Heterocyclic compounds as cbl-b inhibitors
Patent Information
- Application Number
- CN202580021024.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2024-03-15
- Filing Date
- 2025-03-14
- Publication Date
- 2026-10-16
AI Technical Summary
b class="d_n">[0238]如表2中所示，可知本发明的化合物具有Cbl-b抑制活性。因此，根据本发明的式1的化合物可以有效地用于与Cbl-b相关的疾病的治疗。
Smart Images
Figure SMS_1 
Figure SMS_28 
Figure SMS_29
Abstract
Description
Technical Field
[0001] This invention relates to novel heterocyclic compounds as inhibitors of Casitas B-cell lymphoma-b (Cbl-b), which can be used to prepare medicaments for treating diseases associated with Cbl-b. These medicaments are particularly useful for the prevention and treatment of cancer. Background Technology
[0002] In recent years, novel therapies aimed at removing suppressive signals from immune cells to enhance the productive immune system have attracted attention. In this regard, Casitas B-cell lymphoma-b (Cbl-b) is a RING-type E3 ubiquitin ligase expressed in various immune cell lineages, where it negatively regulates immune cell activity. Effector T cells are key players in regulating the immune system against a variety of diseases and conditions, including cancer, and compounds that activate effector T cells, such as inhibitors of Cbl-b, have been shown to enhance the secretion and proliferation of T-cell-derived cytokines and exhibit anti-cancer activity. Given the important role of Cbl-b in regulating multiple signal transduction mechanisms in both innate and adaptive immunity, inhibition of Cbl-b offers opportunities for treating various diseases, including cancer immunotherapy.
[0003] This invention relates to the development of low molecular weight compounds required for the effective inhibition of the E3 ubiquitin ligase Cbl-b as described above. Summary of the Invention
[0004] [Technical Issues]
[0005] The object of this invention is to provide a novel heterocyclic compound represented by Formula 1 that exhibits inhibitory activity against Casitas B-cell lymphoma-b (Cbl-b).
[0006] Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diseases associated with the activation of Cbl-b, comprising a heterocyclic compound of formula 1 as an active ingredient.
[0007] Solution to the problem
[0008] According to one aspect of the invention, a compound of formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof, is provided:
[0009] Formula 1
[0010]
[0011] in,
[0012] A is a heteroarylene or a partially unsaturated heterocyclic group;
[0013] R1 is a heterocyclic alkyl, cycloalkylamino, or cycloalkyl-alkylamino; wherein the heterocyclic alkyl and cycloalkyl are optionally substituted with one or more substituents selected from hydroxyl, halogen, alkyl, and dialkylamino.
[0014] R2 is -H, halogen, alkyl, haloalkyl, alkoxy, oxo (=O), alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl or dialkylamino;
[0015] R3 and R4 are each independently -H, alkyl, or cycloalkyl; or R3 and R4 together with the carbon atoms to which they are attached form a cycloalkyl or heterocycloalkyl group; wherein the cycloalkyl or heterocycloalkyl group is optionally substituted with one or more substituents selected from hydroxyl, halogen, cyano (-CN), alkyl, and alkoxy groups;
[0016] R5 is a heteroaryl or partially unsaturated heterocyclic group; wherein the heteroaryl or partially unsaturated heterocyclic group is optionally substituted by one or more substituents selected from alkyl and alkoxy groups;
[0017] n is 0, 1, or 2;
[0018] m is 0, 1, or 2; and
[0019] The heterocyclic alkyl, heterocyclic, heterocyclic, heteroaryl, and heteroarylene groups contain one or more heteroatoms selected from N, O, and S;
[0020] The condition is that when A is a 6-membered heteroarylene, R3 and R4 do not form cyclobutane and oxetane together with the carbon atoms they are attached to.
[0021] In this article, the concept of substituents is defined for the compounds of Formula 1.
[0022] In this invention, the term "hydroxyl group" refers to -OH.
[0023] In this invention, the term "halogen," alone or in combination with other terms (e.g., haloalkyl), refers to a free radical of fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
[0024] In this invention, the term "oxo" group means =O (i.e., oxygen with a double bond).
[0025] In this invention, the term "carbonyl" group refers to -C(=O)-.
[0026] In this invention, the term "sulfonyl" group refers to -S(=O)2-.
[0027] In this invention, the term "cyano" group refers to -CN.
[0028] In this invention, the term "amino" group can refer to a primary, secondary, or tertiary amino group bonded by a nitrogen atom, alone or in combination with others.
[0029] In this invention, the term "alkyl", alone or in combination with other terms, refers to a free radical of a saturated aliphatic hydrocarbon group, such as a straight or branched chain having 1 to 7 carbon atoms or 1 to 5 carbon atoms.
[0030] In this invention, the term "alkoxy" refers to an alkoxy group (-O-alkyl), such as an alkoxy group having 1 to 7 carbon atoms or 1 to 5 carbon atoms.
[0031] In this invention, the term "cycloalkyl" refers to a free radical of a saturated aliphatic hydrocarbon group, such as a cyclic type having 3 to 10 carbon atoms or 3 to 8 carbon atoms. The cycloalkyl group may include a bridged structure, a fused structure, or a spirocyclic structure.
[0032] In this invention, the term "heterocyclic alkyl" refers to a cyclic, for example, 4- to 12-membered or 4- to 10-membered saturated aliphatic hydrocarbon, which includes one or more heteroatoms selected from N, O, and S as ring members.
[0033] In this invention, the term "heteroaryl" or "heteroarylene" refers to, for example, 5- to 12-membered or 5- to 10-membered aromatic hydrocarbons, which include one or more heteroatoms selected from N, O, and S as ring members.
[0034] In this invention, the term "partially unsaturated heterocyclic group" or "partially unsaturated heterocyclic subcyclic group" refers to a cyclic, for example, 4- to 12-membered or 6- to 10-membered partially unsaturated hydrocarbon, which includes one or more heteroatoms selected from N, O, and S as ring members.
[0035] Compounds of Formula 1 according to the invention can form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acid addition salts formed by forming non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; organic carboxylic acids like tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc.; and sulfonic acids like methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, etc. Additionally, alkali metal (e.g., sodium and potassium) salts are also included. Furthermore, salts of other acids or bases known and used in the art are also included, such as those belonging to aromatic amidine derivatives or lactam derivatives. Compounds of Formula I according to the invention can be converted into their salts by conventional methods.
[0036] Compounds of Formula 1 according to the invention may have an asymmetric carbon center and an asymmetric axis or asymmetric plane, and therefore may exist as stereoisomers, such as E- or Z-isomers, R- or S-isomers, or racemates, and these isomers and mixtures thereof are included within the scope of the invention. When a compound of Formula 1 according to the invention is a racemate, the racemate can be separated into its respective isomers by conventional separation methods, such as normal-phase or reversed-phase chiral column chromatography, by mixing with the corresponding developing solvent, preferably hexane, ethyl acetate, dichloromethane, methanol, etc. in the normal phase, or by water and acetonitrile, etc. in the reversed phase.
