WO2023169170A1 - Composé hétérocyclique utilisé en tant qu'inhibiteur de shp2, composition comprenant un composé hétérocyclique, et procédé l'utilisant - Google Patents

Composé hétérocyclique utilisé en tant qu'inhibiteur de shp2, composition comprenant un composé hétérocyclique, et procédé l'utilisant Download PDF

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WO2023169170A1
WO2023169170A1 PCT/CN2023/076423 CN2023076423W WO2023169170A1 WO 2023169170 A1 WO2023169170 A1 WO 2023169170A1 CN 2023076423 W CN2023076423 W CN 2023076423W WO 2023169170 A1 WO2023169170 A1 WO 2023169170A1
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compound
formula
pharmaceutically acceptable
optionally substituted
solvate
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PCT/CN2023/076423
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Chinese (zh)
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利群
张劲涛
简善忠
李傲
袁霞
徐汶
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捷思英达控股有限公司
徐汶
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Publication of WO2023169170A1 publication Critical patent/WO2023169170A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure belongs to the field of medical technology, and particularly relates to a heterocyclic compound as a SHP2 inhibitor, a composition including the heterocyclic compound, and a method of using the same.
  • novel heterocyclic compounds that can act as inhibitors of SHP2 (Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2).
  • pharmaceutical compositions comprising at least one such compound, and methods of using at least one such compound in the treatment of SHP2-modulated diseases and disorders, such as cancer.
  • SHP2 is a ubiquitous non-receptor protein tyrosine phosphatase encoded by the human PTPN11 gene, with relatively conserved structure and function. It contains a protein tyrosine phosphatase catalytic domain (PTP domain), two SH2 domains, and a C-terminal tail with two tyrosine phosphorylation sites and a proline-rich motif . SHP2 catalyzes the dephosphorylation of phosphotyrosine, a key control element in mammalian signal transduction.
  • the N-SH2 domain binds to specific phosphotyrosine residues on cell surface receptors to induce conformational changes, thereby exposing and catalytically activating the PTP domain, resulting in SHP2 activation (Qu CK,el al. Cell Res 2000,10,279-88).
  • SHP2 acts downstream of receptor tyrosine kinase and upstream of RAS (Yuan XR et.al.J Med Chem 2020,10.1021/acs.jmedchem.0c00249).
  • the immune checkpoint PD-1 signals through SHP2 to inhibit the activity of T cells in the tumor microenvironment (Marasco et al., Sci. Adv. 2020; 6:eaay4458).
  • Dysregulation of SHP2 is associated with a range of human diseases, including cancer.
  • SHP2 mainly regulates the survival and proliferation of cancer cells by activating the RAS-ERK signaling pathway (Matozaki T, el al. Cancer Sci 2009, 100, 1786-93).
  • SHP2 mutations cause Noonan and Leopardskin syndromes, and mutations that increase the basal activity of SHP2 are the most common cause of sporadic juvenile myelomonocytic leukemia (Tartaglia, M, et al. Nat. Genet. 2003, 34, 148-150) . These rare diseases predispose patients to cancer.
  • SHP2 activity is closely related to tumorigenesis ((Marsh-Armstrong B, et al. ACS Omega 2018, 3, 15763-15770)).
  • SHP2 is important for RTK-driven (Chen YN, et al. Nature 2016, 535, 148-52) and mutant KRAS-driven cancers (Mainardi S, et al. Nat Med 2018, 24, 961-7; Ruess DA, et al. Nat Med 2018, 24, 954-60) is required for growth and survival.
  • SHP2 inhibition triggers anti-tumor immunity and enhances PD-1 blockade (Zhao, MX, et al. Acta Pharmaceutica Sinica B, 2019, 9, 304-315). Therefore, SHP2 has emerged as an attractive target in the treatment of various diseases mediated by SHP2.
  • compositions comprising at least one such novel compound, methods of preparing the novel compounds, and methods of using at least one such compound to treat SHP2-mediated diseases and disorders (eg, cancer).
  • Y is selected from:
  • R 1 is selected from H, NH 2 and optionally substituted C1-C3 alkyl
  • R 2 is selected from H, halogen, -CN, -OH, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkenyl, optionally substituted C1-C3 alkynyl, optionally substituted C1-C3 alkoxy and optionally substituted C1-C3 haloalkyl;
  • Each R 3 is independently selected from H and optionally substituted C1-C3 alkyl
  • R 4 is selected from H and optionally substituted C1-C6 alkyl
  • R 5 is selected from H, halogen, NH 2 , -CN, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkenyl, optionally substituted C1-C3 alkynyl, optionally substituted C1-C3 alkoxy and optionally substituted C1-C3 haloalkyl;
  • R 6 is selected from H and optionally substituted C1-C3 alkyl
  • X 1 is selected from -O- and -C(R 7 ) 2 -, wherein R 7 is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S as ring members; or, wherein R 4 , R 7 and are located in the R 4 and R
  • the two carbon atoms between 7 may together optionally form 4-7 selected from C3-C6 cycloalkyl, saturated or unsaturated containing 1-2 heteroatoms selected from N, O and S as ring members cyclic groups containing 1 to 4 heteroatoms selected from N, O and S as ring members; and
  • compositions comprising a compound of Formula I and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of a compound of Formula I disclosed herein, and a pharmaceutically acceptable Acceptable carrier.
  • a treatable disease by inhibiting SHP2 in a patient, said method comprising administering to a patient identified in need of such treatment an effective amount of a compound of Formula I and/or a steric form of a compound of Formula I disclosed herein. isomers, stable isotopes, or pharmaceutically acceptable salts or solvates.
  • a treatable disease by inhibiting SHP2 in a patient comprising administering to a patient identified in need of such treatment an effective amount of a pharmaceutical composition comprising a compound of Formula I disclosed herein and/or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of the compounds of formula I, and pharmaceutically acceptable carriers.
  • the cancer is selected from juvenile myelomonocytic leukemia, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma cell carcinoma, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.
  • the cancer is selected from juvenile myelomonocytic leukemia, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma , gastric cancer, anaplastic large cell lymphoma and glioblastoma.
  • compositions of Formula I and compounds of subclasses of Formula I disclosed herein as well as pharmaceutically acceptable salts or solvates of these compounds, as well as all stereoisomers (including diastereoisomers) and enantiomers, as well as isotopically enriched variants (including deuterium substitutions).
  • the compounds can be used to treat conditions that are responsive to SHP2 inhibition, such as those disclosed herein, and can be used to prepare medicaments for treating these disorders.
  • compositions and methods disclosed herein may also be used or formulated with co-therapeutics; for example, compounds of Formula I and compounds of its subformulas may be used with one or more agents selected from the group consisting of SHP2 kinase inhibitors and non-SHP2 kinase inhibitors and other Used together or formulated with therapeutic agents.
  • a dash ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent.
  • -CONR a R b is connected through a carbon atom.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • Halogen-substituted groups and moieties such as alkyl groups substituted with halogen elements (haloalkyl), may be monohalogenated, polyhalogenated, or perhalogenated.
  • chlorine and fluorine are examples of halogen substituents on alkyl or cycloalkyl groups; unless otherwise specified, fluorine, chlorine, and bromine are, for example, on aryl groups. group or heteroaryl group used on.
  • heteroatom refers to a nitrogen (N) atom or an oxygen (O) atom or a sulfur (S) atom.
  • alkyl optionally substituted with X includes both “alkyl not substituted with X” and “alkyl substituted with X.”
  • substituents are independently selected unless otherwise stated, so that where 2 or 3 substituents are present, for example, those substituents may be the same or different.
  • substituted with at least one group means that one hydrogen on the specified atom or group is replaced with one selected from the specified group of substituents. In some embodiments, “substituted with at least one group” means that two hydrogens on a specified atom or group are independently replaced with two selected from the specified group of substituents. In some embodiments, “substituted with at least one group” means that three hydrogens on a specified atom or group are independently replaced with three selected from the specified group of substituents. In some embodiments, "substituted with at least one group” means that four hydrogens on a specified atom or group are independently replaced with four selected from the specified group of substituents.
  • alkyl refers to a group selected from groups having up to 18 carbon atoms, such as from 1 to 12 carbon atoms, further such as from 1 to 8 carbon atoms, even further such as from 1 to 6 carbon atoms) straight-chain and branched-chain saturated hydrocarbon radicals.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neo Pentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.
  • an alkyl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogens on the alkyl group) are substituted in place of the hydrogen atoms of the unsubstituted alkyl group.
  • substituents eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogens on the alkyl group
  • alkoxy refers to a linear or branched alkyl group containing 1 to 18 carbon atoms (such as methoxy, ethoxy, propoxy, isopropoxy) connected through an oxygen bridge. , n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy base, 3-methylpentyloxy, etc.).
  • an alkoxy group includes 1 to 6 carbon atoms (eg, 1 to 4 carbon atoms) connected through an oxygen bridge.
