[go: up one dir, main page]

WO2025214293A1 - Composé hétérocyclique, composition pharmaceutique de celui-ci et utilisation associée - Google Patents

Composé hétérocyclique, composition pharmaceutique de celui-ci et utilisation associée

Info

Publication number
WO2025214293A1
WO2025214293A1 PCT/CN2025/087514 CN2025087514W WO2025214293A1 WO 2025214293 A1 WO2025214293 A1 WO 2025214293A1 CN 2025087514 W CN2025087514 W CN 2025087514W WO 2025214293 A1 WO2025214293 A1 WO 2025214293A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
stereoisomer
atropisomer
deuterated derivative
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/087514
Other languages
English (en)
Chinese (zh)
Inventor
邓小兵
李勃
赵燕
王婷婷
杜志超
肖栋槐
田文嘉
陈辉玲
张恂
王艳红
张晓波
曹硕
苏亚宁
周宜遂
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Double Crane Runchuang Technology Co Ltd
Original Assignee
Beijing Double Crane Runchuang Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Double Crane Runchuang Technology Co Ltd filed Critical Beijing Double Crane Runchuang Technology Co Ltd
Publication of WO2025214293A1 publication Critical patent/WO2025214293A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C07D401/10—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 carbon chain containing aromatic rings
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/10—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 two hetero rings linked by a carbon chain containing aromatic 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
    • 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

