines MDA-MB-436, MDA-MB-453, MDA-MB-231, MCF -7; human-derived lung cancer cell lines A549, H460, and PC9 in order to investigate the half-degradation rate activity of small-molecule compounds shown in Formula 2 on tumor cell lines of different origins.
  • Tumor cell lines with a cell fusion rate of 90% were digested with 0.25% trypsin at 37 degrees Celsius for 1-2 minutes. Complete digestion with 10% FBS was added to stop digestion and pipetting. Single cell suspension was obtained. Single cells were collected in a 15 ml centrifuge tube, centrifuged at 800 rpm for 3 minutes, the cells were resuspended with fresh medium, and the cell count plate was used to count the number of cells. Tumor cells were seeded in 24-well plates at 800k cells per well.
  • the half-molecular degradation activity of the small-molecule compound shown in Formula 2 of the present invention on FAK in different tumor cell lines is as follows:
  • the small molecule compound shown in Formula 2 has a strong activity on the degradation of FAK protein in ovarian cancer PA1 cell line and breast cancer MDA-MB-436, MDA-MB-453, and MDA-MB-231 cell lines.
  • the concentration is less than 2nM.
  • the half-degradation concentration (DC 50 ) of FAK protein was less than 100 nM, and the results are shown in FIG. 6. From this result, it can be seen that the small molecule compound represented by Formula 2 has a strong degradation effect on FAK proteins in most tumor cell lines.
  • the compounds of the present invention have a strong degradation effect on FAK proteins of tumor cell lines of different origins.
  • the compound of the present invention has a strong degradation effect on the FAK protein in mouse reproduction-related cell lines.
  • the small molecule compound represented by Formula 2 is used as an example for testing below.
  • the degradation activity of the small molecule compound represented by formula 2 of the present invention on mouse ovarian SRD15 and mouse testis TM3 cell lines is as follows:
  • the degradation rate of FAK in the mouse ovarian SRD15 cell line by the small molecule compound represented by Formula 2 at about 10 nM was about 46%.
  • the degradation of FAK in the mouse testis TM3 cell line reached more than 70%, and the results are shown in FIG. 7. From this result, it is known that the small-molecule compound represented by Formula 2 has a strong degradation effect on FAK protein in mouse reproduction-related cell lines.
  • the compound of the present invention has a strong degradation effect on FAK protein in mouse reproduction-related cell lines.
  • the compound of the present invention has a strong degradation effect on FAK in mouse testis primary supporter cells.
  • the small molecule compound shown in Formula 2 is used as an example for testing below.
  • Isolation and culture of mouse testis primary support cells Primary support cells were isolated from mice at 16 days. After 16 days of sacrifice, the B6 mice were sacrificed, and the testes were removed and placed in a 3cm petri dish in PBS. The white membrane of the testicular tissue was removed under a stereo microscope, and the testis tissue was transferred to another 3cm petri dish containing PBS; Disperse the spermatozoon tubules of the testicular tissue under a stereo microscope, then transfer the testicular tissue to a 15 ml centrifuge tube containing an appropriate amount of digestive juice I, digest for 5 minutes at room temperature, and gently shake from time to time; centrifuge at 1500 rpm for 5 minutes at room temperature, discard Supernatant; Add 5 times the volume of digestive fluid II to the testis tissue pellet, digest for 5 minutes at room temperature, and shake vigorously; add an appropriate amount of DMEM / F12, terminate the digestion, and filter the digested tissue with a 70 mesh filter to remove the digestion Incomplete tissue pieces;
  • the cell count was 0.5
  • the density of X10 6 cells / cm 2 was seeded in a 12-well plate (coated with Matrigel) and cultured in a cell incubator at 5% CO 2 at 37 ° C. After 24 hours, the solution was changed and PBS was used to wash away non-adherent cells; 36 20m in hours Tris-HCL pH 7.4, washed for 3 minutes, washed twice with PBS, and added the medium to continue the culture.
  • the reagent formulation used in the above experiment is as follows:
  • Digestive fluid I type IV collagenase (2mg / ml, Sigma) + DNaseI (75U / ml, Sigma), configured with DMEM / F12 (invitrogen), and filtered through a 0.22 ⁇ m Millipore needle filter.
  • Digestive fluid II type IV collagenase (2mg / ml, Sigma) + type IV hyaluronidase (2mg / ml, Sigma) + DNaseI (75U / ml, Sigma), DMEM / F12 (invitrogen) configuration , Suction filtered through a 0.22 ⁇ m Millipore syringe filter.
  • the supporting cell culture medium is: DMEM / F12 (invitrogen) + Bovine Insulin (Sigma) + Human transferring (R & D) + Epidermal growth factor (R & D) + 1% double antibody (invitrogen);
  • the degradation activity of the small molecule compound represented by formula 2 of the present invention on FAK in mouse testis primary support cells is as follows:
  • the small-molecule compound shown in Formula 2 has a half-degradation concentration of FAK in mouse testis primary support cells reaching 1.31 nM, which has a strong degradation effect.
  • the results are shown in Figures 8-1 and 8-2.
  • the compound of the present invention has a strong degradation effect on FAK in mouse testis primary support cells.

Abstract

L'invention concerne un composé de formule I ou un stéréoisomère, un isomère géométrique, un tautomère, un oxyde d'azote, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci : X-Y-Z formule I, dans laquelle X représente le ligand de la protéine FAK, Z représente le ligand de la ligase E3, et Y représente le lieur liant X et Z.
PCT/CN2018/094594 2018-07-05 2018-07-05 Composé de dégradation ciblée de protéine fak et utilisation associée WO2020006724A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11760761B2 (en) 2020-08-17 2023-09-19 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1

Citations (4)

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WO2004046118A2 (fr) * 2002-05-06 2004-06-03 Bayer Pharmaceuticals Corporation Derives de 2-4-(di-phenyl-amino)-pyrimidine convenant pour traiter des pathologies hyper-proliferantes
WO2006023381A1 (fr) * 2004-08-16 2006-03-02 Taigen Biotechnology Composés de type pyrimidinone
WO2008129380A1 (fr) * 2007-04-18 2008-10-30 Pfizer Products Inc. Dérivés de sulfonyle amide pour le traitement d'une croissance cellulaire anormale
WO2010141406A2 (fr) * 2009-06-01 2010-12-09 Osi Pharmaceuticals, Inc. Composés anticancéreux amino pyrimidine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004046118A2 (fr) * 2002-05-06 2004-06-03 Bayer Pharmaceuticals Corporation Derives de 2-4-(di-phenyl-amino)-pyrimidine convenant pour traiter des pathologies hyper-proliferantes
WO2006023381A1 (fr) * 2004-08-16 2006-03-02 Taigen Biotechnology Composés de type pyrimidinone
WO2008129380A1 (fr) * 2007-04-18 2008-10-30 Pfizer Products Inc. Dérivés de sulfonyle amide pour le traitement d'une croissance cellulaire anormale
WO2010141406A2 (fr) * 2009-06-01 2010-12-09 Osi Pharmaceuticals, Inc. Composés anticancéreux amino pyrimidine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11760761B2 (en) 2020-08-17 2023-09-19 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1

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