WO2023025324A1 - Composé servant de régulateur de p53 - Google Patents
Composé servant de régulateur de p53 Download PDFInfo
- Publication number
- WO2023025324A1 WO2023025324A1 PCT/CN2022/115635 CN2022115635W WO2023025324A1 WO 2023025324 A1 WO2023025324 A1 WO 2023025324A1 CN 2022115635 W CN2022115635 W CN 2022115635W WO 2023025324 A1 WO2023025324 A1 WO 2023025324A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- alkyl
- cycloalkyl
- optionally substituted
- hydrogen
- Prior art date
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a new type of derivative containing tricyclic heteroaryl, its synthesis method and its use as a p53 regulator in the preparation of medicines for the treatment of tumors and other related diseases in the application.
- TP53 mutations are closely related to poor prognosis of various tumors, and germline TP53 mutations can lead to a rare familial cancer-prone disease: Li Fraumeni syndrome.
- p53 provides an important barrier to tumor transformation and progression.
- p53 is very sensitive to cellular stress and coordinates a complex signaling pathway to maintain cellular homeostasis and genome stability.
- Most of the TP53 mutations are missense mutations, where the codon encoding a certain amino acid becomes the codon encoding another amino acid after base substitution.
- mutated p53 may support tumor progression by promoting adaptive responses to tumor-associated stress.
- cancer cells are exposed to a variety of internal and external stressors. Mutated p53 can sense a variety of cellular stresses and induce cellular adaptive mechanisms to exert cancer-promoting effects.
- the p53Y220C mutation is one of the common missense mutation types of p53. This mutation exists in cancer types such as breast cancer, lung cancer, colon cancer, gastric cancer, and head and neck cancer. There are about 100,000 new cancer patients with this mutation every year worldwide. people. Therefore, the development of compounds targeting this mutation to reactivate the function of wild-type p53 is crucial for cancer therapy.
- the purpose of the present invention is to provide a new class of p53 regulators.
- the first aspect of the present invention provides a compound with the structure shown in the following formula (I), or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate :
- Ring A is selected from aryl or heteroaryl
- Ring B is selected from aryl or heteroaryl
- C ring is selected from C 3-8 cycloalkyl or 4- to 12-membered heterocyclyl
- D is selected from a chemical bond, -C ⁇ C-, -CR a ⁇ CR a -, or a C 3-6 cyclic group;
- E is selected from chemical bonds, -(CR a R a ) q -, -O-, -NR b -, C 3-6 cyclic groups, or 3- to 6-membered heterocyclic groups;
- F is selected from a chemical bond, -NR b -, -O-, or -(CR a R a ) q -;
- U is selected from a chemical bond, -NR c -, -O-, -NR c C(O)R c -, -NR c C(O)-;
- Each R 2 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl , C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3 -6 cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR b , SR b , or NR b R b ; R b is as defined above;
- R 3 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered Heterocyclyl, aryl, heteroaryl, CN, OR b , SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b , C(O) )N(OR b )R b , NR b C(O)R d , NR b S(O) 2 R d , S(O) 2 R d , S(O)(NR b )R d , S(O )R d , NR b S(O) 2 R d , S(O)(NR b )R d , S(O )R d , NR b S
- Each R 4 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl , C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl , C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C 2-4 alkenyl -O-, C 2-4 haloalkenyl-O-, C 2-4 alkynyl-O-, C 2-4 haloalkynyl-O-, C 3-6 cycloalkyl-O-, 3 - to 8-membered heterocyclyl-O-, CN, SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b ; the alkyl , alk
- R 4 and R in E and the ring atoms on the F and B rings connected to it together form an optionally substituted 6- to 8-membered ring structure
- R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered Heterocyclyl, CN, OR b , SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b , C(O)NR b (OR b ) , NR b C(O)R d , NR b S(O) 2 R d , S(O) 2 R d , S(O)(NR b )R d , S(O)R d , NR b S( O) 2 R d , S(O) 2 NR b R b ; each R b is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl;
- Each R 6 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkane Base, 3- to 6-membered heterocyclyl, CN, SR b , NR b R b ; each R b is defined as above; m is selected from 0, 1, 2, 3, or 4;
- n is selected from 0, 1, 2, 3, or 4;
- p is selected from 0, 1, 2, 3, or 4;
- q is selected from 0, 1, 2, or 3;
- each of the above-mentioned alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups is optionally and independently replaced by 1-3 substituents independently selected from the following group Substitution: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, Aryl, Heteroaryl, CN, NO2, OR b , SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b , NR b C(O )R d , NR b S(O) 2 R d , or S(O) 2 R d , provided that the formed chemical structure is stable and meaningful; wherein each R b is
- the above-mentioned aryl group is an aromatic group containing 6-12 carbon atoms;
- the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group;
- the ring structure is Single ring, parallel ring, condensed ring or heterocyclic ring, said ring structure may be saturated or partially unsaturated (but not aromatic).