Definitions

  • the present application refers to the entire contents of the above-mentioned international application.
  • the present invention belongs to the field of pharmaceutical chemistry and relates to a heterocyclic compound, a pharmaceutical composition thereof and an application thereof.
  • Nrf2 is an important transcription factor that plays a key role in regulating cellular redox balance and resisting oxidative stress. However, in cancer, Nrf2 is often found to be in an aberrantly activated state, which may play an important role in tumor development.
  • Nrf2 activation is closely related to the occurrence, development and treatment resistance of tumors.
  • Shibata et al. found that excessive activation of Nrf2 in tumors is closely related to increased malignant transformation and tumor invasion. This phenomenon may be because Nrf2 activation can promote the survival, proliferation and migration of tumor cells, while reducing sensitivity to oxidative stress and chemotherapeutic drugs (Tatsuhiro Shibata et al. Cancer-related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy, Proc Natl Acad Sci U S A. 2008 Sep 9; 105(36): 13568-73).
  • Nrf2 Nrf2-Keap1 signaling pathway in cancer.
  • Nrf2 mutations are prevalent in primary tumors of approximately 20 organs (Gao J, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013;6:p11.), and these mutations have been found to be associated with its enhanced transcriptional activity (Kim YR, et al. Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J Pathol 2010;220:446-51.).
  • Nrf2 mutations carries the highest frequency of Nrf2 mutations (approximately 19%), followed by head and neck squamous cell carcinoma (approximately 10%) and esophageal adenocarcinoma (approximately 8.5%). Therefore, abnormal activation of Nrf2 in cancer may be both a driver of tumor development and a novel therapeutic target for tumor treatment.
  • Developing inhibitors that directly target Nrf2 is very challenging, and some indirect therapies have been reported, such as inhibitors targeting Nrf2-dependent KARS (WO2021005586A1).
  • no anti-tumor therapies that selectively target the NRF2/KEAP1 pathway have been approved, and this remains an unmet clinical need.
  • the present invention provides a heterocyclic compound, specifically as follows:
  • Ring A is an aryl group, a heteroaryl group or a heterocyclic group
  • each R 1 is independently H, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, or -C( ⁇ O)N(R 1a ) 2 , or two R 1a , taken together with the atoms to which they are attached, form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; each R 1a is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three -OH, C1-C6 alkyl, or C1
  • Each R 2 is independently H, halogen, -CN, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 alkoxy;
  • R4 is and R 4a is H, D, halogen or C1-C6 haloalkyl
  • p and q are each independently 0, 1, 2 or 3; m is an integer from 1 to 12; n is an integer from 1 to 10;
  • X 1 is N or CR 2 ;
  • n may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the compound has the structure of the following formula (I-1) or (I-2):
  • p and q are each independently 0, 1, or 2.
  • the compound has the structure of the following formula (I-1-1) or formula (I-1-2):
  • ring A is: a 5-6 membered monocyclic heteroaryl group or an 8-10 membered bicyclic heteroaryl group, wherein the heteroatom is N and the number of heteroatoms is 1, 2 or 3.
  • ring A is: a 6 membered monocyclic heteroaryl group, wherein the heteroatom is N and the number of heteroatoms is 2.
  • Ring A is the following structure:
  • Ring A is the following structure:
  • Ring A is The end marked with "#" indicates the connected.
  • each R 1 is independently H, F, Br, Cl, C1-C3 alkyl, or -C( ⁇ O)N(R 1a ) 2 , C1-C3 alkyl is optionally substituted with one, two, or three F, Br, Cl, or C1-C3 alkyl, and each R 1a is independently H or C1-C6 alkyl.
  • each R 1 is independently H, F, -CH3 or -CHF2 , preferably H.
  • each R 2 is independently F, Br, or Cl, preferably Cl.
  • each R 3 is independently H, halogen, -NH 2 , -NHR 3a , -N(R 3a ) 2 , -C( ⁇ O)NH 2 , -C( ⁇ O)NH(C1-C3 alkyl), -C( ⁇ O)N(C1-C3 alkyl) 2 , -SH( ⁇ O)( ⁇ NH), or -S( ⁇ O)( ⁇ NH)R 3a , and each R 3a is independently C1-C6 alkyl.
  • ring A and R 2 are located at any two positions of the 1st, 3rd, or 5th positions of the ring.
  • the compound is any of the following:
  • the present invention also provides a compound of the following formula (II) or (III), a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing:
  • Xa is N or CH
  • Each R b is independently F, Br or Cl;
  • Ring A is the following structure:
  • the compound has any of the following structures:
  • the atoms in any compound of any of the above schemes, its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers, its pharmaceutically acceptable salts of atropisomers, or a solvate of any of them are atoms at natural abundance.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any compound described in any of the foregoing embodiments, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any of them; and at least one pharmaceutically acceptable excipient.
