WO2022171184A1 - Composé hétérocyclique utile en tant qu'inhibiteur de sos1 - Google Patents
Composé hétérocyclique utile en tant qu'inhibiteur de sos1 Download PDFInfo
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- WO2022171184A1 WO2022171184A1 PCT/CN2022/075934 CN2022075934W WO2022171184A1 WO 2022171184 A1 WO2022171184 A1 WO 2022171184A1 CN 2022075934 W CN2022075934 W CN 2022075934W WO 2022171184 A1 WO2022171184 A1 WO 2022171184A1
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- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium(IV) ethoxide Substances [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 1
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- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- the invention relates to the field of medicinal chemistry; in particular, the invention relates to a novel derivative containing a tricyclic heteroaryl group, its synthesis method and its use as a SOS1 inhibitor in the preparation of medicines for the treatment of tumors and other related diseases applications in .
- RAS Radiar Oncogene Homolog
- RAS family proteins are highly conserved in the GTP binding domain, and the C-terminal differences are relatively large.
- RAS protein itself has relatively weak GTPase hydrolysis function and slow nucleotide exchange rate, combined with GTPase activating proteins (GAP), such as NF1, RASA1-3, etc., can enhance the GTP hydrolysis function of RAS protein.
- GAP GTPase activating proteins
- SOS1 (Son of Sevenless 1) is a kind of guanine nucleotide exchange factor (Guanine Nucleotide Exchange Factors, GEF). SOS1 binds to RAS, promotes the release of GDP from RAS proteins, and binds to GTP.
- the RAS protein In the GTP-bound state, the RAS protein is in an activated state, recruiting downstream effector proteins, activating signaling pathways such as Raf-MEK-ERK and PI3K-AKT-mTOR, thereby promoting cell growth, proliferation, survival, metabolism, and angiogenesis.
- RAS Under normal physiological conditions, the activity of RAS is regulated by upstream growth factor signals, such as receptor tyrosine kinases, integrins, and G protein-coupled receptors.
- upstream growth factor signals such as receptor tyrosine kinases, integrins, and G protein-coupled receptors.
- RAS When RAS is mutated, its intrinsic or GAP-induced GTPase activity is inhibited, RAS is always in a GTP-bound state, and the molecular switch is continuously opened, which in turn leads to continuous activation of various downstream signaling pathways, and abnormal cell proliferation and growth.
- the frequency of KRAS mutations (G12, G13, Q61, and A146, etc.) is relatively high, and is more common in lung cancer, colon cancer, and pancreatic cancer.
- HRAS mutations (G12, G13, and Q61, etc.) and NRAS mutations (G12, G13, Q61, and A146, etc.) frequency is relatively low, mainly occurs in cancer types such as melanoma, leukemia and thyroid cancer.
- abnormal activation of RAS protein (such as gene mutation, amplification and overexpression, etc.) is also closely related to the resistance of some anti-tumor drugs, such as EGFR monoclonal antibodies and EGFR small molecule inhibitors. Therefore, RAS-related signaling pathways have become important anti-tumor targets.
- SOS SOS proteins
- RAS-GRP1-4 RAS guanine nucleotide releasing proteins
- RAS-GRF1 RAS guanine nucleotide releasing factors
- RAS-GRF2 RAS guanine nucleotide releasing factors
- SOS proteins Guanine nucleotide exchange factors involved in cancer-related signaling pathways are mainly SOS proteins, especially SOS1. Reducing the expression of SOS1 can significantly inhibit the proliferation and survival of KRAS-mutated cancer cells. In addition to this, the signaling pathways that SOS1 is involved in activating also play important roles in other mutant types of cancer.
- SOS1 can interact with the adaptor protein Grb2 to form a SOS1/Grb2 complex that binds to activated receptor tyrosine kinases (such as EGFR, HER2, Erbb4, TRKA, TRKB, TRKC, RET, and AXL, etc.).
- activated receptor tyrosine kinases such as EGFR, HER2, Erbb4, TRKA, TRKB, TRKC, RET, and AXL, etc.
- SOS1 can also be recruited to phosphorylated cell surface receptors, such as T-cell receptor, B-cell receptor, and monocyte colony-stimulating factor receptor.