- the ring B is selected from phenyl or 5-7 membered heteroaryl.
- the C ring is selected from C 5-7 cycloalkyl or 5- to 8-membered heterocyclyl.
- R 3 is selected from C(O)NR b (OR b ), P(O)R f R f , P(O)(NR b R b )R f , or P(O)( OR b ) R f ; each R f is independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, OR b , NR b R b ; or two R f together with the phosphorus atom connected to them together form a 4- to 8-membered ring structure optionally substituted, this ring structure can additionally contain 0-1 optional selected from N, O , a heteroatom of S; each R b is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; or two R b together with the nitrogen atom connected to them form any substituted 4 - to 8-membered ring structure, which may additionally contain 0-1 hetero
- R3 is selected from: Wherein, "—" represents the position where R 3 is connected to other parts of the compound of formula (I); the definition of R b is as above.
- formula (I) is formula (II):
- R 1 is selected from the following groups:
- Each R 2 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, CN, OR b , SR b , or NR b R b ; m is selected from 0, 1, or 2; R b is as defined above;
- R 3 is selected from the following groups:
- R 4 is selected from the following groups:
- fragment Groups selected from the following groups:
- F is selected from -NH-, -NMe-, or -O-.
- R3 is selected from the following groups:
- fragment Groups selected from the following groups:
- R is selected from the following groups:
- R 4 is selected from the following groups:
- formula (I) is formula (III):
- each X is independently selected from CH or N, provided that at least two Xs are selected from CH, and the formed structure is stable; wherein the H on one CH is replaced by C(O) in formula (III) NH(OR b ) is substituted, H on other CH is optionally substituted by R 4 ; R b is selected from hydrogen or C 1-4 alkyl;
- R 1 , R 2 , m, F, ring C, R 5 , R 6 , p are as defined above.
- formula (I) is formula (IV):
- each X is independently selected from CH or N, provided that at least two Xs are selected from CH, and the formed structure is stable; wherein the H on one CH is replaced by P(O) in formula (IV) Rf is substituted with Rf , and H on other CHs are optionally substituted with R4 ; each Rf is independently selected from C1-4 alkyl, C3-6 cycloalkyl, 3- to 8-membered heterocycle group, aryl group, heteroaryl group, OR b , NR b R b ; or two R f together with the phosphorus atom connected to them form an optionally substituted 4- to 8-membered ring structure, the ring structure May additionally contain 0-1 heteroatoms optionally selected from N, O, S; the alkyl, cycloalkyl, heterocyclyl, or ring structure described in R f are optionally substituted by the following substituents: Hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C
- R 1 , R 2 , m, F, ring C, R 4 , R 5 , R 6 , p, R b are as defined above.
- formula (I) is formula (V):
- R 1 , R 2 , m, R 4 , R 5 , R 6 , p, R b are as defined above.