  • the present invention provides any compound described in any of the foregoing embodiments, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer, its pharmaceutically acceptable salt of its deuterated derivative, or a solvate of any of them; or use of the pharmaceutical composition according to the present invention in the preparation of a medicament that mediates KEAP1 activation and thereby inhibits Nrf2.
  • the present invention provides any compound described in any of the foregoing schemes, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any of them, or the use of the composition described above in the preparation of a medicament for treating the following diseases or conditions, wherein the disease or condition is cancer; preferably, the cancer is non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, prostate cancer, lymphoma, leukemia or myelodysplastic syndrome (MDS), and the esophageal cancer is, for example, esophageal squamous cell carcinoma.
  • NSCLC non-small
  • the present invention provides a method for treating a subject suffering from a disease or condition caused by abnormal activation of Nrf2, the method comprising administering to the subject a therapeutically effective amount of any compound described in any of the foregoing schemes, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any of them; or the pharmaceutical composition described above; wherein the disease or condition is cancer; preferably, the cancer is non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, prostate cancer, lymphoma, leukemia or myelodysplastic syndrome (MDS), and the esophageal cancer
  • the present invention provides any compound described in any of the foregoing schemes, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer, its pharmaceutically acceptable salt of its deuterated derivative, or a solvate of any of them; or the use of the pharmaceutical composition according to the present invention in a drug for treating a disease or condition with abnormal activation of Nrf2; wherein the disease or condition is cancer; preferably, the cancer is non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, prostate cancer, lymphoma, leukemia or myelodysplastic syndrome (MDS), and the esophageal cancer is, for example, esophageal squamous
  • halogen is used interchangeably herein to refer to fluorine, chlorine, bromine, or iodine.
  • Preferred halogen groups include -F, -Cl, and -Br.
  • alkyl as used herein includes saturated monovalent hydrocarbon groups having straight or branched chains.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl.
  • C1-6 in C1-6 alkyl is defined to designate a straight or branched chain group having 1, 2, 3, 4 , 5 , or 6 carbon atoms.
  • alkyl abbreviations include: Me( -CH3 ), Et( -CH2CH3 ), iPr(-CH(CH3)2 ) , nPr ( -CH2CH2CH3 ), n-Bu ( -CH2CH2CH2CH3 ), or i-Bu( -CH2CH ( CH3 ) 2 ).
  • haloalkyl refers to an alkyl group as described above substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br).
  • the haloalkyl group is interchangeably -C 1-6 haloalkyl or halo-C 1-6 alkyl, wherein the C 1-6 in -C 1-6 haloalkyl or halo-C 1-6 alkyl indicates that the total number of carbon atoms in the alkyl group is 1 to 6.
  • the -C 1-6 haloalkyl group is a -C 1-3 haloalkyl group.
  • the -C 1-3 haloalkyl group is a methyl, ethyl, propyl, or isopropyl group substituted with 1, 2, 3, 4, 5, or 6 -F groups; preferably, the -C 1-3 haloalkyl group is -CF 3 .
  • alkylene refers to a difunctional group obtained by removing an additional hydrogen atom from an alkyl group as defined above, for example, methylene (i.e., -CH2- ), ethylene (i.e., -CH2- CH2- or -CH( CH3 )-), and propylene (i.e., -CH2 - CH2- CH2- , -CH( -CH2 - CH3 )-, or -CH2 -CH( CH3 )-).
  • alkenyl refers to a straight or branched hydrocarbon group containing one or more double bonds, typically 2 to 20 carbon atoms in length.
  • -C2-6 alkenyl contains 2 to 6 carbon atoms.
  • alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
  • alkynyl refers to a straight or branched hydrocarbon group containing one or more triple bonds, typically 2 to 20 carbon atoms in length.
  • -C2-6alkynyl contains 2 to 6 carbon atoms.
  • representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • alkoxy refers to oxygen ethers formed from the aforementioned alkyl groups, including but not limited to -OCH3 , -OCH2CH3 , -OCH2CH2CH3 , -OCH( CH3 ) 2 , -CH2OCH3 , -CH2CH2OCH3 .
  • haloalkoxy refers to an alkoxy group substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br).
  • the haloalkoxy group is interchangeably a -C 1-6 haloalkoxy group or a halo-C 1-6 alkoxy group, wherein the C 1-6 in the -C 1-6 haloalkoxy group or the halo-C 1-6 alkoxy group indicates that the total carbon atoms of the alkoxy group are 1 to 6.
  • the -C 1-6 haloalkoxy group is a -C 1-3 haloalkoxy group.
  • the -C 1-6 haloalkoxy group is substituted with 1, 2, 3, 4, 5, or 6 -F groups (methoxy, ethoxy, propoxy, or isopropoxy); a preferred -C 1-3 haloalkoxy group is -OCF 3 .
  • aryl or “aromatic ring” as used herein refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing only carbon ring atoms.
  • Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems, such as phenyl, naphthyl, etc.