- phosphorylated cell surface receptors such as T-cell receptor, B-cell receptor, and monocyte colony-stimulating factor receptor.
- SOS1 is also involved in the activation of other GTP hydrolases, such as RAC1.
- RAC1 has also been implicated in the pathogenesis of various human cancers and other diseases.
- SOS1 mutations are present in cancer types such as lung cancer, embryonal rhabdomyosarcoma, and granulosa cell tumor of the skin, and SOS1 overexpression is present in cancer types such as bladder cancer and prostate cancer.
- hereditary SOS1 mutations have also been implicated in the pathogenesis of RAS lesions, including Noonan syndrome, cardiofacial-cutaneous syndrome, and hereditary gingival fibroma type 1.
- the inhibitor binds to the catalytic site of SOS1, blocks the mutual binding of SOS1 and RAS protein, and inhibits the activation of RAS protein by SOS1.
- the application range of the compound includes a variety of cancer types, such as cancers with altered RAS family signaling pathways (gene mutation, amplification and overexpression, etc.), cancer types with abnormal activation of receptor tyrosine kinases, and cancer types with abnormal activation of SOS1.
- RAC1-dependent cancer types may also be sensitive to these compounds based on the important role of SOS1 in RAC1 activation.
- Other SOS1-related diseases such as the aforementioned Noonan syndrome, heart-facial-skin syndrome, and hereditary gingival fibroma type 1 may also benefit from such inhibitors.
- the purpose of the present invention is to provide a new class of SOS1 inhibitors.
- the first aspect of the present invention provides a compound of the structure represented by the following formula (I), or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, and solvates:
- R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 halo Alkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 1-6 alkoxy, C 1-4 haloalkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 alkoxy C 1-4 haloalkyl, C 3-6 cycloalkyl C 1-4 haloalkyl, or C 3-6 cycloalkyl-OC 1-4 haloalkyl, NR i R i ; wherein, The cycloalkyl group may be optionally substituted with a substituent selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy , or hydroxyl; each R i
- Z is selected from the group consisting of O, NH, NCH3 ;
- A is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, saturated or unsaturated C 3-10 cycloalkyl, or saturated or unsaturated 4- to 12-membered heterocyclyl;
- the cycloalkyl or heterocyclic group can be optionally substituted by 0-4 R 5 ; when U is a bond, and A is a saturated or unsaturated 4- to 12-membered heterocyclic group containing N atoms, A may optionally be linked to other moieties of the structure of formula (I) through an N-N bond;
- Each R 5 is each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkyne base, C 2-4 haloalkynyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO 2 , OR h , SR h , NR h R h , C(O)R t , C(O)OR h , OC(O)R t , C(O)NR h Rh , NR h C(O)R t , S(O) 2 R t , NR h S(O) 2 R t , or NR h S(O) 2 NR h R h ; the alkyl group may be optionally substituted with a substituent selected from the group consisting of CN, NO
- each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is optionally and each independently substituted with 1-3 substituents each independently selected from the group of Substituted: 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, ORh , SRh , NRhRh , C(O) Rt , C(O ) ORh , C(O ) NRhRh , NRhC ( O)R t , NR h S(O) 2 R t , or S(O) 2 R t , provided that the resulting chemical structure is stable and meaningful; where Rh and R t are as defined above said;
- 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 compound of formula (I) has the structure shown in formula (II):
- T is selected from CR 6 or N;
- Y is selected from CR 7 R 8 , NR 9 , O;
- n and n are independently 0, 1, 2, or 3; the premise is that m and n cannot be 0 at the same time;
- p 0, 1, 2, 3, or 4;
- R 6 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl;
- the group may be optionally substituted with a substituent selected from the group consisting of CN, NO2, ORh , SRh , NRhRh , C(O ) Rt , C(O ) ORh , OC(O)R t , C(O) NRhRh , NRhC (O) Rt , S(O ) 2Rt , NRhS ( O ) 2Rt , or NRhS ( O ) 2NRhRh ;
- Each R 7 and R 8 is each independently selected from the group consisting of hydrogen , halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2 -4alkynyl , CN, NO2, ORh , SRh , NRhRh , C(O) Rt , C(O ) ORh , OC(O ) Rt , C(O ) NRhRh , NR h C(O)R t , S(O) 2 R t , or NR h S(O) 2 R t , or NR h S(O) 2 NR h R h ; the alkyl group may be optional is substituted with a substituent selected from the group consisting of halogen, CN, NO2, ORh , SRh , NRhRh , C(O ) Rt , C(O ) ORh ,
- R is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 4- to 8 -membered heterocyclyl, aryl, heteroaryl, C( O) Rt , C(O) ORh , C(O ) NRhRh , S(O )2Rt , or S ( O ) 2NRhRh ;
- R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , Rh , R t are as defined above.