- each R is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, OR b , SR b , or NR b R b ;
- Each R 4 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkane Base-O-, 3- to 8-membered heterocyclyl-O-; said alkyl, alkoxy, cycloalkyl, heterocyclyl are optionally replaced by one or more groups selected from the following group Substitution: halogen, CN, OR b , SR b , NR b R b ;
- Each R 6 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkane Base, 3- to 6-membered heterocyclic group, CN, SR b , NR b R b ; each R b is as defined above;
- n is selected from 0, 1, 2, or 3;
- p is selected from 0, 1, 2, 3, or 4;
- formula (I) is formula (VI):
- T is selected from a chemical bond or -NR c -;
- R c is selected from hydrogen or C 1-4 alkyl;
- Z is selected from N or CR k ;
- R k is selected from hydrogen or C 1-4 alkyl;
- Each R e is independently selected from hydrogen, fluorine, or C 1-4 alkyl; the alkyl group in the R e is optionally substituted by the following substituents: CN, OR b , SR b , NR b R b , C(O)OR b ;
- R 1 , R 2 , m, R 4 , R 5 , R 6 , p, R b are as defined above.
- formula (I) is formula (VIIa) or (VIIb):
- Each R e is independently selected from hydrogen, fluorine, or C 1-4 alkyl; the alkyl group in the R e is optionally substituted by the following substituents: CN, OR b , SR b , NR b R b , C(O)OR b ; each R b is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl;
- R 3 is selected from the following groups:
- Rf is as defined above;
- R 1 , R 2 , m, R 4 , R 6 , p, R b , R d are as defined above.
- the compound of formula (I) is selected from the following group:
- "*" represents a chiral center, which can be optionally R configuration or S configuration, or a mixture of R configuration and S configuration; use
- the bonded carbon atom may optionally be in the R or S configuration, or optionally in cis or trans.
- the second aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated Derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.
- the third aspect of the present invention provides a compound as described in the first aspect of the present invention, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate The use of it for the preparation of a pharmaceutical composition for treating a disease, disease or condition related to the p53 Y220C mutation.
- the disease, disease or condition is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, Granulosa cell tumor of the skin, melanoma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, Head and neck squamous cell carcinoma, cervical cancer, osteosarcoma, esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma , Non-Hodgkin's lymphoma, monocytic leukemia,
- the inventors unexpectedly discovered a class of p53 modulators with novel structures and their preparation methods and applications.
- the compound of the present invention can be applied to the treatment of various diseases related to the activity of the transcription factor. Based on the above findings, the inventors have accomplished the present invention.
- each chiral carbon atom may optionally be in R configuration or S configuration, or a mixture of R configuration and S configuration.
- alkyl refers to a straight chain (i.e., unbranched) or branched chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight chain and branched chain groups .
- the alkyl group is defined by the number of carbon atoms (such as C 1-10 ), it means that the said alkyl group contains 1-10 carbon atoms.
- C 1-8 alkyl refers to an alkyl group containing 1-8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or Similar groups.
- alkenyl refers to a straight or branched, carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the number of carbon atoms (eg C 2- 8 ) is limited before the alkenyl group, it means that the alkenyl group contains 2-8 carbon atoms.
- C 2-8 alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups group.
- alkynyl alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
- the alkynyl group can be straight or branched, or a combination thereof. When the number of carbon atoms is limited before the alkynyl group (such as C 2-8 alkynyl group), it means that the alkynyl group contains 2-8 carbon atoms.
- C2-8 alkynyl refers to a straight or branched chain alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.
- cycloalkyl alone or as part of another substituent, refers to a monocyclic or polycyclic (fused, bridged or spiro) ring system group having a saturated or partially saturated ring .
- a cycloalkyl group is preceded by a restriction on the number of carbon atoms (such as C 3- 10 ), it means that the cycloalkyl group contains 3-10 carbon atoms.
- C 3-8 cycloalkyl refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group with 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclo Pentyl, cycloheptyl, or similar groups.
- Spirocycloalkyl means a bicyclic or polycyclic group in which the single rings share a single carbon atom (called a spiro atom), these may contain one or more double bonds, but none of the rings has fully conjugated pi electrons system.
- “Fused cycloalkyl” means an all-carbon bicyclic or polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more bicyclic bonds, but none of the rings have a fully conjugated ⁇ -electron system.
- “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system .
- the atoms contained in the cycloalkyl group are all carbon atoms.
- the following are some examples of cycloalkyl groups, and the present invention is not limited only to the cycloalkyl groups described below.
- Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, eg, phenyl and naphthyl.