[0037] According to one embodiment of the present invention, in formula 1 above,
[0038] A is a 5-12 membered heteroarylene or a partially unsaturated 4-12 membered heterocyclic group;
[0039] R1 is a 4-12 membered heterocyclic alkyl group, C3-C4 10 Cycloalkylamino or C3-C 10 Cycloalkyl-C1 to C7 alkylamino; wherein the heterocycloalkyl and cycloalkyl are optionally substituted by 1 to 4 substituents selected from hydroxyl, halogen, C1 to C7 alkyl and di(C1 to C7 alkyl)amino;
[0040] R2 is -H, halogen, C1-C7 alkyl, halogen-C1-C7 alkyl, C1-C7 alkoxy, oxo, C1-C7 alkyl carbonyl, C1-C7 alkoxy carbonyl, C1-C7 alkyl sulfonyl or di(C1-C7 alkyl)amino.
[0041] R3 and R4 are each independently -H, C1-C7 alkyl, or C3-C4 alkyl. 10 Cycloalkyl groups; or R3 and R4 together with the carbon atoms they are attached to form C3-C4 groups. 10 Cycloalkyl or 4- to 12-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1 to 4 substituents selected from hydroxyl, halogen, cyano, C1- to C7 alkyl and C1- to C7 alkoxy;
[0042] R5 is a 5- to 12-membered heteroaryl group or a partially unsaturated 4- to 12-membered heterocyclic group; wherein the heteroaryl group and the partially unsaturated heterocyclic group are optionally substituted by 1 to 4 substituents selected from C1- to C7 alkyl and C1- to C7 alkoxy groups;
[0043] n is 0, 1, or 2;
[0044] m is 0, 1, or 2; and
[0045] The heterocyclic alkyl, heterocyclic, heterocyclic alkylene, heteroaryl, and heteroarylene groups comprise 1 to 4 heteroatoms selected from N, O, and S.
[0046] The condition is that when A is a 6-membered heteroarylene, R3 and R4 do not form cyclobutane and oxobutane together with the carbon atoms they are attached to.
[0047] According to another embodiment of the present invention, in Formula 1 above, A is a 5- to 10-membered heteroarylene or a partially unsaturated 6- to 10-membered heterocyclic group; wherein the heteroarylene and heterocyclic group comprise 1 to 3 heteroatoms selected from N, O and S.
[0048] According to another embodiment of the present invention, in formula 1 above, A is... , , , , , , , , , , , , or .
[0049] According to another embodiment of the present invention, in formula 1 above, A is... , , , , , , , , , , or .
[0050] According to another embodiment of the present invention, in Formula 1 above, R1 is a 4- to 10-membered heterocyclic alkyl, a C3- to C8 cycloalkylamino, or a C3- to C8 cycloalkyl-C1- to C5 alkylamino; wherein the heterocyclic alkyl and cycloalkyl are optionally substituted by 1 to 3 substituents selected from hydroxyl, halogen, C1- to C5 alkyl, and di(C1- to C5 alkyl)amino.
[0051] According to another embodiment of the present invention, in Formula 1 above, R2 is -H, halogen, C1-C5 alkyl, halogen-C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl carbonyl or C1-C5 alkyl sulfonyl.
[0052] According to another embodiment of the present invention, in Formula 1 above, R3 and R4 are each independently -H, C1-C5 alkyl or C3-C8 cycloalkyl; or R3 and R4 together with the carbon atoms to which they are attached form C3-C8 cycloalkyl or 4-10 heterocyclic alkyl; wherein the cycloalkyl and heterocyclic alkyl are optionally substituted by 1 to 3 substituents selected from hydroxyl, halogen, cyano, C1-C5 alkyl and C1-C5 alkoxy.
[0053] According to another embodiment of the present invention, in Formula 1 above, R5 is a 5- to 10-membered heteroaryl group or a partially unsaturated 4- to 10-membered heterocyclic group; wherein the heteroaryl group and the partially unsaturated heterocyclic group are optionally substituted by 1 to 3 substituents selected from C1-C5 alkyl and C1-C5 alkoxy groups.
[0054] According to another embodiment of the invention, representative examples of compounds of formula 1 may include, but are not limited to, the following compounds:
[0055] ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)thiazo-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 1);
[0056] ( S )-2-(5-(2-(4-methyl- ... H -1,2,4-triazol-3-yl)propane-2-yl)thiazo-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 2);
[0057] ( S )-2-(5-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)thiazo-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 3);
[0058] ( S )-2-(5-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)thiophen-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 4);
[0059] ( S )-2-(5-(2-(4-methyl- ... H-1,2,4-triazol-3-yl)propane-2-yl)thiophen-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 5);
[0060] ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)thiophen-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 6);
[0061] ( S )-2-(5-(5-(4-methyl-4 H -1,2,4-triazol-3-yl)spiro[2.3]hexane-5-yl)thiophen-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 7);
[0062] ( S )-2-(5-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 8);
[0063] ( S )-2-(5-(2-(4-methyl- ... H -1,2,4-triazol-3-yl)propane-2-yl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 9);
[0064] ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 10);
[0065] ( S )-2-(5-(5-(4-methyl-4 H -1,2,4-triazol-3-yl)spiro[2.3]hexane-5-yl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 11);
[0066] ( S )-2-(5-(3-methoxy-1-(4-methyl-4-) H-1,2,4-triazol-3-yl)cyclobutyl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 12);
[0067] ( S )-3-(4-methyl-4 H -1,2,4-triazol-3-yl)-3-(4-(6-((3-methylpiperidin-1-yl)methyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)thiophen-2-yl)cyclobutane-1-nitrile (compound 13);
[0068] 2-(5-(4-(4-methyl-4-) H -1,2,4-triazol-3-yl)spiro[2,3]hexane-4-yl)thiophen-3-yl)-6-((( S )-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 14);
[0069] 2-(5-(cyclobutyl(4-methyl-4-)) H -1,2,4-triazol-3-yl)methyl)thiophen-3-yl)-6-((( S )-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 15);
[0070] ( S )-2-(6-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)pyrimidin-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 16);
[0071] ( S )-2-(6-(2-(4-methyl-4-) H -1,2,4-triazol-3-yl)propane-2-yl)pyrimidin-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 17);
[0072] ( S )-2-(4-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)pyrimidin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 18);
[0073] ( S )-2-(4-(2-(4-methyl-4-) H-1,2,4-triazol-3-yl)propane-2-yl)pyrimidin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 19);
[0074] ( S )-2-(7-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 20);
[0075] ( S )-2-(7-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-5-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 21);
[0076] ( S )-2-(5-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 22);
[0077] ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 23);
[0078] ( S )-2-(5-(2-(4-methyl- ... H -1,2,4-triazol-3-yl)propane-2-yl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 24);
[0079] ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopropyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 25);
[0080] ( S)-2-(5-(3-(4-methyl- ... H -1,2,4-triazol-3-yl)oxetane-3-yl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 26);
[0081] ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 27);
[0082] ( S )-2-(5-(3-methyl-1-(4-methyl-4-methyl-4-methyl-4-methyl-1-( ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 28);
[0083] ( S )-2-(5-(3,3-difluoro-1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 29);
[0084] ( S )-3-(4-methyl-4 H -1,2,4-triazol-3-yl)-3-(7-(6-((3-methylpiperidin-1-yl)methyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-2,3-dihydrobenzofuran-5-yl)cyclobutane-1-nitrile (compound 30);
[0085] ( S )-2-(5-(3-methoxy-1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 31);
[0086] 2-(5-(cyclobutyl(4-methyl-4-)) H -1,2,4-triazol-3-yl)methyl)-2,3-dihydrobenzofuran-7-yl)-6-((( S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 32);
[0087] ( S )-2-(6-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)benzo[ d [1,3]dioxacyclopenten-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 33);
[0088] ( S )-2-(2-fluoro-5-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)benzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 34);
[0089] ( S )-2-(4-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-6-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 35);
[0090] ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)furan-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 36);
[0091] ( S )-2-(4-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)furan-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 37);
[0092] 2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-(piperidin-1-ylmethyl)-4-(trifluoromethyl)isoindoline-1-one (compound 38).