  • an alkoxy group may optionally be present in the unsubstituted number of hydrogens on the alkoxy group) in place of the hydrogen atoms of the unsubstituted alkyl portion of the alkoxy group.
  • suitable substituents are selected from, for example, those listed above for alkyl groups, except that hydroxyl and amino groups are generally not present in direct connection with the oxygen of the substituted alkyl-O group. on the carbon.
  • alkenyl groups may be selected from ethenyl or vinyl (-CH ⁇ CH 2 ), prop-1-enyl (-CH ⁇ CHCH 3 ), prop-2-enyl (- CH 2 CH ⁇ CH 2 ), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-Methylbut-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl group.
  • the point of attachment can be on an unsaturated carbon or a saturated carbon.
  • an alkenyl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogens on the alkenyl group) are substituted in place of the unsubstituted hydrogen atoms of the alkenyl group.
  • substituents eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogens on the alkenyl group
  • suitable substituents are selected, for example, from those listed above for alkyl groups.
  • alkynyl refers to a hydrocarbon group selected from straight and branched chain hydrocarbon groups including at least one -C ⁇ C- triple bond and 2 to 18 (eg, 2 to 6) carbon atoms.
  • alkynyl groups include ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ CCH 3 ), 2-propynyl (propargyl, -CH 2 C ⁇ CH), 1-butanyl Alkynyl, 2-butynyl and 3-butynyl groups.
  • the point of attachment can be on an unsaturated carbon or a saturated carbon.
  • an alkynyl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogens on the alkynyl group) are substituted in place of the unsubstituted hydrogen atoms of the alkynyl group.
  • substituents eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogens on the alkynyl group
  • suitable substituents are selected, for example, from those listed above for alkyl groups.
  • alkylene refers to a divalent alkyl group containing 1 to 10 carbon atoms and two expanded valence bonds to other molecular moieties.
  • the two molecular moieties attached to the alkylene group may be on the same carbon atom or on different carbon atoms.
  • propylene is a 3-carbon alkylene group which may be 1,1-disubstituted, 1,2-disubstituted or 1,3-disubstituted.
  • alkylene refers to a moiety including 1 to 6 carbon atoms (eg, 1 to 4 carbon atoms).
  • alkylene include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, tert-butylene, n-pentylene base, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-Octyl, n-nonyl, n-decyl, etc.
  • a substituted alkylene group is an alkylene group containing one or more (such as one, two or three) substituents; unless otherwise specified, suitable substituents are selected from, for example, as listed above Substituents for alkyl groups.
  • an alkylene group may optionally be present in the unsubstituted number of hydrogen atoms on the alkylene group) in place of the unsubstituted hydrogen atoms of the alkylene group.
  • suitable substituents are selected, for example, from those listed above for alkyl groups.
  • alkenylene and alkynylene respectively refer to alkylene groups including double or triple bonds; for example, they are 2-6 (eg, 2-4) carbon atoms in length and may Substituted as discussed above for alkylene groups.
  • haloalkyl refers to a hydrocarbyl group, as defined herein, substituted with one or more halogen groups, as defined herein. Unless otherwise specified, the hydrocarbyl portion of a haloalkyl group includes 1 to 4 carbon atoms.
  • the haloalkyl group may be monohaloalkyl, dihaloalkyl, trihaloalkyl or polyhaloalkyl (including perhaloalkyl).
  • a monohaloalkyl group may have one iodine, bromine, chlorine or fluorine within the hydrocarbyl group.
  • Dihaloalkyl groups and polyhaloalkyl groups may have two or more of the same halogen atoms or a combination of different halogen groups within the hydrocarbyl group.
  • Polyhaloalkyl groups include, for example, up to 6, or 4, or 3, or 2 halogen groups.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, Difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perhaloalkyl refers to a hydrocarbon group in which all hydrogen atoms are replaced by halogen atoms (for example, trifluoromethyl).
  • haloalkyl groups include monofluoro-, difluoro-, and trifluoro-substituted methyl and ethyl groups (e.g., -CF 3 , -CF 2 H, - CFH 2 and -CH 2 CF 3 ).
  • a haloalkyl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogen atoms on the haloalkyl group) are substituted in place of the unsubstituted hydrogen atoms of the haloalkyl group.
  • substituents eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogen atoms on the haloalkyl group
  • suitable substituents are selected, for example, from those listed above for alkyl groups.
  • haloalkoxy refers to haloalkyl-O-, wherein haloalkyl is as defined above.
  • haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, 2-chloroethoxy, 2,2,2-trifluoro Ethoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy, etc.
  • haloalkoxy groups include 1-4 carbon atoms and up to three halogen elements, for example, monofluoro, difluoro and trifluoro substituted methoxy groups and ethoxy groups .
  • a haloalkoxy group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to The number of hydrogens on the haloalkoxy group) is substituted for the hydrogen atoms of the unsubstituted alkyl portion of the haloalkoxy group.
  • substituents are selected from, for example, those listed above for alkyl groups, except that hydroxyl and amino groups are generally not present in direct connection with the oxygen of the substituted haloalkyl-O group on the carbon.
  • cycloalkyl refers to saturated and partially unsaturated cyclic hydrocarbon radicals (such as monocyclic and polycyclic (e.g., bicyclic and tricyclic, adamantyl and Spirocycloalkyl) group) hydrocarbyl.
  • Monocycloalkyl groups are cyclic hydrocarbyl groups containing from 3 to 20 carbon atoms (eg, from 3 to 8 carbon atoms).
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecanyl, cyclododecyl, and cyclohexenyl.
  • Bicycloalkyl groups include bridged bicycloalkyl, fused bicycloalkyl and spirocycloalkyl.
  • Bridged bicycloalkyl contains a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are bridged by an alkylene group of one to three additional carbon atoms (i.e., -(CH 2 )n-form A bridging group, where n is 1, 2 or 3) is connected.
  • bridged bicycloalkyl groups include, but are not limited to, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2 .2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, etc.
  • Fused bicycloalkyl contains a monocyclic cycloalkyl ring fused to one of phenyl, monocyclic cycloalkyl, and monocyclic heteroaryl.
  • fused bicycloalkyl groups include, but are not limited to, bicyclo[4.2.0]oct-1,3,5-triene, 2,3-dihydro-1H-indene, 6,7-dihydro-5H-cyclo Penta[b]pyridine, 5,6-dihydro-4H-cyclopenta[b]thiophene and decalin, etc.
  • Spirocycloalkyl groups contain two monocyclic ring systems that share carbon atoms to form a bicyclic ring system. Examples of spirocycloalkyl include, but are not limited to Bicyclic cycloalkyl groups include, for example, 7 to 12 carbon atoms.
  • a tricycloalkyl group includes a bridged tricycloalkyl group as used herein, which bridged tricycloalkyl refers to: 1) a bridged bicycloalkyl ring, wherein the bridged bicycloalkyl ring The two are incompatible The adjacent carbon atoms are connected through an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group of the form -(CH 2 )n-, where n is 1, 2, or 3); or 2) fused Bicycloalkyl rings in which the two non-shared ring atoms on each ring are bridged by an alkylene group of one to three additional carbon atoms (i.e., a bridging group of the form -(CH 2 )n-, where n is 1, 2 or 3) linkage, where "f
  • bridged tricycloalkyl groups include, but are not limited to, adamantyl As used herein, a bridged tricycloalkyl group is attached to the parent molecular moiety through any ring atom. Ring atoms disclosed herein refer to carbon atoms in the ring backbone. Cycloalkyl groups may be saturated or include at least one double bond (ie, partially unsaturated), but are not fully conjugated and are not aromatic (as defined herein) cycloalkyl groups. Cycloalkyl groups may be substituted by at least one heteroatom selected from, for example, O, S and N.
  • a cycloalkyl group may optionally be present in the unsubstituted
  • the number of hydrogen atoms on the cycloalkyl group) is substituted in place of the hydrogen atoms of the unsubstituted cycloalkyl group.
  • substituted cycloalkyl groups contain 1-4, such as 1-2 substituents.
  • suitable substituents are selected, for example, from those listed above for alkyl groups.
  • cycloalkylene or "cycloalkylene ring” disclosed herein refers to a divalent cycloalkane ring connected via the same carbon atoms of the cycloalkane ring by removing two hydrogen atoms from the same carbon atom.
  • cycloalkylene rings include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene. It can be represented illustratively by the following structure, where n is 1, 2, 3, 4 or 5.
  • heterocycloalkyl refers to a "cycloalkyl” as defined above in which at least one ring carbon atom is replaced by a heteroatom independently selected from O, N, S. base".
  • Heterocyclyl groups include, for example, 1, 2, 3, or 4 heteroatoms, and each of N, C, and S can be independently oxidized in the cyclic ring system. N atoms can also be substituted to form tertiary amines or ammonium salts.