  • heterocyclyl or “heterocycle” as used herein refers to a saturated or unsaturated group of a non-aromatic ring system having ring carbon atoms and one or more ring heteroatoms, wherein each heteroatom is independently selected from one or more of nitrogen, oxygen, sulfur, boron, phosphorus and silicon, and optionally containing 0, 1, 2 or 3 double or triple bonds, including monocyclic heterocycles, bicyclic heterocycles, bridged heterocycles, fused heterocycles and spirocyclic heterocycles.
  • the point of attachment may be a carbon or nitrogen atom, as valence permits.
  • a 4-8 membered heterocyclyl is preferred, which is a 4 to 8 membered non-aromatic ring system having ring carbon atoms and one or more ring heteroatoms; heterocyclyl also includes ring systems in which the above heterocyclyl ring is fused to one or more cycloalkyl groups, where the point of attachment is on the heterocyclyl ring, or ring systems in which the above heterocyclyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system.
  • Heterocyclyl also includes heterocyclyl rings in which the substituents on any non-adjacent carbon or nitrogen atoms are linked to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl also includes heterocyclyl rings in which the substituents on the same carbon atom are linked to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiirane.
  • Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl.
  • Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • heterocycloalkyl refers to a cyclic group having a specified number of ring atoms (e.g., 3-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom species (1, 2, or 3 of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon), which is a monocyclic, bridged, or spirocyclic ring, and each ring is saturated.
  • Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, and piperidinyl.
  • heteroaryl refers to an aromatic ring system containing carbon and at least one heteroatom.
  • the heteroatom may be nitrogen, oxygen, or sulfur.
  • the heteroaryl or heteroaromatic ring may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl may have 1 to 4 heteroatoms in its ring, while a polycyclic heteroaryl may contain 1 to 10 heteroatoms.
  • a polycyclic heteroaryl ring may contain a fused ring, for example, a bicyclic heteroaryl is a polycyclic heteroaryl.
  • a bicyclic heteroaryl ring may contain 8 to 12 atoms.
  • a monocyclic heteroaryl ring may contain 5 to 8 atoms (carbon atoms and heteroatoms).
  • the "heteroaryl” is monocyclic or bicyclic, wherein the heteroatoms are selected from one or more of nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, 3, or 4.
  • heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl, or isoquinolinyl.
  • Carbocyclyl refers to a substituted or unsubstituted monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring system containing only carbon atoms.
  • the ring is three to ten members and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two, or three, are included in this definition.
  • Carbocyclyl includes, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • Exemplary "cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • cycloalkyl refers to a saturated cyclic group having a specified number of ring carbon atoms (eg, C3-C12, eg, C3-C6), wherein the ring atoms consist solely of carbon atoms.
  • one or more means one or more. In some embodiments, “one or more” means 1, 2, 3, 4, 5, or 6. In some embodiments, “one or more” means 1, 2, 3, or 4. In some embodiments, “one or more” means 1, 2, or 3. In some embodiments, “one or more” means 1 or 2. In some embodiments, “one or more” means 1. In some embodiments, “one or more” means 2. In some embodiments, “one or more” means 3. In some embodiments, “one or more” means 4. In some embodiments, “one or more” means 5. In some embodiments, “one or more” means up to 6.
  • each substituent when a ring is substituted with one or more substituents, it means that each substituent can be substituted independently on each ring atom of the ring, including but not limited to a ring carbon atom or a ring nitrogen atom.
  • each substituent when the ring is polycyclic, such as a fused ring, a bridged ring or a spiro ring, each substituent can be substituted independently on each ring atom of the polycyclic ring.
  • oxo refers to an oxygen atom and the carbon atom to which it is attached forming an group.
  • composition is intended to encompass a product comprising a specific amount of a specific ingredient, as well as any product produced directly or indirectly by a combination of specific amounts of a specific ingredient. Therefore, pharmaceutical compositions containing a compound of the present invention as an active ingredient and methods for preparing the compound of the present invention are also part of the present invention. Moreover, some crystalline forms of the compound may exist in the form of polymorphs and are therefore intended to be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the present invention.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • compounds of the present invention are basic, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Since the compounds of the present invention are intended for pharmaceutical use, they are preferably provided in a substantially pure form, for example at least 60% pure, more suitably at least 75% pure, and especially at least 98% pure (% by weight).