[0093] 6-(((3 R 5 S)-3,5-dimethylpiperidin-1-yl)methyl)-2-(5-(1-(4-methyl-4) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 39);
[0094] 2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-(morpholinomethyl)-4-(trifluoromethyl)isoindoline-1-one (compound 40);
[0095] ( R )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((2-methylmorpholino)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 41);
[0096] ( R )-6-((4,4-difluoro-3-methylpiperidin-1-yl)methyl)-2-(5-(1-(4-methyl-4) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 42);
[0097] ( S )-6-((2-isopropyl-4-methylpiperazin-1-yl)methyl)-2-(5-(1-(4-methyl-4 ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 43);
[0098] ( S )-6-((3-Fluoropyrrolidone-1-yl)methyl)-2-(5-(1-(4-methyl-4 ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 44);
[0099] 6-((5-azaspiro[2.4]heptane-5-yl)methyl)-2-(5-(1-(4-methyl-4-yl) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 45);
[0100] 6-(((3,3-difluorocyclopentyl)amino)methyl)-2-(5-(1-(4-methyl-4-methyl) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 46);
[0101] 6-((((1 S ,2 R )-2-hydroxycyclopentyl)amino)methyl)-2-(5-(1-(4-methyl-4 H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 47);
[0102] 2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-(((1-methylcyclopropyl)amino)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 48);
[0103] ( S )-6-(((1-cyclobutylethyl)amino)methyl)-2-(5-(1-(4-methyl-4 H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 49);
[0104] 6-((((1-hydroxycyclobutyl)methyl)amino)methyl)-2-(5-(1-(4-methyl-4-methyl) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 50);
[0105] ( S )-2-(5-(1-(4-ethyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 51);
[0106] ( S )-2-(5-(1-(1,3,4-diazol-2-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 52);
[0107] (S )-2-(5-(1-(1,2,4-diazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 53);
[0108] ( S )-2-(5-(2-(4-methyl- ... H -1,2,4-triazol-3-yl)ethyl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 54);
[0109] ( S )-2-(5-(1-((4-methyl- ... H -1,2,4-triazol-3-yl)methyl)cyclopentyl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 55);
[0110] ( S )-2-(5-(2-(4-methyl- ... H -1,2,4-triazol-3-yl)ethyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 56);
[0111] ( S )-2-(5-(1-((4-methyl- ... H -1,2,4-triazol-3-yl)methyl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 57);
[0112] ( S )-2-(7-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzo[ b [1,4]dioxane-5-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 58);
[0113] ( S )-2-(2,2-dimethyl-5-(1-(4-methyl-4 ... H-1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 59);
[0114] ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 60);
[0115] ( S )-2-(1-methyl-5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 61);
[0116] ( S )-2-(6-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 62);
[0117] ( S )-2-(1-methyl-6-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 63);
[0118] ( S )-2-(1-acetyl-6-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindololin-1-one (compound 64);
[0119] ( S )-2-(6-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-1-(methanesulfonyl)-1 H-Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 65);
[0120] ( S )-2-(3-methyl-6-(1-(4-methyl-4-methyl-6 ... H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindololin-1-one (compound 66);
[0121] ( S )-2-(1,3-dimethyl-6-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 67);
[0122] ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)benzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 68);
[0123] ( S )-2-(2-methyl-6-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 69);
[0124] ( S )-2-(1-methyl-4-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-6-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 70);
[0125] 2-(5-(3-methyl-1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)thiophen-3-yl)-6-((( S )-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 71);
[0126] 2-(5-(3-methyl-1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)thiophen-3-yl)-6-((( S )-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 72);
[0127] ( S )-2-(5-(5-(4-methyl-4 H -1,2,4-triazol-3-yl)spiro[2,3]hexane-5-yl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 73);
[0128] 6-((3-(dimethylamino)azacyclobutane-1-yl)methyl)-2-(5-(1-(4-methyl-4-yl)) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 74);
[0129] 6-((6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)methyl)-2-(5-(1-(4-methyl-4-yl) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 75);
[0130] 6-((cyclohexylamino)methyl)-2-(5-(1-(4-methyl-4-methyl) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 76);
[0131] 6-((cyclohexylamino)methyl)-2-(5-(1-(4-methyl-4-methyl) H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 77);
[0132] 6-(((3 S 5 R )-3,5-dimethylpiperidin-1-yl)methyl)-2-(5-(1-(4-methyl-4) H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 78);
[0133] ( S )-6-(((3,3-difluorocyclopentyl)amino)methyl)-2-(5-(1-(4-methyl-4 H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 79);
[0134] ( S )-6-((2-isopropyl-4-methylpiperazin-1-yl)methyl)-2-(5-(1-(4-methyl-4 ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 80);
[0135] ( S )-6-(((1-cyclobutylethyl)amino)methyl)-2-(5-(1-(4-methyl-4 H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 81);
[0136] 2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-(piperidin-1-ylmethyl)-4-(trifluoromethyl)isoindoline-1-one (compound 82);
[0137] ( S )-6-((3-Fluoropyrrolidone-1-yl)methyl)-2-(5-(1-(4-methyl-4 ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 83);
[0138] 2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-(((1-methylcyclopropyl)amino)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 84);
[0139] 2-(5-((1 s ,3 s )-3-methyl-1-(4-methyl-4- H-1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-(piperidin-1-ylmethyl)-4-(trifluoromethyl)isoindoline-1-one (compound 85);
[0140] 6-(((3 S 5 R )-3,5-dimethylpiperidin-1-yl)methyl)-2-(5-((1 s ,3 S )-3-methyl-1-(4-methyl-4- H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 86);
[0141] 6-((( S )-2-isopropyl-4-methylpiperazin-1-yl)methyl)-2-(5-((1 s ,3 R )-3-methyl-1-(4-methyl-4- H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 87);
[0142] 6-((cyclohexylamino)methyl)-2-(5-((1 s ,3 s )-3-methyl-1-(4-methyl-4- H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 88);
[0143] 2-(5-((1 s ,3 s )-3-methyl-1-(4-methyl-4- H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-(((1-methylcyclopropyl)amino)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 89);
[0144] 6-(((( S )-1-Cyclobutylethyl)amino)methyl)-2-(5-((1 s ,3 R )-3-methyl-1-(4-methyl-4- H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 90);
[0145] 2-(5-((1 s ,3 R )-1-(4-ethyl-4 H -1,2,4-triazol-3-yl)-3-methylcyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((( S )-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 91);
[0146] ( S )-2-(5-(1-(4-ethyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 92);
[0147] ( S )-2-(5-(5-(4-ethyl-4 H -1,2,4-triazol-3-yl)spiro[2.3]hexane-5-yl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 93);
[0148] ( S )-2-(5-(3-((4-methyl- ... H -1,2,4-triazol-3-yl)methyl)oxetane-3-yl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 94);
[0149] ( S )-6-((2-isopropyl-4-methylpiperazin-1-yl)methyl)-2-(5-(3-((4-methyl-4) H -1,2,4-triazol-3-yl)methyl)oxetane-3-yl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 95);
[0150] 6-((cyclohexylamino)methyl)-2-(5-(3-((4-methyl-4-methyl) H -1,2,4-triazol-3-yl)methyl)oxetane-3-yl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 96); and
[0151] ( S)-6-(((3,3-difluorocyclopentyl)amino)methyl)-2-(5-(3-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)oxetane-3-yl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 97).