  • the point of attachment to a heterocyclyl group can be on a heteroatom or on a carbon.
  • Heterocyclyl herein also refers to a 5- to 7-membered saturated or partially unsaturated carbocyclic ring (heterocycle) including at least one heteroatom selected from, for example, N, O, and S, which carbocyclic ring is identical to the 5-membered , 6-membered and/or 7-membered cycloalkyl, heterocyclic or carbocyclic aromatic rings are fused, provided that when the heterocyclic ring is fused with the carbocyclic aromatic ring, the connection point is at the heterocyclic ring, and when the heterocyclic ring is fused with the carbocyclic aromatic ring, When an alkyl group is fused, the point of attachment can be at the cycloalkyl group or the heterocycle.
  • Heterocyclyl as used herein also refers to an aliphatic spirocycle including at least one heteroatom selected from, for example, N, O, and S.
  • the ring may be saturated or have at least one double bond (ie, partially unsaturated).
  • Heterocyclyl groups may be substituted, for example, by oxo groups.
  • the point of attachment can be a carbon or a heteroatom.
  • Heterocyclyl is not heteroaryl as defined herein.
  • heterocycles include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, oxiranyl, aziridinyl, thiazanyl Cyclopropanyl, azetidinyl, oxetanyl, thietanyl, dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thio Oxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxeptanyl, thieptanyl, oxithianyl, dioxanyl , oxazepanyl, oxazepanyl, dithiazepanyl, thiazepanyl and diazepanyl, dithiazepanyl , azathianeyl,
  • Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholine base, 1,1-dioxo-1-thiomorpholinyl,
  • a heterocyclyl group may optionally be present in the unsubstituted
  • the number of hydrogen atoms on the heterocyclyl group) is substituted in place of the hydrogen atoms of the unsubstituted heterocyclyl group.
  • substituted heterocyclyl contains 1-4, such as 1-2 or 1-3 substituents.
  • suitable substituents are selected, for example, from those listed above for alkyl groups.
  • aryl refers to an aromatic hydrocarbon group containing 5 to 15 carbon atoms in the ring portion.
  • aryl refers to a group selected from the group consisting of 5- and 6-membered carbocyclic aromatic rings, e.g., phenyl; selected from, e.g., naphthalene, indane, and 1,2,3,4-tetrahydroquinoline Bicyclic ring systems (such as 7- to 12-membered bicyclic ring systems in which at least one ring is carbocyclic and aromatic); and tricyclic ring systems (such as 10- to 15-membered tricyclic ring systems in which at least one ring is carbocyclic and aromatic), for example, fluorene.
  • the aryl group is selected from a heterocycle fused to a 5- to 7-membered cycloalkyl group or optionally including at least one heteroatom selected from, for example, N, O, and S (e.g., "heterocycle” below).
  • base or “heterocycle” of 5- and 6-membered carbocyclic aromatic rings, provided that when the carbocyclic aromatic ring is fused to the heterocyclic ring, the point of attachment is at the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused to the heterocyclic ring When an aromatic ring is fused to a cycloalkyl group, the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group.
  • a divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene group.
  • a naphthyl group with two points of attachment is called a naphthylene group.
  • aryl does not include or overlap in any way with heteroaryl, which is separately defined below. Therefore, if one or more carbocyclic aromatic rings are fused to a heterocyclic aromatic ring (e.g., heteroaryl, as defined below), the resulting ring system is a heteroaryl, as defined herein, and not an aryl .
  • an aryl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or as many as 1 to 4 substituents present in the unsubstituted number of hydrogens on the aryl group) are substituted in place of the hydrogen atoms of the unsubstituted aryl group.
  • substituents eg, one, two, or three substituents, or 1 to 4 substituents, or as many as 1 to 4 substituents present in the unsubstituted number of hydrogens on the aryl group
  • substituted aryl groups contain 1-5 substituents.
  • suitable substituents are selected, for example, from those listed above for alkyl groups.
  • heteroaryl refers to a group selected from a 5- to 7-membered aromatic monocyclic ring that includes at least one (e.g., 1 to 4) heteroatoms, or In some embodiments, 1 to 3 heteroatoms) are selected from heteroatoms such as N, O, and S, wherein the remaining ring atoms are carbon; 8 to 12 membered bicyclic rings, the 8 to 12 membered bicyclic rings include at least One (e.g., 1 to 4 heteroatoms, or in some embodiments, 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms) is selected from the group consisting of, for example, N, O, and S Atoms wherein the remaining ring atoms are carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring and wherein the point of attachment is on any ring and is on a carbon or heteroatom; and 11-membered to 14-membered tricyclic rings, the 11-
  • a heteroaryl group contains a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring.
  • the point of attachment can be at the heteroaromatic ring or at the cycloalkyl ring.
  • a heteroaryl group contains a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered aryl ring.
  • the point of attachment can be at the heteroaromatic ring or at the aryl ring.
  • Non-limiting examples include quinolinyl and quinazolinyl.
  • a heteroaryl group contains a 5- to 7-membered heterocyclic aromatic ring fused to an additional 5- to 7-membered heterocyclic aromatic ring.
  • Non-limiting examples include 1H-pyrazolo[3,4-b]pyridyl and 1H-pyrrolo[2,3-b]pyridyl.
  • the total number of S atoms and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S atoms and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S atoms and O atoms in the aromatic heterocycle does not exceed 1.
  • heteroaryl groups include, but are not limited to, pyridyl, zolinyl, pyrazinyl, pyrimidinyl, imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiazolyl Diazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazine base, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, triazolyl, quinolyl, isoquinolyl, isoquinolyl, pyrazolyl, pyrrolopyridyl (such as 1H-pyrrolo[2,3-b] Pyridin-3-yl), pyrazo
  • a heteroaryl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to The number of hydrogen atoms on the heteroaryl group) is substituted in place of the hydrogen atoms of the unsubstituted heteroaryl group.
  • substituted heteroaryl groups contain 1, 2, or 3 substituents.
  • suitable substituents are selected, for example, from those listed above for alkyl groups.
  • Compounds disclosed herein may contain asymmetric centers and, therefore, may exist as enantiomers. Where compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to the broader category of stereoisomers. It is well known in the art how to prepare optically active bodies, for example by resolving materials or by asymmetric synthesis. All such possible stereoisomers (eg, substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereoisomers) are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless otherwise explicitly mentioned, reference to one isomer applies to any one of the possible isomers. When no isomeric composition is specified, all possible isomers are included.
  • salts include, but are not limited to, salts with inorganic acids selected from, for example, hydrochlorides, phosphates, hydrogen phosphates, hydrobromides, sulfuric acid salts Salts, sulfinates and nitrates; and salts with organic acids selected from, for example, malates, maleates, fumarates, tartrates, succinates, citric acid Salt, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, alkanoate (such as acetate), and with Salts formed by HOOC-(CH2) n -COOH, where n is selected from 0 to 4.
  • examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • the free base can be obtained by basifying a solution of the acid salt.
  • the addition salt can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for the preparation of acid addition salts from base compounds (e.g. Pharmaceutically acceptable addition salts).
  • base compounds e.g. Pharmaceutically acceptable addition salts.
  • One skilled in the art will recognize a variety of synthetic methods that can be used to prepare nontoxic pharmaceutically acceptable addition salts without undue experimentation.
  • Treating refers to the administration of at least one compound disclosed herein, and/or at least One stereoisomer thereof (if any), at least one stable isotope thereof, or at least one pharmaceutically acceptable salt thereof.
  • an effective amount refers to at least one compound disclosed herein, and/or at least one stereoisomer thereof, if any, that is effective for “treating” (as defined above) a disease or disorder in a subject ), at least one stable isotope thereof, or at least one pharmaceutically acceptable salt thereof.
  • Embodiment 1 A compound of formula I:
  • Y is selected from:
  • R 1 is selected from H, NH 2 and optionally substituted C1-C3 alkyl
  • R 2 is selected from H, halogen, -CN, -OH, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkenyl, optionally substituted C1-C3 alkynyl, optionally substituted C1-C3 alkoxy and optionally substituted C1-C3 haloalkyl;
  • Each R 3 is independently selected from H and optionally substituted C1-C3 alkyl
  • R 4 is selected from H and optionally substituted C1-C6 alkyl
  • R 5 is selected from H, halogen, NH 2 , -CN, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkenyl, optionally substituted C1-C3 alkynyl, optionally substituted C1-C3 alkoxy and optionally substituted C1-C3 haloalkyl;
  • R 6 is selected from H and optionally substituted C1-C3 alkyl
  • X 1 is selected from -O- and -C(R 7 ) 2 -, where R 7 is selected from H, optionally substituted C1-C3 alkyl, optionally Substituted C1-C3 alkoxy, C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S as ring members; or, wherein, R 4 , R 7 and the two carbon atoms located between R 4 and R 7 may together optionally form a group selected from C3-C6 cycloalkyl, saturated or unsaturated containing 1-2 selected from N, O and S 4-7-membered heterocyclyl, C6-C10 aryl, and 5-10-membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S as ring members. group; and
  • R 8 and R 9 are independently selected from H, optionally substituted C1-C3 alkyl and -COOH.