  • any substituent or variable at a particular position in a molecule is intended to be independent of the definitions of substituents or variables at other positions in the molecule. It is understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the invention to provide chemically stable compounds that can be readily synthesized by techniques known in the art and the methods illustrated herein.
  • the compounds of the present invention may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the present invention includes all stereoisomers of the compounds and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. In the synthetic steps used to prepare these compounds, or in the process of using racemization or epimerization methods known to those skilled in the art, the products of these steps may be mixtures of stereoisomers.
  • stereoisomer refers to isomers resulting from differences in spatial arrangement of atoms or groups of atoms in a molecule in the same order of interconnection. This includes configurational isomers and conformational isomers. Configurational isomers further include geometric isomers and optical isomers. Optical isomers primarily include enantiomers and diastereomers. The present invention encompasses all possible stereoisomers of the compound.
  • Certain compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule.
  • the compounds provided herein include all atropisomers, including pure individual atropisomers, enriched atropisomers of each, or nonspecific mixtures of each. If the barrier to rotation about a single bond is high enough and the interconversion between conformations is slow enough, separation of atropisomers may be permitted.
  • the present invention is intended to include all atomic isotopes present in the compounds of the present invention.
  • Isotopes are atoms with the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of hydrogen can be represented as 1H (hydrogen), 2H (deuterium) and 3H (tritium). They are also commonly represented as D (deuterium) and T (tritium).
  • CD 3 represents a methyl group in which all hydrogen atoms are deuterium.
  • Isotopes of carbon include 13C and 14C .
  • Isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotopically labeled reagents instead of non-labeled reagents.
  • the term “deuterated derivative” refers to a compound having the same chemical structure as a reference compound, but in which one or more hydrogen atoms have been replaced by a deuterium atom ("D"). It will be recognized that some variation in natural isotopic abundance will occur in the synthetic compounds, depending on the source of the chemical materials used in the synthesis. The concentration of the naturally abundant stable hydrogen isotope, although such variation is small and insignificant, is compared to the degree of stable isotopic substitution of the deuterated derivatives described herein.
  • the deuterated derivatives disclosed herein have an isotopic enrichment factor per deuterium atom of at least 3500 (containing 52.5% deuterium in each specified deuterium), at least 4500 (containing 67.5% deuterium), at least 5000 (containing 75% deuterium), at least 5500 (containing 82.5% deuterium), at least 6000 (containing 90% deuterium), at least 6333.3 (containing 95% deuterium), at least 6466.7 (containing 97% deuterium), or at least 6600 (containing 99% deuterium).
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof and mixtures thereof, unless otherwise specifically stated.
  • a "solvate of a substance” refers to a substance formed by the combination of the substance and a solvent. Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
  • compositions of the present invention comprise as active ingredients a compound of the present invention, a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing, and a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration.
  • the pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any method well known in the pharmaceutical art.
  • the compounds of the present invention can be combined as an active ingredient with a pharmaceutical carrier in an intimate mixture according to conventional pharmaceutical formulation techniques.
  • a pharmaceutical carrier in an intimate mixture according to conventional pharmaceutical formulation techniques.
  • the carrier can take a variety of forms, such as oral or parenteral (including intravenous) routes of administration.
  • compositions of the present invention can be presented as discrete units suitable for oral administration, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient.
  • compositions can be presented in powder form, granular form, solution form, suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion.
  • the compound represented by Formula I can also be administered by controlled release and/or delivery devices.
  • the composition can be prepared by any pharmaceutical method. Typically, such methods include the step of combining the active ingredient with a carrier constituting one or more essential ingredients. Typically, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both. The product can then be conveniently formed into the desired form.