[0152] The names of the compounds listed above are described using the structure-based nomenclature provided by CambridgeSoft's CS ChemDraw Ultra software.
[0153] Furthermore, the present invention includes hydrated or solvated forms of compounds of Formula 1. These hydrates or solvates can be prepared by known methods and are preferably non-toxic and water-soluble, particularly preferably hydrates or solvates containing 1 to 5 water molecules or alcohol solvent molecules.
[0154] According to another aspect of the invention, a pharmaceutical composition for the prevention or treatment of diseases associated with Cbl-b is provided, comprising a compound of formula 1 or a pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient, and a pharmaceutically acceptable carrier.
[0155] Furthermore, the present invention provides the use of compounds of Formula 1 or pharmaceutically acceptable salts or stereoisomers thereof in the prevention or treatment of diseases associated with Cbl-b.
[0156] Furthermore, the present invention provides a method for preventing or treating diseases associated with Cbl-b, the method comprising administering a compound of Formula 1 or a pharmaceutically acceptable salt or stereoisomer thereof to a subject in need of such treatment.
[0157] In another embodiment of the invention, the diseases associated with Cbl-b may be selected from the group consisting of solid tumors, hematologic malignancies, radiation- or drug-resistant cancers, and metastatic cancers. In another embodiment of the invention, diseases associated with Cbl-b may be selected from the group comprising: triple-negative breast cancer, breast cancer, male breast cancer, ovarian cancer, cervical cancer, endometrial cancer, uterine sarcoma, vaginal cancer, female genital tumors, female external genital cancer, female urethral cancer, prostate cancer, penile cancer, male genital tumors, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, small bowel cancer, colorectal cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, thyroid cancer, oral cancer, thoracic tumors, small cell lung cancer, non-small cell lung cancer, thymoma, mediastinal tumors, esophageal cancer, laryngeal cancer, oropharyngeal cancer, nasal / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, brain cancer, brain tumors, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, craniopharyngioma, ependymoma, brainstem tumors, head and neck cancers, and skin cancer.
[0158] In addition to the compounds of Formula 1 or their pharmaceutically acceptable salts or stereoisomers as active ingredients, the pharmaceutical compositions of the present invention may be formulated according to conventional methods and further comprise conventional, non-toxic, pharmaceutically acceptable additives, such as carriers, excipients, diluents, and supplements.
[0159] The pharmaceutical compositions of the present invention can be formulated into various oral administration forms, such as tablets, pills, powders, capsules, syrups or emulsions, or parenteral administration forms, such as intramuscular injection, intravenous injection or subcutaneous injection.
[0160] Examples of additives that can be used in the pharmaceutical compositions of the present invention include sweeteners, binders, solubilizers, solubilizing agents, humectants, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, and flavorings. Examples include lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycine, silicon dioxide, talc, stearic acid, stearyl alcohol, magnesium stearate, magnesium aluminum silicate, starch, gelatin, gum arabic, alginic acid, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange extract, strawberry extract, and vanilla flavoring.
[0161] By mixing additives with active ingredients, the pharmaceutical compositions of the present invention can be formulated into oral administration forms, wherein examples of additives include cellulose, calcium silicate, corn starch, lactose, sucrose, glucose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc.
[0162] By mixing additives with active ingredients, the pharmaceutical compositions of the present invention can be formulated into injectable forms, wherein examples of additives include water, saline solutions, glucose solutions, similar sugar solutions, alcohols, polyols, ethers, oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifiers, etc.
[0163] [The effects of the invention]
[0164] The compounds of Formula 1 according to the present invention, or their pharmaceutically acceptable salts or stereoisomers, can effectively prevent or treat diseases associated with Cbl-b.
[0165] [Detailed Implementation of the Invention]
[0166] The present invention will be explained in more detail below through the following embodiments and experimental examples. However, it must be understood that the scope of protection of the present invention is not limited to these embodiments and experimental examples.
[0167] Example 1: ( S)-2-(5-(1-(4-methyl- ... H Synthesis of -1,2,4-triazol-3-yl)cyclopentyl)thiazolyl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one
[0168]
[0169] Synthesis of (a) 1-(2-bromothiazo-5-yl)cyclopentane-1-nitriles
[0170] To a stirred mixture of 2-(2-bromothiazol-5-yl)acetonitrile (200 mg, 984.93 µmol) and 1,4-diiodobutane (305.24 mg, 984.93 µmol, 129.89 µL) in N,N-dimethylformamide (4.77 mL), 1,4,7,10,13,16-hexaoxane (26.03 mg, 98.49 µmol) and sodium hydride (78.79 mg, 1.97 mmol, 60% purity) were added sequentially. The reaction mixture was further stirred at 25 °C for 15 hours under an argon atmosphere. The resulting mixture was cooled to 0 °C, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-(2-bromothiazol-5-yl)cyclopentane-1-onitrile (181.3 mg, 71.58%) as a yellow liquid.