- the compound of formula (I) has the structure shown in the following formula (III):
- formula (I) is the structure shown in the formula (V):
- R 1 is selected from the group consisting of C 1-4 haloalkoxy, or C 3-6 cycloalkyl C 1-4 haloalkyl.
- R 4 is selected from the group consisting of methyl, ethynyl, or cyclopropyl.
- R 4 is selected from the following group: ethynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, or 4 - to 8-membered heterocyclyl; the remaining groups in formula (VII) are as defined above.
- formula (I) is the structure shown in the formula (VIII):
- each R 10 is each independently selected from halogen or C 1-4 alkyl; t is 0, 1, or 2; q is 1, 2, 3, or 4;
- R 1 , R 2 , R 3 , U, and A are as defined above.
- described formula (I) is the structure shown in formula (IX):
- each R 10 is each independently selected from halogen or C 1-4 alkyl; t is 0, 1, or 2; q is 1, 2, 3, or 4;
- R 1 , R 2 , R 3 , and R 6 are as defined above.
- described formula (I) is the structure shown in formula (X):
- R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-4 haloalkane oxy, C 2-6 haloalkynyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, or NR i R i ;
- R 6 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl;
- the group may be optionally substituted with a substituent selected from the group consisting of CN, NO2, ORh , SRh , NRhRh , C(O ) Rt , C(O ) ORh , OC(O)R t , NRhC (O) Rt , or NRhS (O )2Rt ;
- R t is a C 1-4 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, or a C 3-8 cycloalkyl group.
- R 6 is selected from C 1-4 alkyl; and the alkyl is substituted by a substituent selected from the following group: OC(O)R t , or NR h S(O) 2 R t .
- the compound of formula (I) is selected from the following group:
- 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 an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrated compounds, solvates, and pharmaceutically acceptable carriers.
- the third aspect of the present invention provides a compound of the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate of the compound.
- the disease, disorder 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, melanoma, embryonal Rhabdomyosarcoma, Granular Cell Tumor of Skin, Liver Cancer, Rectal Cancer, Bladder Cancer, Throat Cancer, Breast Cancer, Prostate Cancer, Glioma, Ovarian Cancer, Head and Neck Squamous Cancer, Cervical Cancer, Esophageal Cancer, Kidney Cancer, Skin Cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, polycythemia splenomegaly, eosinophilic leukemia syndrome multiple, bone marrow cancer and other solid tumors and blood tumor, and various diseases associated with hereditary mutations in SOS1, including but not limited to neurofibromat
- the inventors After long-term and in-depth research, the inventors have unexpectedly discovered a class of SOS1 inhibitors containing tricyclic aryl compounds with novel structures, as well as their preparation methods and applications.
- the compounds of the present invention can be applied to the treatment of various diseases related to the activity of the kinases. Based on the above findings, the inventors have completed the present invention.
- each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
- alkyl refers to a straight chain (ie, unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched chain groups .
- a carbon number limitation eg C 1-10
- 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 an alkenyl group is preceded by a carbon number limitation (eg, C 2-8 ), it means that the alkenyl group contains 2, 3, 4, 5, 6, 7 or 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 the like group.
- alkynyl 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.
- a carbon number limitation eg, C 2-8 alkynyl
- C 2-8 alkynyl refers to straight or branched chain alkynyl groups having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, including ethynyl, propynyl, isopropynyl , butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.
- cycloalkyl refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system having saturated or partially unsaturated group.