  • the pharmaceutical compositions of the present invention may include a compound, a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing and a pharmaceutically acceptable carrier.
  • a compound of formula (I), (II), (III), (I-1), (I-2), (I-1-1), (I-1-2) or a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing may also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier used can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, or stearic acid.
  • liquid carriers are syrup, peanut oil, olive oil, or water.
  • gaseous carriers include carbon dioxide or nitrogen.
  • any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oil, alcohol, flavorings, preservatives, colorants, etc.
  • oral liquid preparations such as suspensions and solutions
  • carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc.
  • oral solid preparations such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units due to their ease of administration, which use solid pharmaceutical carriers.
  • tablets can be coated using standard aqueous or non-aqueous techniques.
  • Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally with one or more auxiliary ingredients or adjuvants.
  • Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant.
  • Molded tablets can be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient.
  • a formulation for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent mixed with an appropriate and convenient amount of carrier material, which may comprise from about 0.05 to about 95% of the total composition.
  • Dosage unit forms generally contain from about 0.01 mg to about 2 g of active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1500 mg or 2000 mg.
  • compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water.
  • Suitable surfactants such as hydroxypropylcellulose, can be included.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • preservatives can be included to prevent the harmful growth of microorganisms.
  • compositions of the present invention suitable for injection include sterile aqueous solutions or dispersions.
  • the composition can be in the form of a sterile powder for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for ease of injection.
  • the pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it is best to preserve it to prevent contamination by microorganisms such as bacteria and fungi.
  • the carrier can be, for example, a solvent or dispersion medium containing water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), a vegetable oil, and a suitable mixture thereof.
  • compositions of the present invention may be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, powder, or the like. These formulations may be prepared using conventional processing methods using the compounds of the present invention or pharmaceutically acceptable salts thereof.
  • a cream or ointment may be prepared by mixing a hydrophilic material and water with about 0.05 wt % to about 10 wt % of the compound to produce a cream or ointment of the desired consistency.
  • the pharmaceutical composition of the present invention can be in a form suitable for rectal administration, wherein the carrier is a solid.
  • the mixture forms a unit dose suppository.
  • Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be easily formed by first mixing the composition with a softened or melted carrier, then cooling and molding in a mold.
  • the above-mentioned pharmaceutical preparations may suitably include one or more additional carrier components, such as diluents, buffers, flavorings, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc.
  • additional carrier components such as diluents, buffers, flavorings, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc.
  • other adjuvants may be included to make the preparation isotonic with the blood of the intended recipient.
  • compositions containing a compound, a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing can also be prepared in the form of a powder or liquid concentrate.
  • dosage levels of about 0.001 mg/kg to about 150 mg/kg of body weight per day are useful for treating the aforementioned conditions, or about 0.05 mg to about 7 g per patient per day.
  • about 0.001 to 50 mg of the compound per kg of body weight per patient per day, or about 0.05 mg to about 3.5 g of the compound per kg of body weight per patient per day may be effective for treating diseases or conditions that inhibit Nrf2 by activating KEAP1, such as, but not limited to, non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colon cancer, rectal cancer, colorectal cancer, renal cancer, melanoma, gastric cancer, prostate cancer, lymphoma, leukemia, or myelodysplastic syndrome (MDS).
  • NSCLC non-small cell lung cancer
  • MDS myelodysplastic syndrome
  • the specific dosage level for any particular patient will depend on a variety of factors including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular condition being treated.
  • the compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein.