- the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated ⁇ -electron system on the carbon atoms in the ring.
- Aryl groups can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited only to the aryl groups described below.
- Heteroaryl refers to an aromatic monocyclic or polycyclic group containing one to more heteroatoms (optionally selected from nitrogen, oxygen and sulfur), or a heterocyclic group (containing one to more heteroatoms optionally A polycyclic group formed by condensing nitrogen, oxygen and sulfur) with an aryl group, and the connection point is located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited only to the heteroaryl groups described below.
- Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
- monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
- a polycyclic heterocyclic group refers to a heterocyclic group including spiro rings, fused rings and bridged rings.
- “Spirocyclic heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, with the remaining ring atoms being carbon.
- “fused ring heterocyclyl” means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none A ring has a fully conjugated pi-electron system, and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
- “Bridged heterocyclyl” means a polycyclic heterocyclic group in which any two rings share two atoms not directly connected, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system , and wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If there are both saturated and aromatic rings in the heterocyclic group (for example, the saturated ring and the aromatic ring are fused together), the point of attachment to the parent must be on the saturated ring. Note: When the point of connection to the parent is on the aromatic ring, it is called heteroaryl, not heterocyclic. The following are some examples of heterocyclic groups, and the present invention is not limited only to the following heterocyclic groups.
- C 3-6 cyclic group refers to a saturated or partially unsaturated monocyclic or bicyclic cyclic group having 3-6 carbon atoms.
- Heterocyclic group means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group (non-aromatic) in which one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
- Ring structure refers to a ring system group having a saturated or partially saturated single ring, bicyclic or polycyclic rings (fused rings, bridged rings or spiro rings) and no heteroatoms in the ring skeleton.
- the cyclic group may be a monovalent, divalent, trivalent or other valent group, preferably a divalent or trivalent group.
- a restriction on the number of carbon atoms such as C 3-10 ) it means that the cycloalkyl group contains 3-10 carbon atoms.
- halogen refers to F, Cl, Br and I, alone or as part of another substituent.
- substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
- the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
- an optionally substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
- a cyclic substituent, such as a heterocyclyl may be attached to another ring, such as a cycloalkyl, to form a spirobicyclic ring system, ie, two rings that share a single carbon atom.
- substituents contemplated by this invention are those that are stable or chemically feasible.
- the substituents are for example (but not limited to): C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl , Aryl, heteroaryl, halogen, hydroxyl, alkoxy, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino.
- a pharmaceutically acceptable salt of a compound of the present invention refers to a salt that is suitable for contact with the tissues of a subject (eg, a human) without undue side effects.
- a pharmaceutically acceptable salt of a compound of the present invention includes a salt of a compound of the present invention having an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or having a basic Salts (eg, sulfates, hydrochlorides, phosphates, nitrates, carbonates) of compounds of the invention.
- the present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereoisomers, if present), hydrates , the use of a pharmaceutically acceptable carrier or excipient for regulating p53.
- the compounds of the present invention are useful as modulators of p53.
- the invention is a p53 regulator, which can prevent, alleviate or cure diseases by regulating the activity of p53.
- the diseases referred to include but are not limited to: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, granulosa cell tumor of the skin, melanoma, hepatocellular carcinoma , intrahepatic cholangiocarcinoma, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, osteosarcoma , esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphom
- compositions can be mixed with pharmaceutically acceptable excipients or The carriers are formulated together and the resulting compositions can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases.
- Compositions can be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections. Sterile powder, etc.
- pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin (increase), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicate and macromolecular polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic) and lubricants (such as magnesium stearate, glycerin, and talc).
- disintegrants such as starch, croscarmellose sodium, complex silicate and macromolecular polyethylene glycol
- granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic
- lubricants such as magnesium stearate, glycerin, and talc
- the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders.
- the amount of the compound or pharmaceutical composition of the present invention administered to the patient is not fixed, and is usually administered in a pharmaceutically effective amount.
- the amount of the compound to be actually administered can be determined by the physician according to the actual situation, including the disease to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and the like. Dosage of the compounds of this invention will depend on the particular use for the treatment, the mode of administration, the state of the patient, and the judgment of the physician.