- a cycloalkyl group is preceded by a carbon number limitation (eg C 3-10 ), it means that the cycloalkyl group contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
- C 3-8 cycloalkyl refers to saturated or partially saturated monocyclic or bicycloalkyl groups having 3, 4, 5, 6, 7 or 8 carbon atoms, including cyclopropyl cyclobutyl, cyclopentyl, cycloheptyl, or similar groups.
- Spirocycloalkyl refers to a bicyclic or polycyclic group in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more double bonds, but none of the rings have fully conjugated pi electrons system.
- “Fused cycloalkyl” refers to an all-carbobicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more bicyclic bonds, but none of the rings have a fully conjugated pi electron system.
- “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more double bonds, but none of the rings have 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 to the following cycloalkyl groups.
- Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as 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 attachment to the parent must be in a conjugated pi-electron system on the carbon atom of the ring.
- Aryl groups can be substituted or unsubstituted.
- 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 A polycyclic group formed by condensing nitrogen, oxygen and sulfur) with an aryl group, and the attachment site 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 to the following heteroaryl groups.
- Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein 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.
- Polycyclic heterocyclyl refers to heterocyclyl including spiro, fused and bridged rings.
- “Spirocyclic heterocyclyl” refers to a polycyclic heterocyclic group in which each ring in the system shares one atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, the remaining ring atoms are carbon.
- “Fused-ring heterocyclyl” refers to 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 no 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” refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more double bonds, but none of the rings have 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. If both saturated and aromatic rings are present in the heterocyclyl group (for example, the saturated and aromatic rings are fused together), the point of attachment to the parent must be on the saturated ring. Note: When the point of attachment to the parent is on an aromatic ring, it is called a heteroaryl group, not a heterocyclyl group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.
- halogen refers to F, Cl, Br, and I.
- substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, an optionally substituted group may have at any substitutable position of the group a substituent selected from a specified group, which may be the same or different at each position.
- a cyclic substituent such as a heterocyclyl
- substituents contemplated by the present invention are those that are stable or chemically achievable.
- 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, carboxyl (-COOH), C 1-8 aldehyde group, C 2-10 acyl group, C 2-10 ester group, amino group.
- a pharmaceutically acceptable salt refers to a salt suitable for contact with the tissue 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 that has an acidic group (eg, potassium, sodium, magnesium, calcium) or has a basic salts of compounds of the invention (eg, sulfates, hydrochlorides, phosphates, nitrates, carbonates).
- the present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrates , the use of a pharmaceutically acceptable carrier or excipient for inhibiting SOS1.
- the compounds of the present invention are useful as a SOS1 inhibitor.
- the present invention is a single inhibitor of SOS1, and achieves the purpose of preventing, relieving or curing diseases by regulating the enzyme activity of SOS1.
- Indicated diseases include non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, granular cell tumor of the skin, melanoma, liver cancer, rectal cancer, bladder cancer , Throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis , B-cell lymphoma, monocytic leukemia, polycythemia splenomegaly, eosinophilic leukemia syndrome multiple, bone marrow cancer and other solid tumors
- compositions may be combined 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.
- the compositions may be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions. Sterile powder, etc.
- the pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin (increase), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and high molecular 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 silicates and high molecular 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, powders.
- the amount of a compound or pharmaceutical composition of the present invention administered to a patient is not fixed, but is usually administered in a pharmaceutically effective amount. Meanwhile, the amount of the compound actually administered can be determined by the physician according to the actual situation, including the condition to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and the like.
- the dosage of a compound of the present invention will depend upon the particular use of the treatment, the mode of administration, the patient's condition, and the judgment of the physician.
- the ratio or concentration of a compound of the present invention in a pharmaceutical composition depends on a variety of factors, including dosage, physicochemical properties, route of administration, and the like.
- DIPEA N,N-diisopropylethylamine
- HATU N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea
- TsOH p-toluenesulfonic acid
- the compound of formula (I) of the present invention can be prepared by the following method:
- compound I-a is hydrolyzed under basic conditions to obtain I-b, compound I-b and compound I-c are obtained by a suitable condensation method to obtain compound I-d, and then the target compound I is obtained by ring closure under acidic conditions.
- Compound I-a can be synthesized by the method of reaction formula 4.