  • Embodiment 2 The compound of Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R is selected from H and optionally Substituted C1-C3 alkyl.
  • Embodiment 3 The compound according to Embodiment 1 or 2 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R 1 is H.
  • Embodiment 4 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-3, wherein R 2 Selected from H, C1-C3 hydroxyalkyl and halogen.
  • Embodiment 5 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-4, wherein R 2 It's H.
  • Embodiment 6 The compound according to any one of embodiments 1-5 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein -N
  • the (R 3 ) 2 group is -NH 2 .
  • Embodiment 7 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-6, wherein R 4 Selected from H and optionally substituted C1-C3 alkyl.
  • Embodiment 8 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-7, wherein R 4 It's CH 3 .
  • Embodiment 9 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-8, wherein R 5 Selected from H and halogen.
  • Embodiment 10 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-9, wherein R 5 It's halogen.
  • Embodiment 11 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-10, wherein R 5 It's Cl.
  • Embodiment 12 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-11, wherein R 6 Selected from H and halogen.
  • Embodiment 13 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-12, wherein R 6 It's H.
  • Embodiment 14 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-13, wherein, X 1 It's -O-.
  • Embodiment 15 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-13, wherein, X 1 is -C(R 7 ) 2 -, said R 7 is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, C6-C10 aryl and containing 5-10 membered heteroaryl with 1-4 heteroatoms selected from N, O and S as ring members; or, wherein R 4 , R 7 and two carbons located between R 4 and R 7
  • the atoms may together optionally form a group selected from C3-C6 cycloalkyl, saturated or unsaturated 4-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring members, C6- C10 aryl groups and 5-10 membered heteroaryl cyclic groups containing 1-4 heteroatoms selected from N, O and S as
  • Embodiment 17 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-16, wherein X 2 Selected from -C(R 8 )-; wherein, R 8 is selected from H, optionally substituted C1-C3 alkyl and -COOH.
  • Embodiment 19 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-18, wherein R 8 Selected from H, -CH 3 , -CF 3 and -COOH.
  • Embodiment 20 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-19, wherein R 9 Selected from H, -CH 3 , -CF 3 and -COOH.
  • Embodiment 21 The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-20, wherein Selected from -CH-, -CH(CH 3 )-, -CH(CF 3 )- and -CH(COOH)-.
  • Embodiment 23 The compound according to Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the compound is selected from the group consisting of Formula IA A compound wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 and X 3 are as defined in Embodiment 1.
  • Embodiment 24 The compound according to Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the compound is selected from the group consisting of Formula IB and IC, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 and X 2 are as defined in Embodiment 1.
  • Embodiment 25 The compound according to Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the compound is selected from the group consisting of the following formula ID and IE, wherein R 1 , R 2 , R 3 , R 4 , R 6 , X 1 and X 2 are as defined in Embodiment 1.
  • Embodiment 26 The compound according to Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the compound is selected from the group consisting of the following formula IF A compound of which R 1 , R 2 , R 3 , R 4 , R 5 and X 1 are as defined in Embodiment 1.
  • Embodiment 29 The compound of Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the compound is selected from the following compounds:
  • Embodiment 30 A pharmaceutical composition comprising a compound of any one of embodiments 1-29 admixed with at least one pharmaceutically acceptable carrier, and/or the Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of a compound.
  • Embodiment 31 A method of treating a disease or disorder associated with SHP2 in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of any one of embodiments 1-29 A compound, and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of said compound, or a pharmaceutical composition as described in Embodiment 30.
  • Embodiment 32 The method of embodiment 31, wherein the method comprises determining whether the disease in the subject is a SHP2-related disease or disorder, and administering to the subject in need thereof a therapeutically effective SHP2-inhibiting amount.
  • Embodiment 33 The method of embodiment 31 or 32, wherein the SHP2-associated disease or disorder is mediated by the activity of SHP2.
  • Embodiment 34 The method of embodiment 33, wherein the disease or disorder associated with SHP2 is selected from Noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, melanoma, acute myeloid leukemia , breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.
  • the disease or disorder associated with SHP2 is selected from Noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, melanoma, acute myeloid leukemia , breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.
  • Embodiment 35 The method of any one of embodiments 31-34, wherein the compound of any one of embodiments 1-29, and/or the stereoisomer of the compound is administered orally. isotope, or a pharmaceutically acceptable salt or solvate, or a pharmaceutical composition as described in Embodiment 30.
  • Embodiment 36 The compound of any one of embodiments 1-29, and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, or as implemented Use of the pharmaceutical composition described in Scheme 30 in the manufacture of a medicament for treating SHP2-related diseases or disorders.
  • Embodiment 37 The use of embodiment 36, wherein the SHP2-related disease or disorder is mediated by the activity of SHP2.
  • Embodiment 38 The use of embodiment 37, wherein the disease or disorder associated with SHP2 is selected from Noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, melanoma, acute myeloid leukemia , breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.
  • the disease or disorder associated with SHP2 is selected from Noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, melanoma, acute myeloid leukemia , breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.
  • Embodiment 39 The use of any one of embodiments 36-38, wherein the medicament is formulated for oral administration.
  • Embodiment 40 The compound of any one of embodiments 1-29, and/or the stereoisomer, stable isotope, or pharmaceutical composition of the compound for use in the treatment of SHP2-related diseases or disorders.
  • Embodiment 41 The medicament or pharmaceutical composition of embodiment 40, wherein the SHP2-related disease or disorder is SHP2-related cancer.
  • Embodiment 42 The medicament or pharmaceutical composition of embodiment 40 or 41, wherein the SHP2-related disease or disorder is a SHP2-related cancer, and the use includes determining whether the cancer in the subject is a SHP2-related cancer. , and administering a therapeutically effective amount of said compound or said composition to a subject in need thereof.
  • Embodiment 43 The medicament or pharmaceutical composition of any one of embodiments 40-42, wherein the SHP2-related cancer is selected from the group consisting of juvenile myelomonocytic leukemia, melanoma, acute myelogenous leukemia, and breast cancer. , esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.
  • the SHP2-related cancer is selected from the group consisting of juvenile myelomonocytic leukemia, melanoma, acute myelogenous leukemia, and breast cancer.
  • esophageal cancer lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.
  • Embodiment 44 A method for inhibiting the interaction with SHP2 using the compound of any one of embodiments 1-29, and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of the compound. Methods related to SHP2 activity in cancer cells in vitro or in vivo.
  • a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF) has a chiral configuration exhibiting more than its enantiomers, and thus the compound is optically active .
  • this article discloses Such compounds are essentially free of opposite enantiomers (i.e., at least 95% of the compounds have the chirality shown above).
  • compositions comprising compounds of Formula I (eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or stereoisomers of compounds of Formula I isotopes, or pharmaceutically acceptable salts or solvates, and pharmaceutically acceptable carriers.
  • a compound of Formula I such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE or Formula IF
  • a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of a compound of formula I such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE or Formula IF
  • Formula I e.g., Formula IA, Formula IB, Formula IC, Formula IA, Formula IB, Formula IC, Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula ID, formula IE, or formula IF
  • Formula I e.g., Formula IA, Formula IB, Formula IC, Formula IA, Formula IB, Formula IC, Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula ID, formula IE, or formula IF
  • compositions comprising Formula I disclosed herein (e.g. Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula IA, formula IB, formula IC, formula ID, formula IE or formula IF) and/or compounds of formula I, and pharmaceutical acceptable carrier.
  • Formula I e.g. Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula IA, formula IB, formula IC, formula ID, formula IE or formula IF
  • pharmaceutical acceptable carrier e.g. Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula IA, formula IB, formula IC, formula ID, formula IE or formula IF
  • a compound of Formula I e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, or Formula IE
  • the cancer is selected from juvenile myelomonocytic leukemia, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma cell carcinoma, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.
  • the cancer is selected from juvenile myelomonocytic leukemia, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma , gastric cancer, anaplastic large cell lymphoma and glioblastoma.
  • formulas including Formula I e.g., Formula IA, Formula IB, Formula IC, Formula ID
  • the pharmaceutical composition of the compound of formula IE and formula IF), and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound of formula I, and a pharmaceutically acceptable carrier can be It is administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implantable kit.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, Intralesional and intracranial injection techniques or infusion techniques.
  • compositions disclosed herein may conveniently be presented in unit dosage form and prepared by any method known in the art.
  • Formula I (e.g., e.g. Compounds of Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceuticals of compounds of Formula I Scientifically acceptable salts or solvates.