[0171] LC / MS ESI (+): 257 / 259 (M+1)
[0172] 1 H-NMR (500MHz, DMSO-D6) δ 7.80 (s, 1H), 2.48-2.43 (m, 2H), 2.18-2.12 (m, 2H), 1.88-1.82 (m, 4H)
[0173]
(b) Synthesis of 1-(2-bromothiazol-5-yl)cyclopentane-1-carboxylic acid
[0174] Dissolve 1-(2-bromothiazol-5-yl)cyclopentane-1-onitrile (159.6 mg, 620.65 µmol) and lithium hydroxide (59.45 mg, 2.48 mmol) in triple-distilled water (3.10 mL). Stir the reaction mixture further at 70 °C for 22 hours under an argon atmosphere. Cool the resulting mixture to 0 °C and acidify to pH 3 with 1 N hydrochloric acid. Extract the aqueous layer with dichloromethane. Wash the combined organic layers with water and dry over anhydrous magnesium sulfate. Filter and concentrate the filtrate under reduced pressure. Use the crude product directly in the next step without further purification.
[0175] LC / MS ESI (+): 276 / 278 (M+1)
[0176] 【(c)2-(1-(2-bromothiazol-5-yl)cyclopentane-1-carbonyl)- N Synthesis of 1-methylhydrazine-1-carbonylthioamide
[0177] exist N,N Dissolve 1-(2-bromothiazol-5-yl)cyclopentane-1-carboxylic acid (171.2 mg, 619.95 µmol) in dimethylformamide (ultrapure, 1.85 mL) and N 1-Methylhydrazine-1-carbonylthioamide (78.23 mg, 743.93 µmol), zabenzotriazole hexafluorophosphate tetramethylureonium (HATU) (353.59 mg, 929.93 µmol), and further added N -Ethyl- N -Isopropylpropane-2-amine (160.25 mg, 1.24 mmol, 216.55 µL). The reaction mixture was further stirred at 25 °C for 1 hour under an argon atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.
[0178] LC / MS ESI (+): 363 / 365 (M+1)
[0179] (d) 5-(1-(2-bromothiazo-5-yl)cyclopentyl)-4-methyl-4 H Synthesis of -1,2,4-triazol-3-thiol
[0180] 2-(1-(2-bromothiazol-5-yl)cyclopentane-1-carbonyl)- N 1-Methylhydrazine-1-carbonylthioamide (540.7 mg, 1.49 mmol) was dissolved in 1N aqueous sodium hydroxide solution (8.93 mL, 8.93 mmol), and the reaction mixture was stirred at room temperature for 6 hours under an argon atmosphere. The reaction mixture was cooled to 0°C and acidified to pH 3 with 1N hydrochloric acid. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.
[0181] LC / MS ESI (+): 345 / 347 (M+1)
[0182] (e)2-bromo-5-(1-(4-methyl-4-)H Synthesis of -1,2,4-triazol-3-yl)cyclopentyl)thiazole
[0183] 5-(1-(2-bromothiazo-5-yl)cyclopentyl)-4-methyl-4 H 1,2,4-Triazol-3-thiol (238.5 mg, 690.74 µmol) was dissolved in dichloromethane (2.09 mL), followed by the addition of acetic acid (539.24 mg, 8.98 mmol, 513.57 µL) and hydrogen peroxide solution (846.68 µL, 8.29 mmol, 30% purity). The reaction mixture was stirred at 25 °C for 15 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography (C18-silica gel) to give 2-bromo-5-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)thiazole (100 mg, 4-step yield: 51.5%).
[0184] LC / MS ESI (+): 313 / 315 (M+1)
[0185] 1 H-NMR (500MHz, DMSO-D6) δ 8.39 (s, 1H), 7.60 (s, 1H), 3.39 (d, J=6.3Hz, 3H), 2.55-2.52 (m, 2H), 2.32-2.29 (m, 2H), 1.76-1.71 (m, 4H)
[0186] (f) Methyl S Synthesis of 2-(bromomethyl)-5-((3-methylpiperidin-1-yl)methyl)-3-(trifluoromethyl)benzoate
[0187] Will( S2.06 g (15.18 mmol) of methyl-2-(bromomethyl)-5-carboxaldehyde-3-(trifluoromethyl)benzoate was dissolved in dichloromethane (ultrapure, 126.5 mL), and triethylamine (4.61 g, 45.54 mmol) and sodium triacetoxyborohydride (9.65 g, 45.54 mmol) were added. The reaction mixture was stirred at 25 °C for 10 min under an argon atmosphere. The reaction mixture was cooled to 0 °C. 4.93 g (15.18 mmol) of methyl-2-(bromomethyl)-5-carboxaldehyde-3-(trifluoromethyl)benzoate was dissolved in dichloromethane (10.3 mL) and added to the reaction mixture. The reaction mixture was further stirred at 25 °C for 3 h under an argon atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.
[0188] LC / MS ESI (+): 408 / 410 (M+1)
[0189] 【(g)( S Synthesis of 6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindololin-1-one
[0190] Will( S Methyl 2-(bromomethyl)-5-((3-methylpiperidin-1-yl)methyl)-3-(trifluoromethyl)benzoate (6.22 g, 15.23 mmol) was dissolved in methanol (ultrapure, 50.78 mL), and 7N ammonia solution (7N ammonia in MeOH, 50.78 mL, 355.46 mmol) was added. The reaction mixture was stirred at 25 °C for 18 hours under an argon atmosphere. The filtrate of the reaction mixture was concentrated under reduced pressure. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography (C18-silica gel) to give a white solid ( S )-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindololin-1-one (2.14 g, two-step yield: 45.05%).
[0191] LC / MS ESI (+): 313 (M+1)
[0192] 【(h)( S )-2-(5-(1-(4-methyl- ... H Synthesis of -1,2,4-triazol-3-yl)cyclopentyl)thiazolyl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one
[0193] 2-bromo-5-(1-(4-methyl-4) H -1,2,4-triazol-3-yl)cyclopentyl)thiazole (30 mg, 95.78 µmol), ( S )-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (29.92 mg, 95.78 µmol), palladium(II) acetate (4.30 mg, 19.16 µmol), (9,9-dimethyl-9 H 1,4-Dioxane (22.17 mg, 38.31 µmol) and cesium carbonate (93.62 mg, 287.34 µmol) were dissolved in 1,4-dioxane (758.20 µL). The reaction mixture was stirred for 1 hour at 150 °C under an argon atmosphere using a microwave reactor. The resulting mixture was cooled to 0 °C and concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography (C18-silica gel) to give a white solid ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)thiazolyl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (7.7 mg, 14.76%).