- R 1 , R 2 , R 3 , R 4 , U and A in Reaction Formula 1 are the same as those in Claim 1.
- the compound of formula (III) of the present invention can be prepared by the following method:
- R 1 , R 2 , R 3 , R 4 , R 5 , Y, m, n, and p in Reaction Formula 2 are the same as those in Claim 3.
- the compound of formula (VI) of the present invention can be prepared by the following method:
- compound I-b and compound VI-a are subjected to a suitable condensation method to obtain compound VI-b, and then the target compound VI is obtained by ring closure under acidic conditions.
- a suitable condensation method to obtain compound VI-b
- the target compound VI is obtained by ring closure under acidic conditions.
- the definition of each group in Reaction Scheme 3 is as described above.
- the compound of formula (VIII) of the present invention can be prepared by the following method:
- compound VIII-a is closed with diethyl malonate under basic conditions to give VIII-b, compound VIII-b in a mixture of phosphorus oxychloride and N,N-dimethylformamide Go through substitution and acylation to obtain compound VIII-c, protect the aldehyde group with ethylene glycol to obtain compound VIII-d, then undergo a substitution reaction with dimethyl malonate to obtain compound VIII-e, and remove a methyl carboxylate by heating The ester obtains compound VIII-f, which undergoes a substitution reaction with a substituted amine to obtain intermediate VIII-g.
- the intermediate VIII-g is hydrolyzed under basic conditions to obtain compound VIII-h, and then the target compound VIII is obtained through condensation reaction and ring closure reaction. .
- R 1 , R 2 , R 3 , R 10 , t, q, U and A in Reaction Formula 4 are the same as the expressions in claim 10 .
- the compounds of formula (IX) of the present invention can be prepared by the following methods:
- Compound IX-a and compound IX-b undergo continuous condensation reaction and ring-closure reaction under alkaline conditions to obtain compound IX-c, and then undergo acylation to obtain compound IX-e.
- Compound IX-e and compound IX-f undergo metal The catalyzed coupling reaction obtains compound IX-g, and compound IX-g is subjected to ring closure reaction in ammonia methanol solution to obtain compound IX-h.
- Compound IX-h is first reacted with a suitable halogenated reagent to generate a halogenated intermediate, and then reacted with an amine. Substitution reaction occurs to give the final product compound IX.
- R 1 , R 2 , R 3 , R 6 , R 10 , t and q in Reaction Formula 5 are the same as the expressions in claim 11 .
- each group is as described above.
- the reagents and conditions of each step can be selected from conventional reagents or conditions in the art for such preparation methods. After the structure of the compound of the present invention is disclosed, the above selection can be performed by those skilled in the art according to the knowledge in the art.
- the conditions of the method such as reactants, solvent, base, acid, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to the following explanations.
- the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
- compositions and methods of administration are provided.
- the compound of the present invention Since the compound of the present invention has excellent inhibitory activity against a series of protein kinases, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are
- the pharmaceutical composition of the main active ingredient can be used for the treatment, prevention and alleviation of diseases related to the activity or expression of SOS1.
- the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
- the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious 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 filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
- Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
- cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
- gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
- the mode of administration of the compounds or pharmaceutical compositions 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 mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
- Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form 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 employed 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, and the like.
- inert diluents conventionally employed 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, dimethylform
- 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 such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
- suspending agents such as 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 excipients include water, ethanol, polyols and suitable mixtures thereof.
- Dosage forms for topical administration of the compounds 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 that 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 suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
- the administration dose is usually 1 to 2000 mg, preferably 5 to 500 mg.
- the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
- novel SOS1 inhibitor with a novel structure, preparation and application thereof, the inhibitor can inhibit the activity of SOS1 at a very low concentration.
- a pharmaceutical composition for treating diseases related to SOS1 activity is provided.
- Compound 1a was synthesized by the method in patent WO2019122129.
- reaction solution containing compound 1b was obtained from compound 1a (25 mg, 0.06 mmol) and used directly for the next reaction.
- triethyl phosphoroacetate (1.68 g, 7.5 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and a solution of potassium tert-butoxide (1.12 g, 10 mmol) in tetrahydrofuran (20 mL) was added, The reaction was carried out until a large amount of solid was precipitated.