  • Compounds of Formula I eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF
  • and /or stereoisomers stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula I.
  • Others may also be used to administer compounds of Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable compounds of Formula I.
  • Acceptable dosage forms of the salt or solvate include ointments, creams, drops, skin patches or powders for topical administration, ophthalmic solutions or suspension forms for ocular administration (i.e., eye drops formulations), aerosol sprays or powder compositions for inhalation or intranasal administration, or creams, ointments, sprays or suppositories for rectal or vaginal administration.
  • Compounds containing formula I may also be used.
  • Gelatin capsules of salts or solvates and at least one powdery carrier selected from, for example, lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc.
  • Similar diluents can be used to prepare compressed tablets.
  • Both tablets and capsules can be formulated as sustained-release products to provide continuous release of the drug over a period of time.
  • Compressed tablets may be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the environment, or enteric-coated to selectively break down in the gastrointestinal tract.
  • Liquid dosage forms for oral administration may also include at least one agent selected from colorants and flavoring agents to increase patient acceptance.
  • solutions for parenteral administration may include a water-soluble salt of at least one compound disclosed herein, at least one suitable stabilizer, and at least one buffering substance, if desired.
  • Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, may be examples of suitable stabilizers.
  • Citric acid and its salts and sodium ethylenediaminetetraacetate (EDTA) may also be used as examples of suitable stabilizers.
  • the injection solution may also include at least one preservative selected from, for example, benzalkonium chloride, methyl and propylparabens, and chlorobutanol.
  • Pharmaceutically acceptable carriers are selected, for example, from carriers that are compatible with (and, in some embodiments, capable of stabilizing the active ingredients) of the pharmaceutical composition and not deleterious to the subject to be treated.
  • solubilizers such as cyclodextrins (which can form specific more soluble complexes with at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein) may be used for delivery of the active ingredient of pharmaceutical excipients.
  • examples of other carriers include colloidal silica, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments (eg, D&C Yellow #10).
  • Suitable pharmaceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the art.
  • Compounds of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutical compounds of Formula I can be examined by in vivo assays. Acceptable Salts or Solvates for their Efficacy in the Treatment of Cancer.
  • a compound of Formula I eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF
  • a compound of Formula I can be administered to an animal (eg, a mouse model) suffering from cancer.
  • Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates, and their therapeutic effects can be obtained.
  • compounds of Formula I for administration by inhalation, compounds of Formula I (eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF) can be conveniently delivered in the form of an aerosol spray from a pressurized package or a nebulizer, and /or stereoisomerism of compounds of formula I conformation, stable isotope, or pharmaceutically acceptable salt or solvate.
  • Compounds of Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF), and/or stereoisomers, stable isotope, or a pharmaceutically acceptable salt or solvate, and the powder composition can be inhaled via an inhaled powder inhalation device.
  • An exemplary delivery system for inhalation may be a metered dose inhalation (MDI) aerosol, which may be formulated as Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula I in at least one suitable propellant selected from, for example, fluorocarbons and hydrocarbons compound) in suspensions or solutions.
  • MDI metered dose inhalation
  • an appropriate weight percent of a compound of Formula I (eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or a compound of Formula I may be used in a suitable ophthalmic vehicle.
  • Formulate ophthalmic preparations using solutions or suspensions of stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates such that Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula Compounds of formula IE and formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula I remain in contact with the optic surface for a period of time sufficient to allow penetration of the compound into the eye cornea and internal areas.
  • Formula I such as Formula IA, Formula IB, Formula IC, Formula ID, Formula Compounds of formula IE and formula IF
  • stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula I remain in contact with the optic surface for a period of time sufficient to allow penetration of the compound into the eye cornea and internal areas.
  • Useful pharmaceutical dosage forms of the salts or solvates include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral vascular injections, and oral suspensions.
  • the dose administered will depend on a variety of factors (such as the age, health and weight of the recipient, the extent of the disease, the type of concurrent treatment (if any), the frequency of treatment and the nature of the desired effect).
  • the daily dose of active ingredient may, for example, range from 0.1 mg/day to 2000 mg/day. For example, 10-500 mg once a day or multiple times a day can be effective in obtaining desired results.
  • compounds of Formula I e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF
  • pharmaceutically acceptable compounds of Formula I Acceptable salts or solvates are available as 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, and 500 mg. The amount is present in the capsule.
  • a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or the stereoisomerism of a compound of Formula I can be prepared by administering, for example, 100 mg of a powder form. form, stable isotope, or pharmaceutically acceptable salt or solvate, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate. Fill each of standard two-piece hard gelatin capsules to prepare large quantities. Unit capsule.
  • compounds of Formula I e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF
  • compounds of Formula I e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF
  • a mixture of an acceptable salt or solvate and a digestible oil such as soybean oil, cottonseed oil, or olive oil
  • a digestible oil such as soybean oil, cottonseed oil, or olive oil
  • compounds of Formula I e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF
  • pharmaceutically acceptable compounds of Formula I Acceptable salts or solvates may be in amounts from 1 mg to 500 mg, such as 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg , 300mg, 400mg and 500mg are present in tablets.
  • a dosage unit includes, for example, 100 mg of a compound of Formula I (eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of a compound of formula I, 0.2 mg silica colloid, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch, and 98.8 mg lactose.
  • Suitable coatings may be applied, for example, to increase palatability or to delay absorption.
  • the compound of Formula I eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF
  • Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of the compounds are used to prepare parenteral compositions suitable for administration by injection.
  • the solution was brought to the desired volume using water for injection and sterilized.
  • aqueous suspensions can be prepared for oral administration.
  • stereoisomers including 100 mg of finely separated compounds of formula I (such as formula IA, formula IB, formula IC, formula ID, formula IE and formula IF) and/or a compound of formula I per 5 ml may be used.
  • stable isotope, or pharmaceutically acceptable salt or solvate 100 mg sodium carboxymethylcellulose, 5 mg sodium benzoate, 1.0 g sorbitol solution (U.S.P.) and 0.025 ml vanillin in an aqueous suspension.
  • a compound of Formula I such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF
  • a stereoisomer, stable isotope, or pharmaceutically acceptable salt of a compound of Formula I or When the solvate is administered stepwise or co-administered with at least one other therapeutic agent, the same dosage form can generally be used.
  • the dosage form and route of administration should be selected based on the compatibility of the combined drugs.
  • co-administration is therefore understood to include the administration of at least two agents simultaneously or sequentially, or alternatively as a fixed dose combination of at least two active ingredients.
  • Compounds of Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvents of compounds of Formula I
  • the compound may be administered as the sole active ingredient or in combination with at least one second active ingredient selected, for example, from the group known to be effective in treating the target disease in a patient, such as cancer, including, for example, colon cancer, Other active ingredients useful in gastric cancer, leukemia, lymphoma, melanoma and pancreatic cancer).
  • optical isomer or “stereoisomer” refers to any of the various stereoisomeric configurations that may exist for a given compound of the present disclosure, and includes geometric isomers . It will be understood that substituents may be attached at the chiral center of the carbon atom.
  • chiral refers to molecules that have non-overlapping properties on their mirror image partners, whereas the term “achiral” refers to molecules that have overlapping properties on their mirror image partners.
  • the present disclosure encompasses enantiomers, diastereomers, or racemates of the compounds. "Enantiomers” are a pair of stereoisomers that are non-overlapping mirror images of each other.
  • a 1:1 mixture of a pair of enantiomers is a "racemic” mixture. Where appropriate, this term is used to designate racemic mixtures.
  • "Diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog IR-SJ system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. Resolved compounds whose absolute configuration is unknown can be assigned (+) or (-) depending on the direction in which they rotate plane-polarized light (dextrorotatory or levorotatory) at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers or axes and thereby can give rise to enantiomers, diastereoisomers and others that may be defined with respect to absolute stereochemistry as (R)- Or the stereoisomeric form of (S)-.
  • compounds can be in the form of one of the possible isomers or as a mixture thereof (e.g., as pure optical isomers) or as a mixture of isomers (according to the asymmetric carbon number of atoms, such as racemates and diastereomeric mixtures)) present.
  • This disclosure encompasses all such possibilities isomers (including racemic mixtures, diastereomeric mixtures and optically pure forms).
  • Optical (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration unless otherwise specified. If a compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration unless otherwise specified.
  • the compounds of the present disclosure are capable of forming acid salts and/or base salts due to the presence of amino groups and/or carboxyl groups or groups similar thereto.
  • salt refers to an acid addition salt or a base addition salt of a compound of the present disclosure.