- the ratio or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, route of administration and the like.
- compositions and methods of administration are provided.
- the pharmaceutical composition of the invention can be used for treating, preventing and alleviating diseases related to p53 activity or expression.
- the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
- safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
- the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose.
- the "one dose” is a capsule or tablet.
- “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
- Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
- cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
- gelatin such as talc
- solid lubricants such as stearic acid , magnesium stearate
- calcium sulfate such
- the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
- Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
- coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
- Examples of usable embedding components are polymeric substances and waxy substances.
- the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
- inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
- compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
- Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
- the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
- the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
- a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
- the dosage is usually 1-2000 mg, preferably 5-500 mg.
- factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
- p53 Y220C regulator with a novel structure, its preparation and application, the inhibitor can activate the activity of p53 Y220C at very low concentration.
- a class of pharmaceutical compositions for treating diseases related to p53 Y220C activity is provided.
- Some representative compounds of the present invention can be prepared by the following synthetic methods.
- the reagents and conditions of each step can be selected from the conventional reagents or conditions of this type of preparation method in the art.
- the above selection can be made by those skilled in the art based on the knowledge in the art.
- DIPEA N,N-diisopropylamine
- HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)
- MgCl 2 magnesium chloride
- PE petroleum ether
- Some compounds of the present invention can be prepared by the following methods:
- Compound IIa-1 was prepared by the method in patent WO2021061643.
- Compound IIa-2 can be prepared by a suitable method.
- Compound IIa-1 and Compound IIa-2 were metal-catalyzed coupling reaction to obtain compound IIa-3, and then the target compound IIa was obtained through deprotection reaction.
- Compound 2 and Compound 3 in the present invention were prepared by the method of Scheme 1.
- the compound of formula (III) can be prepared by the following method.
- Compound III-1 was prepared by the method in patent WO2021061643. Compound III-1 is hydrolyzed to obtain compound III-2, and then subjected to condensation to obtain the compound of formula (III).
- the compound of formula (V) can be prepared by the following method.
- V-4 The key step in the synthesis of these compounds is the synthesis of intermediate V-4.
- V-1 dialkylphosphine oxide
- V-2 can be reduced to obtain V-4 (route A);
- V-4 prepared by reacting phosphinate V-3 with Grignard reagent can be used (route B).
- V-4 was alkylated with bromopropyne and protected by Boc to obtain compound V-5 with a terminal triple bond and different phosphorocarbonyl substitutions.
- V-5 was coupled with different 2-position OTf substituted indole compounds to obtain V-6. Then carry out Buchward condensation and deprotection with substituted piperidine amino compound to obtain compound V.
- the compound of formula (VI) can be prepared by the following method.
- Compound VI-1 was prepared by the method in patent WO2021061643, VI-2 was synthesized from tetracyclic carbonyl as raw material, VI-1 and VI-2 were condensed to obtain VI-3, and then deprotected to obtain compound VI.
- the compound of formula (VII) can be prepared by the following method.
- Compound VII-1 was prepared by the method in patent WO2021061643, and was subjected to Buchward condensation with piperidine derivatives VII-2-a and VII-2-b with exocyclic double bonds to obtain the precursor, and then deprotected to obtain the target Compounds VII-a and VII-b.
- Embodiment 1 the preparation of compound 1
- compound 1-g 80 mg, 0.13 mmol was dissolved in anhydrous 1,4-dioxane, and 2-(dicyclohexylphosphine) 3,6-dimethoxy-2' was added in sequence, 4',6'-triisopropyl-1,1'-biphenyl (8.37mg, 0.0091mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'- Biphenyl (8.5 mg, 0.018 mmol), cesium carbonate (169 mg, 0.52 mmol) and compound 1-h (35 mg, 0.17 mmol). The reaction mixture was warmed up to 100°C and stirred for 16h.
- Embodiment 2 the preparation of compound 2
- Embodiment 3 the preparation of compound 3
- reaction solution was warmed to zero, and water (0.15mL), 15% aqueous sodium hydroxide solution (0.15mL), and water (0.3mL) were added dropwise in sequence, and the reaction mixture was warmed to room temperature and stirred for 15 minutes, and an appropriate amount of anhydrous sodium sulfate was added, and stirred After 15 minutes, it was filtered and the filtrate was concentrated under reduced pressure.