  • the examples outlining specific synthetic routes are intended to provide guidance to synthetic chemists skilled in the art, who will readily understand that solvents, concentrations, reagents, protecting groups, the order of synthetic steps, times, temperatures, etc. can be modified as needed within the skill and judgment of those skilled in the art.
  • the following abbreviations are used in the examples:
  • KYSE70 cells in the logarithmic growth phase were plated at 3000 cells per well, with 90 ⁇ L of cell suspension per well. After 24 hours of culture, the compound was diluted to 3 mM with DMSO, and a 3-fold serial dilution was performed at 9 concentration points, with DMSO as a negative control. The above compound was further diluted 100-fold with RIPM-1640 medium, and the compound molecules were added to the culture medium in the wells at 10 ⁇ M per well, so that the final dilution effect was 1000-fold. The final concentration of the compound was 3 ⁇ M, and 9 concentration points were diluted 3-fold.
  • the cell group containing 0.1% DMSO was set as the solvent control group, and the cell group containing only culture medium and 0.1% DMSO was set as the blank control group. Three replicates were set for each compound concentration and control well. The cells were returned to the cell culture incubator and incubated for about 1.5 hours. The OD value at 450 nm was read using a microplate reader. The inhibition rate was calculated according to the following formula, and the inhibition curve was plotted using Graphpad Prism software, and the EC50 was calculated.
  • cell inhibition rate [(vehicle control wells - test compound wells) / (vehicle control wells - blank control wells)] ⁇ 100%.
  • Comparative Examples 1 to 3 are as follows, and the synthesis methods refer to WO2024073587A1.
  • mice Male were used for each compound. Mice were treated with a single 10 mg/kg dose of the compound (oral administration). For each mouse, blood samples were collected at 0.5, 1, 2, 4, and 8 hours after administration. Whole blood samples were placed in a test tube containing EDTA-K2, inverted several times, and then centrifuged at 6000 rpm, 4°C for 15 minutes to obtain plasma. The concentration of the compound in the plasma sample was determined using LC-MS/MS.
  • Preparation of compound working solution Prepare 10 mM DMSO stock solutions of the test substance and control compound verapamil (i.e., Varapamil), and dilute them to 200 ⁇ M working solution with acetonitrile before the experiment. The final concentration of the test substance and verapamil is 1 ⁇ M.
  • verapamil i.e., Varapamil
  • phosphate buffer Weigh 7.098 g of disodium hydrogen phosphate and add 500 mL of pure water. Dissolve by ultrasonication. Weigh 3.400 g of potassium dihydrogen phosphate and add 250 mL of pure water. Adjust the pH to 7.4 ⁇ 0.2.
  • Preparation of 10mM NADPH Weigh an appropriate amount of NADPH (reduced coenzyme II) and prepare a fresh 10mM working solution in phosphate buffered saline for a final concentration of 1mM.
  • Preparation of incubation system Prepare the suspension according to Table 5 and add it to the incubation plate, and pre-incubate in a 37°C water bath for 10 minutes.
  • Test Add 2 ⁇ L of positive control or test compound working solution to 358 ⁇ L incubation system and vortex to mix evenly. All samples are prepared in duplicate. Add 40 ⁇ L 10 mM NADPH to the system, vortex to mix evenly, start the reaction timer, take 50 ⁇ L of the above suspension at 0.5, 5, 10, 15, 30, and 60 min, add 400 ⁇ L acetonitrile (containing 100 ng/ml dexamethasone) stop solution, and vortex to mix evenly. Centrifuge at 4700 rpm and 4°C for 15 minutes to precipitate the protein. Transfer 100 ⁇ L of supernatant to the sample plate, add 100 ⁇ L of pure water and mix well, and use for UPLC-MS/MS analysis. The results are shown in Table 6.
  • Rats were administered with each compound. Rats were treated with a single 25 mg/kg dose (oral gavage). Blood samples were collected from each rat at 0.083, 0.25, 0.5, 1, 2, 4, and 8 hours post-dose. Whole blood samples were placed in a tube containing EDTA-K2, inverted several times, and then centrifuged at 6000 rpm, 4°C for 15 minutes to obtain plasma. The concentration of the compound in the plasma sample was determined using LC-MS/MS.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé hétérocyclique, une composition pharmaceutique de celui-ci et une utilisation associée. Plus particulièrement, la présente invention concerne un composé de formule (I), un stéréoisomère, un atropisomère, un dérivé deutéré, un sel pharmaceutiquement acceptable de celui-ci, un sel pharmaceutiquement acceptable du stéréoisomère de celui-ci, un sel pharmaceutiquement acceptable de son atropisomère, un sel pharmaceutiquement acceptable du dérivé deutéré de celui-ci, ou un solvate de l'un quelconque des précédents. Le composé présente une activité inhibitrice significativement élevée contre les cellules cancéreuses KYSE70 et présente de bonnes propriétés pharmacocinétiques.
PCT/CN2025/087514 2024-04-08 2025-04-07 Composé hétérocyclique, composition pharmaceutique de celui-ci et utilisation associée Pending WO2025214293A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CNPCT/CN2024/086596 2024-04-08
CN2024086596 2024-04-08
CN2024099373 2024-06-14
CNPCT/CN2024/099373 2024-06-14
CNPCT/CN2024/108011 2024-07-27
CN2024108011 2024-07-27