  • Salt specifically includes “pharmaceutically acceptable salt”.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and generally are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, for example, acetates, adipates, aluminum salts, ascorbates, aspartates, benzoates, benzenesulfonates , bromide/hydrobromide, hydrocarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caproate, chloride/hydrochloride, chloroprocaine, chlorophylline Salt (chlortheophyllonate), citrate, ethylenediaminetetraacetate, calcium edetate, ethandisulfonate, ethyl sulfonate, ethylenediamine, fumarate, galactose galactarate (mucate), glucoheptonate, gluconate, glucuronate, glutamate, glycolate, hexyl resorcinate ), hippurate, hydroiodide/iodide, hydroxynapthoate
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethylsulfonate acid, toluenesulfonic acid, trifluoroacetic acid, sulfosalicylic acid, etc.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic or organic bases, and can have inorganic or organic counterions.
  • Inorganic counterions of such basic salts include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table.
  • the counterion is selected from sodium, potassium, ammonium, alkylammonium having one to four C1-C4 alkyl groups, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts Contains ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like.
  • Suitable organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the basic or acidic moieties by conventional chemical methods.
  • the free acid forms of these compounds are reacted with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates of Na, Ca, Mg or K, etc.) or the free base forms of these compounds are
  • a suitable base such as hydroxides, carbonates, bicarbonates of Na, Ca, Mg or K, etc.
  • Such salts can be prepared by reaction with stoichiometric amounts of the appropriate acid. Such reactions are usually carried out in water or in organic solvents or in water and a mixture of organic solvents.
  • non-aqueous media such as diethyl ether, ethyl acetate, tetrahydrofuran, toluene, chloroform, methylene chloride, methanol, ethanol, isopropanol or acetonitrile is desired where feasible.
  • Any formula given herein is intended to represent the unlabeled form of a compound (ie, a compound in which all atoms are present in natural isotopic abundance and are not isotopically enriched) as well as isotopically enriched or labeled forms.
  • An isotopically enriched or labeled compound has a structure depicted by the formula given herein, except that at least one atom of the compound is substituted by an atomic mass or mass number of the same element but with an atomic mass or mass number that is different from the naturally occurring atomic mass or atomic mass distribution. Atomic substitution.
  • isotopes that may be incorporated into enriched or labeled compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, respectively , 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the present disclosure encompasses various isotopically labeled compounds as defined herein, for example those in which radioactive isotopes (such as 3H and 14C) or non-radioactive isotopes (such as 2 H and 13 C) those compounds.
  • isotopically labeled compounds are useful in metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection techniques, or imaging techniques such as positron emission tomography including drug or matrix tissue distribution determination. (PET) or single photon emission computed tomography (SPECT)), or radioactive therapy of patients.
  • PET drug or matrix tissue distribution determination.
  • SPECT single photon emission computed tomography
  • 18F or labeled compounds may be particularly desirable for PET studies or SPECT studies.
  • Isotopically labeled reagents may generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples and Preparations, using appropriate isotopically labeled reagents in place of previously employed unlabeled reagents. Compounds of formula I.
  • deuterium i.e., H or D
  • substitution with heavier isotopes may provide certain therapeutic advantages derived from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements or therapeutic index improvement).
  • deuterium is considered herein to be a substituent in the compounds of Formula I if incorporated at levels substantially above the natural isotope abundance.
  • the present disclosure encompasses isotopically enriched variations of compounds (eg, deuterated as well as non-deuterated variations). Deuterated variations can be deuterated at a single site or at multiple sites.
  • the degree of incorporation of such isotopes (especially deuterium) in an isotopically enriched compound can be defined by the isotope enrichment coefficient.
  • isotopic enrichment coefficient means the ratio between the isotopic abundance of a particular isotope in a sample and the natural abundance of that isotope in a non-enriched sample.
  • a substituent in a compound of the present disclosure is labeled deuterium, such compound has for each designated deuterium atom at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation) , at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping) , an isotope enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • solvates according to the present disclosure include those in which the solvent crystallization may be isotopically substituted (eg, D2O , d6-acetone, d6 -DMSO), as well as those with non-enriched solvents Solvates.
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents Agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavor enhancers, dyes, etc. and combinations thereof, as those skilled in the art have Known (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in the event that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
  • terapéuticaally effective amount of a compound of the present disclosure means one that will cause a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity), or ameliorate symptoms, alleviate a condition, slow or delay disease progression, or prevention Amounts of compounds of the present disclosure for diseases, etc.
  • the term "therapeutically effective amount” refers to an amount of a compound of the present disclosure that, when administered to a subject, is effective to: (1) at least partially alleviate, inhibit, Preventing and/or ameliorating a condition or disorder or disease (i) mediated by a kinase (e.g., SHP2) or (ii) associated with the activity of a kinase (e.g., SHP2) or (iii) based on the activity of SHP2 (normal or abnormal); or (2) reduce or inhibit the activity of SHP2 or (3) reduce or inhibit the expression of SHP2.
  • a kinase e.g., SHP2
  • the term "therapeutically effective amount” refers to an amount of a compound of the present disclosure that is effective, at least in part, when administered to a cell or tissue or non-cellular biological material or medium. Reduce or inhibit the activity of SHP2 or at least partially reduce or inhibit the expression of SHP2.
  • the term "subject” refers to an animal. Typically, animals are mammals. Subjects also refer to, for example, primates (eg, humans, male or female animals), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In certain embodiments, the subject is human.
  • the terms “inhibit,” “inhibition,” or “inhibiting” refer to the reduction or suppression of a given condition, activity, effect, symptom, or disorder, or disease, or A significant decrease in the baseline activity of a biological activity or process.
  • the terms “treat,” “treating,” or “treatment” of any disease or disorder refer to ameliorating the disease or disorder (i.e., slowing or preventing or Reduce the development of the disease or at least one of its clinical symptoms).
  • “treat,” “treating,” or “treatment” refers to alleviating or improving at least one physical parameter (including those physical parameters that are not discernible by the patient).
  • “treat,” “treating,” or “treatment” refers to physical aspects (e.g., stabilization of discernible symptoms), physiological aspects (e.g., improvement of physical parameters). stabilizing), or regulating disease or disorder in the body and physiology.
  • “treat,” “treating,” or “treatment” refers to delaying the development or progression of a disease or disorder.
  • a subject has an affirmative "need" for such treatment if such subject is expected to benefit biologically, medically, or in terms of quality of life.
  • Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the present disclosure may be in a racemic or enantiomerically enriched configuration (e.g., (R)-, (S)-, or (R)- ,S)-configuration) exists.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, (R)- or (S)-configuration Isomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess; i.e., for optical activity
  • Compounds typically use one enantiomer to the substantial exclusion of the other.
  • substituents at atoms with carbon-carbon double bonds may be present in the cis-(Z)- or trans-(E)-form, and unless otherwise stated, both are included within this disclosure.
  • a compound of the present disclosure may be in the form of one of the possible isomers, rotamers, atropisomers, or as a mixture thereof (e.g., as a substantially pure geometric (cis) (form or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof).
  • substantially pure or substantially free of other isomers means that the product contains less than 5% by weight (e.g., less than 2% by weight) relative to the amount of the preferred isomer. % by weight) of other isomers.
  • Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers on the basis of physicochemical differences in the components, for example by chromatography and/or fractional crystallization. body, racemate.
  • Any resulting racemate of the final product or intermediate product may be converted into a racemate by known methods (for example, by isolating a diastereomeric salt to obtain an optically active acid or base, and releasing the optically active acidic compound or optically basic compound).
  • Split into optical antipodes may be employed to resolve the compounds of the present disclosure into their optical antipodes, for example, by fractional crystallization with an optically active acid (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, Salts formed from di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid).
  • Racemic products can also be resolved by chiral chromatography (eg, high pressure liquid chromatography (HPLC) using chiral adsorbents).
  • the compounds of the present disclosure may also be obtained in the form of their hydrates or contain other solvents for their crystallization.
  • the compounds of the present disclosure may form solvates, intrinsically or by design, with pharmaceutically acceptable solvents, including water; thus, the present disclosure is intended to encompass both solvated and unsolvated forms.
  • solvate refers to a molecular complex of a compound of the present disclosure (including pharmaceutically acceptable salts thereof) and one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and known to be harmless to the recipient (eg, water, ethanol, etc.).
  • hydrate refers to a complex in which the solvent molecule is water.
  • Schemes 1-2 illustrate general methods for preparing compounds and intermediates of the present disclosure. Detailed descriptions and synthetic methods are disclosed in the examples below. One skilled in the art will be able to find other synthetic methods or modify the methods described below using conventional chemistry to prepare suitable compounds encompassed by Formula I. Accordingly, these methods are equally applicable to the preparation of compounds of other embodiments. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of compounds and/or reaction conditions.
  • the heteroaryl thiol of formula 3 can be prepared by a two-step method: first, the compound of formula 1 (Z 1 is Cl, Br or -OTf) and 2-ethylhexyl 3-mercaptopropionate of formula 2 are prepared under Pd catalytic conditions.