[0194] LC / MS ESI (+): 545 (M+1)
[0195] 1 H-NMR (500MHz, DMSO-D6) δ 8.39 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.48 (s, 1H), 5.24 (s, 2H), 3.63 (d, J=9.8Hz, 2H), 3.40 (s, 3H), 2.72-2.68 (m, 2H), 2.58- 2.52 (m, 2H), 2.38-2.33 (m, 2H), 1.94-1.90 (m, 1H), 1.81-1.72 (m, 4H), 1.66-1.57 (m, 4H), 1.50-1.43 (m, 1H), 0.89-0.80 (m, 4H)
[0196] The compounds of Examples 2 to 97 were synthesized in a manner similar to that of Example 1, and the data of the compounds of Examples 1 to 97 are shown in Table 1.
[0197] Table 1
[0198]
[0199]
[0200]
[0201]
[0202]
[0203]
[0204]
[0205]
[0206]
[0207]
[0208]
[0209]
[0210]
[0211]
[0212]
[0213]
[0214]
[0215]
[0216]
[0217]
[0218]
[0219]
[0220]
[0221]
[0222]
[0223]
[0224]
[0225]
[0226]
[0227]
[0228] [Experimental Example: Cbl-b Inhibitory Activity]
[0229] The ability to inhibit Cbl-b activity was measured by monitoring the degree of Cbl-b ubiquitination in the presence of candidate compounds.
[0230] In 1% DMSO (final concentration), the concentrations of the example compounds were serially diluted 3-fold from the highest concentration of 1 µM to 0.00005 µM to prepare a total of 10 concentrations. Each concentration of the example compound was pre-incubated with 0.5 nM Cbl-b (BPSBioscience, 80415) in U2 detection buffer (BPS Bioscience, 78856) for 30 min and then measured at room temperature in a 10 µL reaction volume in a 384-well plate (Corning, 3824). After a 30-minute pre-incubation with the compounds of the examples, the reaction was initiated by adding 5 µL of substrate mixture (consisting of 20 nM UBE1 (BPSBioscience, 80301), 50 nM UbcH5b (BPS Bioscience, 80314), 1.5 nM TYRO3 (BPSBioscience, 40293), and 0.25 × Ubi-Mix (BPS Bioscience, 82185)) and 5 µL of 15.5 µM ATP (ThermoFisher, R0441) to each well of the plate. The enzyme reaction was allowed to proceed for 2 hours, and the change in enzyme activity over time was measured every 3 minutes using a SpectraMax i3x plate reader (Molecular Devices) at 615 / 665 nm. After all reactions were completed, the IC50 was calculated from the obtained data values using the following four-parameter logistic curve equation. 50 value.
[0231]
[0232] In the above equation, "Top" represents the maximum value of the y-axis, and "Bottom" represents the minimum value of the y-axis. Furthermore, "Hillslope" represents the slope of the tangent line at the inflection point of the dose-response curve.
[0233] Cbl-b amino acid residues 39–426:
[0234] AA ADRRTVEKTW KLMDKVVRLC QNPKLQLKNS PPYILDILPD TYQHLRLILS KYDDNQKLAQLSENEYFKIY IDSLMKKSKR AIRLFKEGKE RMYEEQSQDR RNLTKLSLIF SHMLAEIKAI FPNGQFQGDNFRITKADAAE FWRKFFGDKT IVPWKVFRQC LHEVHQISSS LEAMALKSTI DLTCNDYISV FEFDIFTRLFQPWGSILRNW NFLAVTHPGY MAFLTYDEVK ARLQKYSTKP GSYIFRLSCT RLGQWAIGYV TGDGNILQTIPHNKPLFQAL IDGSREGFYL YPDGRSYNPD LTGLCEPTPH DHIKVTQEQY ELYCEMGSTF QLCKICAENDKDVKIEPCGH LMCTSCLTAW QESDGQGCPF CRCEIKGTEP IIVDPF
[0235] The results of evaluating the Cbl-b inhibitory activity of the compounds in the examples are shown in Table 2.
[0236] Table 2
[0237]
[0238] As shown in Table 2, the compounds of the present invention exhibit Cbl-b inhibitory activity. Therefore, the compounds of Formula 1 according to the present invention can be effectively used for the treatment of diseases related to Cbl-b.
Claims
1. The compound represented by Formula 1 below, or its pharmaceutically acceptable salt or stereoisomer: Formula 1 in, A is a heteroarylene or a partially unsaturated heterocyclic group; R1 is a heterocyclic alkyl, cycloalkylamino, or cycloalkyl-alkylamino; wherein the heterocyclic alkyl and cycloalkyl are optionally substituted with one or more substituents selected from hydroxyl, halogen, alkyl, and dialkylamino. R2 is -H, halogen, alkyl, haloalkyl, alkoxy, oxo (=O), alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl or dialkylamino; R3 and R4 are each independently -H, alkyl, or cycloalkyl; or R3 and R4 together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl group; wherein the cycloalkyl or heterocycloalkyl group is optionally substituted by one or more substituents selected from hydroxyl, halogen, cyano (-CN), alkyl, and alkoxy groups; R5 is a heteroaryl or partially unsaturated heterocyclic group; wherein the heteroaryl or partially unsaturated heterocyclic group is optionally substituted by one or more substituents selected from alkyl and alkoxy groups; n is 0, 1, or 2; m is 0, 1, or 2; and The heterocyclic alkyl, heterocyclic, heterocyclic, heteroaryl, and heteroarylene groups contain one or more heteroatoms selected from N, O, and S; The condition is that when A is a 6-membered heteroarylene, R3 and R4 do not form cyclobutane and oxetane together with the carbon atoms they are attached to.
2. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein... A is a 5-12 membered heteroarylene or a partially unsaturated 4-12 membered heterocyclic group; R1 is a 4-12 membered heterocyclic alkyl group, C3-C4 10 Cycloalkylamino or C3-C 10 Cycloalkyl-C1 to C7 alkylamino; wherein the heterocycloalkyl and cycloalkyl groups are optionally substituted with 1 to 4 substituents selected from hydroxyl, halogen, C1 to C7 alkyl and di(C1 to C7 alkyl)amino; R2 is -H, halogen, C1-C7 alkyl, halogen-C1-C7 alkyl, C1-C7 alkoxy, oxo, C1-C7 alkyl carbonyl, C1-C7 alkoxy carbonyl, C1-C7 alkyl sulfonyl or di(C1-C7 alkyl)amino. R3 and R4 are each independently -H, C1-C7 alkyl, or C3-C4 alkyl. 10 Cycloalkyl groups; or R3 and R4 together with the carbon atoms they are attached to form C3-C4 groups. 10 Cycloalkyl or 4- to 12-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1 to 4 substituents selected from hydroxyl, halogen, cyano, C1- to C7 alkyl and C1- to C7 alkoxy; R5 is a 5- to 12-membered heteroaryl group or a partially unsaturated 4- to 12-membered heterocyclic group; wherein the heteroaryl group and the partially unsaturated heterocyclic group are optionally substituted by 1 to 4 substituents selected from C1- to C7 alkyl and C1- to C7 alkoxy groups; n is 0, 1, or 2; m is 0, 1, or 2; and The heterocyclic alkyl, heterocyclic, heterocyclic alkylene, heteroaryl, and heteroarylene groups comprise 1 to 4 heteroatoms selected from N, O, and S. The condition is that when A is a 6-membered heteroarylene, R3 and R4 do not form cyclobutane and oxetane together with the carbon atoms they are attached to.
3. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, Where A is a 5-10 membered heteroarylene or a partially unsaturated 6-10 membered heterocyclic group; The heteroarylene and heterocyclic groups therein comprise 1 to 3 heteroatoms selected from N, O and S.
4. The compound according to claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A is... , , , , , , , , , , , , or .
5. The compound according to claim 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A is... , , , , , , , , , , or .
6. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, R1 is a 4-10 membered heterocyclic alkyl, a C3-C8 cycloalkylamino, or a C3-C8 cycloalkyl-C1-C5 alkylamino; The heterocyclic alkyl and cycloalkyl groups are optionally substituted with 1 to 3 substituents selected from hydroxyl, halogen, C1 to C5 alkyl and di(C1 to C5 alkyl)amino.
7. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is -H, halogen, C1-C5 alkyl, halogen-C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl carbonyl, or C1-C5 alkyl sulfonyl.
8. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, in R3 and R4 are each independently -H, C1-C5 alkyl, or C3-C8 cycloalkyl; or R3 and R4 together with the carbon atoms they are attached to form C3-C8 cycloalkyl or 4-10 heterocyclic alkyl; The cycloalkyl and heterocycloalkyl groups thereon are optionally substituted with 1 to 3 substituents selected from hydroxyl, halogen, cyano, C1 to C5 alkyl and C1 to C5 alkoxy groups.
9. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, R5 is a 5-10 membered heteroaryl group or a partially unsaturated 4-10 membered heterocyclic group; The heteroaryl and partially unsaturated heterocyclic groups are optionally substituted by 1 to 3 substituents selected from C1 to C5 alkyl and C1 to C5 alkoxy groups.
10. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula 1 is selected from: ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)thiazo-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 1); ( S )-2-(5-(2-(4-methyl- ... H -1,2,4-triazol-3-yl)propane-2-yl)thiazo-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 2); ( S )-2-(5-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)thiazo-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 3); ( S )-2-(5-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)thiophen-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 4); ( S )-2-(5-(2-(4-methyl- ... H -1,2,4-triazol-3-yl)propane-2-yl)thiophen-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 5); ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)thiophen-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 6); ( S )-2-(5-(5-(4-methyl-4 H -1,2,4-triazol-3-yl)spiro[2.3]hexane-5-yl)thiophen-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 7); ( S )-2-(5-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 8); ( S )-2-(5-(2-(4-methyl- ... H -1,2,4-triazol-3-yl)propane-2-yl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 9); ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 10); ( S )-2-(5-(5-(4-methyl-4 H -1,2,4-triazol-3-yl)spiro[2.3]hexane-5-yl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 11); ( S )-2-(5-(3-methoxy-1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclobutyl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 12); ( S )-3-(4-methyl-4 H -1,2,4-triazol-3-yl)-3-(4-(6-((3-methylpiperidin-1-yl)methyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)thiophen-2-yl)cyclobutane-1-nitrile (compound 13); 2-(5-(4-(4-methyl-4-) H -1,2,4-triazol-3-yl)spiro[2,3]hexane-4-yl)thiophen-3-yl)-6-((( S )-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 14); 2-(5-(cyclobutyl(4-methyl-4-)) H -1,2,4-triazol-3-yl)methyl)thiophen-3-yl)-6-((( S )-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 15); ( S )-2-(6-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)pyrimidin-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 16); ( S )-2-(6-(2-(4-methyl-4-) H -1,2,4-triazol-3-yl)propane-2-yl)pyrimidin-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 17); ( S )-2-(4-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)pyrimidin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 18); ( S )-2-(4-(2-(4-methyl-4-) H -1,2,4-triazol-3-yl)propane-2-yl)pyrimidin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 19); ( S )-2-(7-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 20); ( S )-2-(7-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-5-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 21); ( S )-2-(5-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 22); ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 23); ( S )-2-(5-(2-(4-methyl- ... H -1,2,4-triazol-3-yl)propane-2-yl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 24); ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopropyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 25); ( S )-2-(5-(3-(4-methyl- ... H -1,2,4-triazol-3-yl)oxetane-3-yl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 26); ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 27); ( S )-2-(5-(3-methyl-1-(4-methyl-4-methyl-4-methyl-4-methyl-1-( ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 28); ( S )-2-(5-(3,3-difluoro-1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 29); ( S )-3-(4-methyl-4 H -1,2,4-triazol-3-yl)-3-(7-(6-((3-methylpiperidin-1-yl)methyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-yl)-2,3-dihydrobenzofuran-5-yl)cyclobutane-1-nitrile (compound 30); ( S )-2-(5-(3-methoxy-1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 31); 2-(5-(cyclobutyl(4-methyl-4-)) H -1,2,4-triazol-3-yl)methyl)-2,3-dihydrobenzofuran-7-yl)-6-((( S )-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 32); ( S )-2-(6-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)benzo[ d [1,3]dioxacyclopenten-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 33); ( S )-2-(2-fluoro-5-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)benzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 34); ( S )-2-(4-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-6-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 35); ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)furan-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 36); ( S )-2-(4-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)furan-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 37); 2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-(piperidin-1-ylmethyl)-4-(trifluoromethyl)isoindoline-1-one (compound 38). 6-(((3 R 5 S )-3,5-dimethylpiperidin-1-yl)methyl)-2-(5-(1-(4-methyl-4) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 39); 2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-(morpholinomethyl)-4-(trifluoromethyl)isoindoline-1-one (compound 40); ( R )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((2-methylmorpholino)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 41); ( R )-6-((4,4-difluoro-3-methylpiperidin-1-yl)methyl)-2-(5-(1-(4-methyl-4) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 42); ( S )-6-((2-isopropyl-4-methylpiperazin-1-yl)methyl)-2-(5-(1-(4-methyl-4 ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 43); ( S )-6-((3-Fluoropyrrolidone-1-yl)methyl)-2-(5-(1-(4-methyl-4 ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 44); 6-((5-azaspiro[2.4]heptane-5-yl)methyl)-2-(5-(1-(4-methyl-4-yl) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 45); 6-(((3,3-difluorocyclopentyl)amino)methyl)-2-(5-(1-(4-methyl-4-methyl) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 46); 6-((((1 S ,2 R )-2-hydroxycyclopentyl)amino)methyl)-2-(5-(1-(4-methyl-4 H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 47); 2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-(((1-methylcyclopropyl)amino)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 