- a solution of compound 14a (1.05 g, 5 mmol) in tetrahydrofuran (5 ml) was added, and the reaction was carried out at 0° C. for 3 hours. The reaction was quenched by adding water (5 mL) and extracted with ethyl acetate (2 ⁇ 30 mL).
- compound 14b 400 mg, 1.4 mmol was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C, lithium aluminum tetrahydrogen (119 mg, 3.22 mmol) was added, and the reaction mixture was slowly warmed to room temperature and reacted for 3 hours. It was quenched by adding 30% NaOH aqueous solution (0.5 g) and stirred until a large amount of solid was precipitated. Add anhydrous magnesium sulfate, dry and concentrate to obtain a crude product, and the crude product is directly used in the next reaction.
- the solid was precipitated, and the solid was filtered off with celite, extracted with ethyl acetate, the organic layer was neutralized with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
- the positive drug and the test compound (10 mM stock solution) were serially diluted 3-fold with 100% DMSO, and 0.1 uL of the compound was transferred to a 384-well plate using a dispenser ECHO.
- Add 5ul Tag2-KRAS G12D>P to a 384-well plate and centrifuge at 1000rpm for 1min.
- Add 5uL Tag1–SOS1 to a 384-well plate and centrifuge at 1000rpm for 1min. Incubate at 25°C for 15min, add 10uL of anti-Tag1-Tb and anti-Tag2-XL665 mixture to a 384-well plate, centrifuge at 1000rpm for 1min, and incubate at 4°C for 3h.
- 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, flow rate is 0.350 ml/min, gradient elution is used , the elution gradient is 0.50min: 10%B; 1.50min: 10%B; 2.30min: 95%B; 2.31min: 10%B; 3.00min: stop. Injection volume: 5 ⁇ L.
- Animals 3 SD male rats, weighing 200-220 g, were raised in the laboratory of the Experimental Animal Center for 2 days after purchase, fasted 12 hours before and 4 hours after administration, and freely drank water during the test. Blood samples were taken at predetermined time points after gavage in rats.
- Drug sample The representative compound of the structure shown in the patent formula (I) of the present invention is generally taken from multiple samples with similar structures (the molecular weight difference is more than 2 units), accurately weighed, and administered together (cassette PK). This allows multiple compounds to be screened simultaneously and their oral absorption rates compared. A single dose was also used to study the pharmacokinetics of drug samples in rats.
- Orbital blood was collected at 0.25, 0.5, 1, 2, 4, 9, 12 and 24 hours after oral administration, and placed in a test tube treated with heparin sodium. After centrifugation, the supernatant plasma was collected for LC-MS/MS analyze.
- Apparatus An LC-MS/MS-13 (TQ5500) mass spectrometer was used. Pharmacokinetic parameters were calculated using the method of statistical moments using Phoenix WinNonlin 7.0 (Pharsight, USA) software. It mainly includes kinetic parameters T max , T 1/2 , C max , AUC (0-t) and the like.
- 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 (0.1% formic acid), and the flow rate is 0.60 ml/min , using gradient elution (0min, 10% B; 0-0.60min, 10%-90% B; 0.60-1.10min, 90% B; 1.10-1.11min, 90%-10% B; 1.11 -1.40min, 10% B). Injection volume: 4 ⁇ L.
- mice 12 ICR male mice, body weight range 17-25g, the animals were transferred from the animal reserve of the experimental institution (999M-018), fasted for 10-16 hours before administration and 4 hours after administration, and freely drank water during the experiment . Mice were randomly divided into two groups, 3 mice in each group, and the drugs were administered by gavage and intravenous injection, respectively.
- Vehicle 0.5% Methycellulose aqueous solution for gavage, 5% DMSO+10% solutol+85% Saline for intravenous injection.
- micro blood was collected at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h and 24h, respectively. 4h, 8h, 10h, 12h and 24h micro-blood was collected, placed in a test tube treated with K2-EDTA, and the supernatant plasma was collected after centrifugation for LC-MS/MS analysis.