- the resulting crude product was separated and purified by silica gel column chromatography to obtain compound 3-c (250 mg, 85%).
- compound 2-d (15 mg, 0.024 mmol), compound 3-f (6 mg, 0.029 mmol), cesium carbonate (31.8 mg, 0.097 mmol), Brettphos Pd G4 (2.2 mg, 0.0024 mmol), 2- Dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (2.2mg, 0.0048mmol) and 1,4-dioxane solution (1mL) in a sealed tube at 110°C React for 16 hours.
- Embodiment 4 the preparation of compound 4
- Embodiment 5 the preparation of compound 5
- Embodiment 6 the preparation of compound 6
- Embodiment 7 the preparation of compound 7
- Embodiment 8 the preparation of compound 8
- Embodiment 9 the preparation of compound 9
- Embodiment 10 the preparation of compound 10
- Embodiment 11 Preparation of compound 11
- Embodiment 12 the preparation of compound 12
- 12-a (19.7g, 91mmol) was dissolved in tetrahydrofuran (25mL), and added dropwise to a tetrahydrofuran solution (75mL) containing magnesium chips (5g, 208mmol), stirred at room temperature for 2h, and then poured into the reaction solution
- Diethyl phosphate (6.4g, 46mmol) in tetrahydrofuran (20mL) continue stirring at room temperature for 1h, add potassium carbonate aqueous solution (30g potassium carbonate dissolved in 50mL water) to the reaction solution to form a large amount of white precipitate, filter The precipitate was washed with ethanol, and the filtrate was collected and concentrated, then added dichloromethane, and dried over anhydrous magnesium sulfate.
- Embodiment 13 Preparation of compound 13
- Embodiment 14 the preparation of compound 14
- Embodiment 15 Preparation of compound 15
- Embodiment 16 Preparation of compound 16
- Embodiment 17 the preparation of compound 17
- Embodiment 18 Preparation of compound 18
- compound 18-b (105 mg, 0.280 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL), and 2-(dicyclohexylphosphine)-3,6-dimethoxy -2',4',6'-triisopropyl-1,1'-biphenyl (20mg, 0.020mmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1, 1'-biphenyl 20 mg, 0.04 mmol), cesium carbonate (459 mg, 1.41 mmol) and compound 7-f (167 mg, 0.337 mmol). The reaction mixture was warmed up to 100°C and stirred for 16h.
- Example 19 In vitro p53 Y220C and DNA binding activity test.
- the HTRF method was used to detect the activation of p53 Y220C protein activity by the compound.
- Compounds were dissolved in DMSO to make 10 mM stock solutions and further diluted to 100 ⁇ M. Transfer 60 ⁇ L of the compound to a 384-well plate, and perform serial dilution according to the multiple of 1:4, with a total of 10 concentrations. Use the Echo to transfer 0.1 ⁇ L of the diluted compound to a 384-well plate, and duplicate each compound. Add 2.5 ⁇ L of p53 Y220C protein solution to the 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate for 10 min.
- activation rate (% activator) 100*(ave Low control-ave cpd well)/(ave Low control-ave High control).
- ave High control is the average reading value of wild-type p53 wells added with equal concentration of DMSO
- ave cpd well is the average reading value of compound wells
- ave Low control is the average reading value of p53 Y220C wells added with equal concentration of DMSO.
- EC 50 is used to represent the concentration required for the compound to restore p53 Y220C DNA-binding function to 50% of the wild type.
- the activity data of representative compounds to activate p53 Y220C protein and DNA binding are shown in Table 1.
- the positive drug Ref-A has an EC 50 value in the range of 60-120nM under the test conditions.
- Example 20 Inhibition of compound on proliferation of p53 Y220C mutated liver cancer cell line Huh7.