  • Heteroarylthiols 3 can be synthesized under Pd catalyzed conditions (such as tris(dibenzylideneacetone)palladium (Pd 2 (dba) 3 ), 4,5-bis(diphenylphosphine)-9,9-dimethyl Xantphos and diisopropylethylamine in tetrahydrofuran in dioxane are reacted with a compound of Formula 4 ( Z2 and Z3 are independently Cl, Br or -OTf) to provide a compound of Formula 5. Coupling the compound of formula 5 and the amine of formula 6 by nucleophilic substitution reaction or by Buchwald-Hartwig reaction gives the compound of formula I.
  • Pd catalyzed conditions such as tris(dibenzylideneacetone)palladium (Pd 2 (dba) 3 ), 4,5-bis(diphenylphosphine)-9,9-dimethyl Xantphos and diisopropyle
  • the amine of Formula 6 can be converted to the compound of Formula 7 by coupling the amine of Formula 6 to the compound of Formula 4 via a nucleophilic substitution reaction or Buchwald-Hartwig reaction.
  • Compounds of formula 7 and heteroaryl thiols of formula 3 under Pd catalytic conditions such as tris(dibenzylideneacetone)palladium (Pd 2 (dba) 3 ), 4,5-bis(diphenylphosphine)-9, 9-Dimethylxanthene (Xantphos) and diisopropylethylamine are coupled in tetrahydrofuran or dioxane solution) to obtain the compound of formula I.
  • Compounds of Formula 7 can also be converted to heteroaryl thiols of Formula 8 by the same two-step process as described above for compounds of Formula 3.
  • the compound of formula 8 and the compound of formula 1 are coupled under Pd catalytic conditions (for example, tris(dibenzylideneacetone)palladium (Pd 2 (dba) 3 ), 4,5-bis(diphenylphosphine)-9, 9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran or dioxane solution) to obtain the compound of formula I.
  • Pd catalytic conditions for example, tris(dibenzylideneacetone)palladium (Pd 2 (dba) 3 ), 4,5-bis(diphenylphosphine)-9, 9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran or dioxane
  • the compound of formula 10 and the amine of formula 6 can obtain the compound of formula 11 through nucleophilic substitution reaction or Buchwald-Hartwig reaction.
  • the compound of formula 7 and the heteroaryl thiol of formula 9 can be synthesized under Pd catalyzed conditions (for example, tris(dibenzylideneacetone)palladium (Pd 2 (dba) 3 ), 4,5-bis(diphenyl) (Xantphos)-9,9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran or dioxane solution) are coupled to obtain the compound of formula 11.
  • Pd catalyzed conditions for example, tris(dibenzylideneacetone)palladium (Pd 2 (dba) 3 ), 4,5-bis(diphenyl) (Xantphos)-9,9-dimethylxanthene (Xantphos) and diisopropylethyl
  • Compounds of formula 11 can be converted to compounds of formula I by reaction with suitable reagents at elevated temperatures in alcoholic solvents such as ethanol and isopropyl alcohol.
  • step 4 To the product of step 4 above (214 mg, 0.783 mmol), (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (200 mg, 0.735 mmol) and A solution of DIPEA (304 mg, 2.35 mmol) in NMP (2 mL) was charged with N2 and stirred at 130 °C for 18 h. The mixture was purified by flash column chromatography (MeOH/ H2O ) on a C18 reverse phase column to give the crude title compound (396 mg, crude yield: >100%).
  • Step 6 ((3S,4S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa -8-azaspiro [4.5]Decyl-4-yl)carbamic acid tert-butyl ester
  • Step 7 ((3S,4S)-8-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl -2-oxa-8- Azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester
  • Step 8 (3S,4S)-8-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl- 2-oxa-8-nitrogen Heterospiro[4.5]decyl-4-amine hydrochloride
  • Step 1 ((3S,4S)-8-(5-((8-chloro-2-methylimidazol[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)- 3-Methyl-2-oxo Hetero-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester
  • Step 2 (3S,4S)-8-5-((8-chloro-3-methylimidazol[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3- Methyl-2-oxa- 8-Azaspiro[4.5]decane-4-amine hydrochloride
  • Step 1 7-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base) Pyrazin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester
  • Step 2 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2- base)thio)- 8-Chloroimidazo[1,2-a]pyridine-3-carboxylic acid
  • Step 1 7-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base)pyridine Ethyl azin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carboxylate
  • Step 2 7-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane- 8-yl)pyridine Azin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carboxylic acid
  • Step 3 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2- base)thio)-8- Chloroimidazo[1,2-a]pyridine-2-carboxylic acid trifluoroacetic acid
  • Step 4 ((3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decyl-4-yl)amino Tertiary formate Butyl ester
  • Step 5 ((3S,4S)-8-(5-((4-chloro-1H-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa -8-Azaspiro[4.5] Decan-4-yl)carbamic acid tert-butyl ester
  • Step 6 (3S,4S)-8-(5-((4-chloro-1H-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-Azaspiro[4.5] Decan-4-yl)amine trifluoroacetate
  • Step 2 ((3S,4S)-8-(6-amino-5-((4-chloro-1H-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl- 2-oxa-8-nitrogen Heterospiro[4.5]decan-4-yl)carbamic acid tert-butyl ester
  • Step 3 3-((4-chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)thio)propionic acid 2-ethyl Hexyl ester
  • Step 5 ((3S,4S)-8-(5-((4-chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) )Thio)pyrazine-2- tert-butyl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate
  • Step 5 7-Chloro-6-mercapto-1H-indazole-1-carboxylic acid tert-butyl ester
  • Step 6 6-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base)pyridine Azin-2-yl)thio)-7-chloro-1H-indazole-1-carboxylic acid tert-butyl ester
  • Step 7 (3S,4S)-8-(5-((7-chloro-1H-indazol-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-Azaspiro[4.5] Decane-4-amine hydrochloride
  • Step 2 7-Chloro-6-((3-((2-methylhexyl)oxy)-3-oxopropyl)thio)-1H-indazole-3-carboxylic acid ethyl ester
  • Step 3 7-Chloro-6-((3-((2-methylhexyl)oxy)-3-oxopropyl)thio)-1H-indazole-1,3-dicarboxylic acid 1- tert-butyl 3-ethyl ester
  • Step 4 1-tert-butyl 3-ethyl 7-chloro-6-mercapto-1H-indazole-1,3-dicarboxylate
  • Step 5 6-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base)pyridine Azin-2-yl)thio)-7-chloro-1H-indazole-1,3-dicarboxylate 1-tert-butyl 3-ethyl ester
  • Step 6 1-(tert-butoxycarbonyl)-6-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-aza miscellaneous snail [4.5]Decan-8-yl)pyrazin-2-yl)thio)-7-chloro-1H-indazole-3-carboxylic acid
  • Step 7 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2- base)thio)-7- Chloro-1H-indazole-3-carboxylic acid hydrochloride
  • Step 1 7-Bromo-1H-pyrazolo[4,3-b]pyridine-1-carboxylic acid tert-butyl ester
  • Step 2 7-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)-1H-pyrazolo[4,3-b]pyridine-1-carboxylic acid
  • Step 3 7-Mercapto-1H-pyrazolo[4,3-b]pyridine-1-carboxylic acid tert-butyl ester
  • Step 4 7-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base)pyridine Azin-2-yl)thio)-1H-pyrazolo[4,3-b]pyridine-1-carboxylic acid tert-butyl ester
  • Step 1 4-Bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester
  • Step 2 4-((3-((2-ethylheptyl)oxy)-3-oxopropyl)thio)-1H-pyrazolo[3,4-b]pyridine-1-carboxy Sour tert-butyrate base ester
  • Step 3 4-Mercapto-1H-pyrazolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester
  • Step 4 4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base)pyridine Azin-2-yl)thio)-1H-pyrazolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester
  • Step 2 2-ethylhexyl 4-((4-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)thio)butyrate
  • Step 4 ((3S,4S)-8-(5-((4-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)thio)pyrazine -2-base)-3-methyl Tert-butyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate
  • Step 5 5-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2- base)thio)-4- Chloro-1H-benzo[d]imidazol-2(3H)-one hydrochloride
  • Step 3 ((3S,4S)-8-(5-((2-aminopyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-nitrogen Miscellaneous snail[4.5] Decan-4-yl)carbamic acid tert-butyl ester
  • Step 4 ((3S, 4S)-3-methyl-8-(5-((2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl )-2-oxa- 8-Azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester
  • Step 5 (3S, 4S)-3-methyl-8-(5-((2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl) -2-oxa- 8-Azaspiro[4.5]decane-4-amine
  • Step 1 (3S,4S)-8-(6-amino-5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3 -Methyl-2- Oxa-8-azaspiro[4.5]decane-4-amine
  • Step 2 tert-Butyl((3S,4S)-8-(6-amino-5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazine-2- base)-3-methyl Base-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate
  • Step 3 (3S,4S)-8-(6-amino-5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3 -Methyl-2- Oxa-8-azaspiro[4.5]decane-4-amine
  • Step 1 ((3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl- 2-oxa-8- Azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester
  • Step 2 ((3S,4S)-8-(6-amino-5-((8-chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazine- 2-base)-3- Methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester
  • reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (30 mL ⁇ 2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was used in the next step without further purification.