- Sample processing 20 ⁇ L plasma sample, 100 ng/mL tolbutamide in methanol (400 ⁇ L) was added, the mixture was vortexed for 1 min and centrifuged at 18000 g for 7 min. Transfer 400 ⁇ L of the supernatant to a 96-well plate. 4 ⁇ L of supernatant was injected for LC-MS/MS analysis.
Abstract
La présente invention concerne un composé utile en tant qu'inhibiteur de SOS1. Plus particulièrement, la présente invention concerne un composé ayant une structure telle que représentée par la formule (I), ou un isomère optique, un sel pharmaceutiquement acceptable, un promédicament, un dérivé deutéré, un hydrate ou un solvate de celui-ci. Le composé peut être utilisé pour traiter ou prévenir des maladies ou des états associés à l'activité ou à la quantité d'expression de SOS1.
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CA3207590A1 (fr) * | 2021-02-08 | 2022-08-11 | Xuejun Zhang | Derive de pyridopyrimidinone, son procede de preparation et son utilisation |
CN113200981A (zh) * | 2021-02-10 | 2021-08-03 | 杭州英创医药科技有限公司 | 作为sos1抑制剂的杂环化合物 |
WO2022214594A1 (fr) | 2021-04-09 | 2022-10-13 | Boehringer Ingelheim International Gmbh | Thérapie anticancéreuse |
CN117957224A (zh) * | 2021-08-03 | 2024-04-30 | 苏州信诺维医药科技股份有限公司 | 稠环化合物、药物组合物及其应用 |
CN117730080A (zh) * | 2021-08-30 | 2024-03-19 | 浙江海正药业股份有限公司 | 吡啶并嘧啶酮类衍生物及其制备方法和用途 |
CN117836278A (zh) * | 2021-09-02 | 2024-04-05 | 上海海和药物研究开发股份有限公司 | 一种sos1抑制剂、其制备方法及用途 |
CN115417868B (zh) * | 2021-09-13 | 2024-04-02 | 石药集团中奇制药技术(石家庄)有限公司 | 一种具有抗肿瘤活性的杂环化合物及其用途 |
WO2023041049A1 (fr) * | 2021-09-17 | 2023-03-23 | 江苏先声药业有限公司 | Composé hétérocyclique utilisé en tant qu'inhibiteur de sos1 et ses utilisations |
CN114456134B (zh) * | 2021-09-30 | 2024-04-26 | 武汉大学 | 一种α-氟烷基取代的环丙基醇类化合物、其制备方法及应用 |
CN115724844A (zh) * | 2021-11-22 | 2023-03-03 | 石药集团中奇制药技术(石家庄)有限公司 | 一种具有抗肿瘤活性的杂环化合物及其用途 |
WO2023125737A1 (fr) * | 2021-12-29 | 2023-07-06 | Silexon Ai Technology Co., Ltd. | Composés hétérocycliques et leur utilisation |
WO2023143147A1 (fr) * | 2022-01-28 | 2023-08-03 | 上海优理惠生医药有限公司 | Composés de pyridazopyridone, composition pharmaceutique de ceux-ci et leur utilisation |
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CN117357650A (zh) * | 2022-07-07 | 2024-01-09 | 武汉人福创新药物研发中心有限公司 | 包含sos1抑制剂的药物组合物 |
WO2024027762A1 (fr) * | 2022-08-05 | 2024-02-08 | 上海艾力斯医药科技股份有限公司 | Composé à cycles fusionnés, son procédé de préparation et son utilisation |
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- 2022-02-10 WO PCT/CN2022/075934 patent/WO2022171184A1/fr active Application Filing
- 2022-02-10 CN CN202280014288.0A patent/CN117295732A/zh active Pending
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CN111372932A (zh) * | 2017-12-21 | 2020-07-03 | 勃林格殷格翰国际有限公司 | 作为sos1抑制剂的新颖苄氨基取代吡啶并嘧啶酮及衍生物 |
WO2020254451A1 (fr) * | 2019-06-19 | 2020-12-24 | Boehringer Ingelheim International Gmbh | Polythérapie anticancéreuse |
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WO2024074827A1 (fr) | 2022-10-05 | 2024-04-11 | Sevenless Therapeutics Limited | Nouveaux traitements de la douleur |
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