- Huh7 cells in good growth state were selected and digested with trypsin. Add fresh medium, mix well, and centrifuge at 800rpm for 3 minutes. According to the seed plate density of 2000 Huh7 cells per well, they were seeded in 96-well plates and cultured overnight in a 37°C incubator. The next day, the culture plate was taken out, and the compound was diluted in a five-fold gradient for administration. Among them, the blank control wells only added normal medium, no cells, and no DMSO; the DMSO wells contained cells and contained 0.5% DMSO. The 96-well plate was placed in a 37°C incubator for 144 hours.
- Chromatographic column ACQUITY UPLC BEH C18 (2.1mm ⁇ 50mm, 1.7 ⁇ m); column temperature 40°C; mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile, the flow rate is 0.350 ml/min, using gradient elution , the elution gradient is 0.50min: 10%B; 1.50min: 90%B; 2.50min: 90%B; 2.51min: 10%B; 3.50min: stop. Injection volume: 1 ⁇ L.
- Animals 3 SD male rats, with a weight range of 200-220g, were used after being raised in the laboratory of the Experimental Animal Center for 2 days after purchase, fasted for 12 hours before administration and within 4 hours after administration, and free to drink water during the test. After the rats were gavaged, blood samples were collected within a predetermined period of time.
- Drug samples generally take multiple samples with similar structures (the difference in molecular weight is more than 2 units), weigh them accurately, and administer them together (cassette PK). This allows multiple compounds to be screened simultaneously and their oral absorption rates compared. Pharmacokinetics of drug samples in rats were also studied using single administration.
- Blood was collected from the orbit at 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours after intragastric administration. Take 50 ⁇ L of plasma sample, add 200 ⁇ L of acetonitrile (containing internal standard verapamil 2ng/mL), vortex for 3 min, centrifuge at 20000 rcf, 4 °C for 10 min, and take the supernatant for LC-MS/MS analysis.
- acetonitrile containing internal standard verapamil 2ng/mL
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Abstract
La présente invention concerne un composé servant de régulateur de p53, et spécifiquement, la présente invention concerne un composé ayant une structure telle que représentée dans la formule (I), ou un isomère optique, un sel pharmaceutiquement acceptable, un promédicament, un dérivé deutéré, un hydrate et un solvate de celui-ci. Le composé peut être utilisé pour traiter ou prévenir des maladies ou des affections associées à l'activité ou au niveau d'expression de p53.
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CN109069481A (zh) * | 2016-02-19 | 2018-12-21 | 皮姆维制药公司 | 用于恢复突变p53功能的方法和化合物 |
WO2021061643A1 (fr) * | 2019-09-23 | 2021-04-01 | Pmv Pharmaceuticals, Inc. | Méthodes et composés pour la restauration de la fonction du p53 mutant |
WO2021262541A1 (fr) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Outil de diagnostic compagnon pour composés de réactivation de p53 mutantes |
WO2021262484A1 (fr) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Polythérapie pour le traitement du cancer |
WO2021262483A1 (fr) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Méthodes et composés pour la restauration de la fonction du p53 mutant |
WO2022213975A1 (fr) * | 2021-04-08 | 2022-10-13 | Jacobio Pharmaceuticals Co., Ltd. | Composés ciblant le mutant y220c de p53 |
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CN109069481A (zh) * | 2016-02-19 | 2018-12-21 | 皮姆维制药公司 | 用于恢复突变p53功能的方法和化合物 |
WO2021061643A1 (fr) * | 2019-09-23 | 2021-04-01 | Pmv Pharmaceuticals, Inc. | Méthodes et composés pour la restauration de la fonction du p53 mutant |
WO2021262541A1 (fr) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Outil de diagnostic compagnon pour composés de réactivation de p53 mutantes |
WO2021262484A1 (fr) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Polythérapie pour le traitement du cancer |
WO2021262483A1 (fr) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Méthodes et composés pour la restauration de la fonction du p53 mutant |
WO2022213975A1 (fr) * | 2021-04-08 | 2022-10-13 | Jacobio Pharmaceuticals Co., Ltd. | Composés ciblant le mutant y220c de p53 |
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US11963953B2 (en) | 2022-01-27 | 2024-04-23 | Pmv Pharmaceuticals, Inc. | Deuterated compounds for restoring mutant p53 function |
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