Publications (1)

Publication Number Publication Date
WO2025214293A1 true WO2025214293A1 (fr) 2025-10-16

Family

ID=97349412

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/087514 Pending WO2025214293A1 (fr) 2024-04-08 2025-04-07 Composé hétérocyclique, composition pharmaceutique de celui-ci et utilisation associée

Country Status (1)

Country Link
WO (1) WO2025214293A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012035055A1 (fr) * 2010-09-17 2012-03-22 Glaxo Group Limited Nouveaux composés
WO2022206939A1 (fr) * 2021-04-03 2022-10-06 海南耀臻生物医药科技有限公司 Composé hétérocyclique servant d'inhibiteur de fgfr et son application
CN115433190A (zh) * 2021-06-02 2022-12-06 药雅科技(上海)有限公司 不可逆杂环化合物fgfr抑制剂的制备方法和用途
CN117800954A (zh) * 2022-10-02 2024-04-02 先声再明医药有限公司 杂环化合物及其应用
WO2024073587A1 (fr) * 2022-09-29 2024-04-04 Vividion Therapeutics, Inc. Dérivés de n-acryloylmorpholine utilisés en tant que modulateurs de keap1 et utilisations associées

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012035055A1 (fr) * 2010-09-17 2012-03-22 Glaxo Group Limited Nouveaux composés
WO2022206939A1 (fr) * 2021-04-03 2022-10-06 海南耀臻生物医药科技有限公司 Composé hétérocyclique servant d'inhibiteur de fgfr et son application
CN115433190A (zh) * 2021-06-02 2022-12-06 药雅科技(上海)有限公司 不可逆杂环化合物fgfr抑制剂的制备方法和用途
WO2024073587A1 (fr) * 2022-09-29 2024-04-04 Vividion Therapeutics, Inc. Dérivés de n-acryloylmorpholine utilisés en tant que modulateurs de keap1 et utilisations associées
CN117800954A (zh) * 2022-10-02 2024-04-02 先声再明医药有限公司 杂环化合物及其应用

Similar Documents

Publication Publication Date Title
CN112533929B (zh) 吲哚类大环衍生物、其制备方法及其在医药上的应用
WO2023280280A1 (fr) Composé à cycle fusionné agissant en tant qu'inhibiteur de kras g12d
CN115836070B (zh) 作为egfr抑制剂的稠环化合物及其制备方法和应用
CN114656482B (zh) 作为egfr抑制剂的大环杂环类化合物及其应用
WO2022017533A1 (fr) Composé utile en tant qu'inhibiteur de kinase cdk7 et son utilisation
CN115785068A (zh) Kif18a抑制剂
WO2020147739A1 (fr) Antagonistes du récepteur de l'acide lysophosphatidique et procédé de préparation associé
KR20240004634A (ko) 삼환식 유비퀴틴 특이적 프로테아제 1 억제제 및 이의 용도
CN115772159A (zh) Kif18a抑制剂
WO2020233641A1 (fr) Composé utilisé comme inhibiteur de kinase ret et son utilisation
TW202311260A (zh) 含有亞磺醯亞胺基的atr抑制劑化合物
WO2023041055A1 (fr) Inhibiteur de kif18a
WO2023061406A1 (fr) Inhibiteur de parp contenant une structure tricyclique condensée, son procédé de préparation et son utilisation médicale
TWI823420B (zh) 用作cdk激酶抑制劑的化合物及其應用
EP4155304A1 (fr) Composé utilisé comme inhibiteur de kinase ret et son application
WO2024051702A1 (fr) Composé utilisé comme inhibiteur de la kinase cdk4 et son utilisation
WO2022037648A1 (fr) Composé d'acide boronique pyrazole, composition pharmaceutique le contenant et utilisations associées
CN113045569B (zh) 用作ret激酶抑制剂的化合物及其应用
CN110407854B (zh) 新的四环化合物
WO2025051211A1 (fr) Composé utilisé comme inhibiteur de kinase cdk4 et son utilisation
WO2025214293A1 (fr) Composé hétérocyclique, composition pharmaceutique de celui-ci et utilisation associée
TWI847445B (zh) 一種噠嗪類化合物、其藥物組合物及應用
CN121001992A (zh) 咪唑基与二硝基苯基结合的衍生物及其用途
WO2024099225A1 (fr) Inhibiteurs d'ulk
WO2023226976A1 (fr) Inhibiteur de sik et composition de celui-ci, son procédé de préparation et son utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25785766

Country of ref document: EP

Kind code of ref document: A1