48); ( S )-6-(((1-cyclobutylethyl)amino)methyl)-2-(5-(1-(4-methyl-4 H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 49); 6-((((1-hydroxycyclobutyl)methyl)amino)methyl)-2-(5-(1-(4-methyl-4-methyl) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 50); ( S )-2-(5-(1-(4-ethyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 51); ( S )-2-(5-(1-(1,3,4-diazol-2-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 52); ( S )-2-(5-(1-(1,2,4-diazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 53); ( S )-2-(5-(2-(4-methyl- ... H -1,2,4-triazol-3-yl)ethyl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 54); ( S )-2-(5-(1-((4-methyl- ... H -1,2,4-triazol-3-yl)methyl)cyclopentyl)thiophen-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 55); ( S )-2-(5-(2-(4-methyl- ... H -1,2,4-triazol-3-yl)ethyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 56); ( S )-2-(5-(1-((4-methyl- ... H -1,2,4-triazol-3-yl)methyl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 57); ( S )-2-(7-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzo[ b [1,4]dioxane-5-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 58); ( S )-2-(2,2-dimethyl-5-(1-(4-methyl-4 ... H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 59); ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 60); ( S )-2-(1-methyl-5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 61); ( S )-2-(6-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 62); ( S )-2-(1-methyl-6-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 63); ( S )-2-(1-acetyl-6-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 64); ( S )-2-(6-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)-1-(methanesulfonyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 65); ( S )-2-(3-methyl-6-(1-(4-methyl-4-methyl-6 ... H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 66); ( S )-2-(1,3-dimethyl-6-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 67); ( S )-2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclopentyl)benzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 68); ( S )-2-(2-methyl-6-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 69); ( S )-2-(1-methyl-4-(1-(4-methyl-4-) H -1,2,4-triazol-3-yl)cyclopentyl)-1 H -Indol-6-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one (compound 70); 2-(5-(3-methyl-1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)thiophen-3-yl)-6-((( S )-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 71); 2-(5-(3-methyl-1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)thiophen-3-yl)-6-((( S )-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 72); ( S )-2-(5-(5-(4-methyl-4 H -1,2,4-triazol-3-yl)spiro[2,3]hexane-5-yl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 73); 6-((3-(dimethylamino)azacyclobutane-1-yl)methyl)-2-(5-(1-(4-methyl-4-yl)) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 74); 6-((6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)methyl)-2-(5-(1-(4-methyl-4-yl) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 75); 6-((cyclohexylamino)methyl)-2-(5-(1-(4-methyl-4-methyl) H -1,2,4-triazol-3-yl)cyclopentyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 76); 6-((cyclohexylamino)methyl)-2-(5-(1-(4-methyl-4-methyl) H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 77); 6-(((3 S 5 R )-3,5-dimethylpiperidin-1-yl)methyl)-2-(5-(1-(4-methyl-4) H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 78); ( S )-6-(((3,3-difluorocyclopentyl)amino)methyl)-2-(5-(1-(4-methyl-4 H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 79); ( S )-6-((2-isopropyl-4-methylpiperazin-1-yl)methyl)-2-(5-(1-(4-methyl-4 ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 80); ( S )-6-(((1-cyclobutylethyl)amino)methyl)-2-(5-(1-(4-methyl-4 H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 81); 2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-(piperidin-1-ylmethyl)-4-(trifluoromethyl)isoindoline-1-one (compound 82); ( S )-6-((3-Fluoropyrrolidone-1-yl)methyl)-2-(5-(1-(4-methyl-4 ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 83); 2-(5-(1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-(((1-methylcyclopropyl)amino)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 84); 2-(5-((1 s ,3 s )-3-methyl-1-(4-methyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-(piperidin-1-ylmethyl)-4-(trifluoromethyl)isoindoline-1-one (compound 85); 6-(((3 S 5 R )-3,5-dimethylpiperidin-1-yl)methyl)-2-(5-((1 s ,3 S )-3-methyl-1-(4-methyl-4- H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 86); 6-((( S )-2-isopropyl-4-methylpiperazin-1-yl)methyl)-2-(5-((1 s ,3 R )-3-methyl-1-(4-methyl-4- H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 87); 6-((cyclohexylamino)methyl)-2-(5-((1 s ,3 s )-3-methyl-1-(4-methyl-4- H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 88); 2-(5-((1 s ,3 s )-3-methyl-1-(4-methyl-4- H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-(((1-methylcyclopropyl)amino)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 89); 6-(((( S )-1-Cyclobutylethyl)amino)methyl)-2-(5-((1 s ,3 R )-3-methyl-1-(4-methyl-4- H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 90); 2-(5-((1 s ,3 R )-1-(4-ethyl-4 H -1,2,4-triazol-3-yl)-3-methylcyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((( S )-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 91); ( S )-2-(5-(1-(4-ethyl- ... H -1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 92); ( S )-2-(5-(5-(4-ethyl-4 H -1,2,4-triazol-3-yl)spiro[2.3]hexane-5-yl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 93); ( S )-2-(5-(3-((4-methyl- ... H -1,2,4-triazol-3-yl)methyl)oxetane-3-yl)-2,3-dihydrobenzofuran-7-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindoline-1-one (compound 94); ( S )-6-((2-isopropyl-4-methylpiperazin-1-yl)methyl)-2-(5-(3-((4-methyl-4) H -1,2,4-triazol-3-yl)methyl)oxetane-3-yl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 95); 6-((cyclohexylamino)methyl)-2-(5-(3-((4-methyl-4-methyl) H -1,2,4-triazol-3-yl)methyl)oxetane-3-yl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 96); and ( S )-6-(((3,3-difluorocyclopentyl)amino)methyl)-2-(5-(3-((4-methyl-4 H -1,2,4-triazol-3-yl)methyl)oxetane-3-yl)-2,3-dihydrobenzofuran-7-yl)-4-(trifluoromethyl)isoindoline-1-one (compound 97).
11. A pharmaceutical composition for the prevention or treatment of diseases associated with Casitas B-cell lymphoma-b (Cbl-b), comprising a compound of Formula 1 as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, as an active ingredient and a pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 11, wherein the disease associated with Cbl-b is selected from the group consisting of solid tumors, hematologic malignancies, radiation- or drug-resistant cancers, and metastatic cancers.
13. The pharmaceutical composition of claim 11, wherein the disease associated with Cbl-b is selected from the group comprising: triple-negative breast cancer, breast cancer, male breast cancer, ovarian cancer, cervical cancer, endometrial cancer, uterine sarcoma, vaginal cancer, female genital tumors, female external genital cancer, female urethral cancer, prostate cancer, penile cancer, male genital tumors, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, small bowel cancer, colorectal cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, thyroid cancer, oral cancer, thoracic tumors, small cell lung cancer, non-small cell lung cancer, thymoma, mediastinal tumors, esophageal cancer, laryngeal cancer, oropharyngeal cancer, nasal / paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, brain cancer, brain tumors, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, craniopharyngioma, ependymoma, brainstem tumors, head and neck cancers, and skin cancer.