  • Step 3 (3S,4S)-8-(6-amino-5-((8-chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazine-2 -base)-3- Methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • Step 4 ((3S,4S)-8-(5-((8-chloro-2-fluoroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)- 3-Methyl-2-oxo Hetero-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester
  • Step 5 ((3S,4S)-8-(5-((8-chloro-2-fluoroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)- 3-Methyl-2-oxo Hetero-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester
  • Step 1 3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-bromo-5-methyl pyrazine-2- Ethyl carboxylate
  • Step 2 6-bromo-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane- 8- (ethyl)-5-methylpyrazine-2-carboxylate
  • Step 3 3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl) -6- ((8-Chloroimidazo[1,2-a]pyridin-7-yl)thio)-5-methylpyrazine-2-carboxylate ethyl ester
  • Step 4 ((3S,4S)-8-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)-3-(hydroxymethyl)-6-methyl pyrazine-2- tert-butyl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate
  • Step 5 (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-((8-chloroimidazole) and[1,2-a] Pyridin-7-yl)thio)-5-methylpyrazin-2-yl)methanol
  • Step 2 2-ethylhexyl 3-[(3,8-dichloroimidazo[1,2-a]pyridin-7-yl)sulfinyl]propionate
  • Step 4 tert-Butyl N-[(3S,4S)-8-(5-[(3,8-dichloroimidazo[1,2-a]pyridin-7-yl)sulfinyl]pyrazine- 2- methyl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate
  • Step 5 (3S,4S)-8-(5-[(3,8-dichloroimidazo[1,2-a]pyridin-7-yl)sulfinyl]pyrazin-2-yl)-3 -Methyl-2- Oxa-8-azaspiro[4.5]decane-4-amine
  • SHP2 is allosterically activated through the binding of a dityrosyl phosphorylated peptide to its Src homology 2 (SH2) domain.
  • the activation step results in the release of the autoinhibitory interface of SHP2, which further renders SHP2PTP active for substrate recognition and reaction catalysis.
  • the catalytic activity of SHP2 was monitored by prompt fluorescence assay using the surrogate substrate DiFMUP.
  • the phosphatase reaction was performed in an OptiPlateTM-384F black assay plate (Perkin Elmer, Cat#6007279) at room temperature using a final reaction volume of 20uL and the following assay buffer conditions: 25mM HEPES, pH 7.2, 25mM KCl, 1mM EDTA, 0.01% Brij-35, 5mM DTT, and 1% DMSO (final).
  • Test samples were prepared by incubating 0.2 nM SHP2 (PTPN11/SHP2-FL, BPS, cat#79018) with 0.5 ⁇ M SHP2 activating polypeptide (BPS, cat#79310-2), and the prepared test samples were used to monitor the test Inhibition of SHP2 by compounds (final concentrations 0.051-1000 nM). After incubation for 20 minutes at room temperature, the surrogate substrate DiFMUP (6,8-difluoro-7-hydroxy-4-methylcoumarin, Invitrogen, cat#D6567, 20 ⁇ M final concentration) was added to the reaction. The plates were read dynamically on Paradigm for 60 minutes (with excitation wavelength 360 nm and emission wavelength 460 nm). Inhibitor dose response curves were analyzed using normalized IC50 regression curves using a control-based normalization method for curve fitting.
  • MiaPaCa-2 cells human pancreatic cancer cells
  • 3D culture To evaluate the inhibitory effect of compounds on cell proliferation, MiaPaCa-2 cells in logarithmic growth phase were seeded at optimal density and grown as spheroids. Cells were cultured for 24 hours before adding different concentrations of compounds. Cells were then cultured with compounds for 5 days, and cell viability was assessed using CCK8. Briefly, 2500 cells were seeded in round-bottom ultra-low adsorption 96-well plates (from Corning), incubated at 37°C, and compounds were dissolved in DMSO (from Sigma) after 24 h to obtain 10 mM stocks. .
  • the 10 mM stock solution was serially diluted with DMSO at a dilution ratio from 3 to 10 times to obtain a series of concentration compound stock solutions.
  • the final concentration of DMSO is 0.1%.
  • Spheroid cells were incubated with the compound for 5 days. Then 20 ⁇ L of WST-8 solution (DOJINDO, Cell Counting KIT-8) was added to each well.
  • CHO-hERG cells are used to specifically evaluate the effect of test compounds on hERG channels.
  • the anterior compound current and the posterior compound current were measured by patch clamp and used to calculate hERG suppression.
  • hERG currents were recorded at room temperature using conventional whole-cell patch-clamp current techniques. Cells were seeded in a recording chamber on an inverted microscope and individual cells in the recording chamber were randomly selected for recording. Cells will be continuously perfused by the perfusion system.
  • the percent inhibition by the test compound was calculated from the recorded current using the following formula: (peak tail current recorded after test compound perfusion/peak tail current recorded by solvent control perfusion) ⁇ 100%.
  • the percent inhibition was calculated from the average data of all recorded cells, and the IC50 value was derived from the concentration effect curve by the Hill equation in Origin software.
  • the incubation mixture containing microsomes, substrate and standard inhibitors or test compounds was heated at 37°C for 10.0 minutes. Start the reaction by adding NADPH and incubate for 10.0 minutes. After incubation, ice-cold acetonitrile was added to terminate the reaction. Metabolites produced by the substrate reaction were determined by LC-MS/MS to determine percent inhibition, and IC50 values were calculated from the concentration effect curve.
  • Test compounds were administered to Sprauge-Dawley rats at 1 mg/kg intravenously and 5 mg/kg orally. Test compounds were dissolved in 10% DMSO+10% Solutol+80% H2O . Blood samples were collected into test tubes containing sodium heparin at 5 minutes, 0.25, 0.50, 1, 2, 4, 6, 8 and 24 hours after dosing and centrifuged at 8000 rpm for 6 minutes to separate plasma. The concentration of test compound in plasma was determined by LC/MS/MS) method. use Professional 5.2's non-partitioned module calculates parameter values.
  • PK parameters (pharmacokinetic parameters) of the selected compounds are listed in Table 4.

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Abstract

La présente invention concerne un composé de formule I, et/ou un stéréoisomère, un isotope stable, ou un sel ou solvate pharmaceutiquement acceptable du composé de formule I, une composition pharmaceutique comprenant le composé, et l'utilisation thérapeutique du composé, le composé étant un inhibiteur de SHP2 potentiellement utile dans le traitement de maladies associées à SHP2 (telles que des cancers liés à SHP2).
PCT/CN2023/076423 2022-03-10 2023-02-16 Composé hétérocyclique utilisé en tant qu'inhibiteur de shp2, composition comprenant un composé hétérocyclique, et procédé l'utilisant WO2023169170A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109311848A (zh) * 2016-06-07 2019-02-05 北京加科思新药研发有限公司 可用作shp2抑制剂的新型杂环衍生物
CN109983001A (zh) * 2016-07-12 2019-07-05 锐新医药公司 作为变构shp2抑制剂的2,5-双取代型3-甲基吡嗪及2,5,6-三取代型3-甲基吡嗪
WO2021249057A1 (fr) * 2020-06-12 2021-12-16 石药集团中奇制药技术（石家庄）有限公司 Composé hétérocyclique et son utilisation
WO2022042331A1 (fr) * 2020-08-25 2022-03-03 四川科伦博泰生物医药股份有限公司 Composé hétérocyclique, son procédé de préparation et son utilisation
WO2023282702A1 (fr) * 2021-07-09 2023-01-12 주식회사 카나프테라퓨틱스 Inhibiteur de shp2 et son utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109311848A (zh) * 2016-06-07 2019-02-05 北京加科思新药研发有限公司 可用作shp2抑制剂的新型杂环衍生物
CN109983001A (zh) * 2016-07-12 2019-07-05 锐新医药公司 作为变构shp2抑制剂的2,5-双取代型3-甲基吡嗪及2,5,6-三取代型3-甲基吡嗪
WO2021249057A1 (fr) * 2020-06-12 2021-12-16 石药集团中奇制药技术（石家庄）有限公司 Composé hétérocyclique et son utilisation
WO2022042331A1 (fr) * 2020-08-25 2022-03-03 四川科伦博泰生物医药股份有限公司 Composé hétérocyclique, son procédé de préparation et son utilisation
WO2023282702A1 (fr) * 2021-07-09 2023-01-12 주식회사 카나프테라퓨틱스 Inhibiteur de shp2 et son utilisation

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