SOS1 inhibitors and uses thereof

Abstract

The present disclosure relates to a compound of formula (I) The present disclosure provides compounds of TIFF2024501280000094.tif4060, pharma- ceutically acceptable salts or stereoisomers, and their use in treating conditions, diseases or disorders in which the inhibition of the interaction between SOS1 and RAS family proteins or RAC1 is therapeutically beneficial, particularly in treating neoplastic diseases.The present disclosure also features compositions containing the same, as well as methods of using and making the same.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to International Patent Application No. PCT / CN2020 / 138288, filed December 22, 2020. The entire contents of the above-mentioned application are incorporated herein by reference. [Background technology]

[0002] RAS family proteins, including KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog) and HRAS (Harvey murine sarcoma viral oncogene), and any mutants thereof, are small GTPases that exist in cells in either GTP-bound or GDP-bound states (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Nimnual et al., Sci. STKE., 2002, 2002(145):pe36). RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rates (Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-35). Binding of GTPase-activating proteins (GAPs), such as NF1, increases the GTPase activity of RAS family proteins. Binding of guanine nucleotide exchange factors (GEFs), such as SOS1 (Son of Sevenless 1), promotes the release of GDP from RAS family proteins, allowing GTP binding (Chardin et al., Science, 1993, 260(51 12):1338-43). When in the GTP-bound state, RAS family proteins are active and associate with effector proteins, including C-RAF and phosphoinositide 3-kinase (PI3K), to promote the RAF / mitogen- or extracellular signal-regulated kinase (MEK / ERK) pathway, the PI3K / AKT / mammalian target of rapamycin (mTOR) pathway, and the RaIGDS (Ral guanine nucleotide dissociation stimulator) pathway (McCormick et al., J. Mol. Med. (Berl). 2016, 94(3):253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6). These pathways affect diverse cellular processes, such as proliferation, survival, metabolism, motility, angiogenesis, immunity and growth (Young et al., Adv. Cancer Res. 2009, 102:1-17; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6).

[0003] Cancer-associated mutations in RAS family proteins suppress these intrinsic and GAP-induced GTPase activities, leading to an expansion of the population of GTP-bound / active RAS family proteins (McCormick et al., Expert Opin. Ther. Targets. 2015, 19(4):451-4; Hunter et al., Mol. Cancer Res. 2015, 13(9):1325-35). This in turn leads to sustained activation of downstream effector pathways of RAS family proteins (e.g., MEK / ERK, PI3K / AKT / mTOR, RaIGDS pathways). KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are found in a variety of human cancers, including lung, colorectal, and pancreatic cancers (Cox et al., Nat. Rev. Drug Discov. 2014, 13(11):828-51). Mutations in HRAS (e.g., amino acids G12, G13, Q61) and NRAS (e.g., amino acids G12, G13, Q61, A146) are also found in a variety of human cancer types, but typically at lower frequencies than KRAS mutations (Cox et al., Nat. Rev. Drug Discov. 2014, 13(11):828-51). Alterations (e.g., mutations, overexpression, gene amplification) in RAS family proteins have been described as a resistance mechanism to cancer drugs, such as the EGFR antibodies cetuximab and panitumumab (Leto et al., J. Mol. Med. (Berl). 2014 July; 92(7):709-22) and the EGFR tyrosine kinase inhibitor osimertinib / AZD9291 (Ortiz-Cuaran et al., Clin. Cancer Res., 2016, 22(19):4837-47; Eberlein et al., Cancer Res., 2015, 75(12):2489-500).

[0004] Son of Sevenless 1 (SOS1) is the human homolog of Son of Sevenless, an originally identified Drosophila protein (Pierre et al., Biochem. Pharmacol., 2011, 82(9):1049-56; Chardin et al., Cytogenet. Cell. Genet., 1994, 66(1):68-9). The SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multidomain protein with two tandem N-terminal histone domains (HDs), followed by a Dbl homology domain (DH), a Pleckstrin homology domain (PH), a helical linker (HL), a RAS exchange motif (REM), a CDC25 homology domain, and a C-terminal proline-rich domain (PR). SOS1 has two binding sites for RAS family proteins, a catalytic site that binds GDP-bound RAS family proteins and promotes guanine nucleotide exchange, and an allosteric site that binds GTP-bound RAS family proteins and further enhances the catalytic GEF function of SOS1 (Freedman et al., Proc. Natl. Acad. Sci. USA, 2006, 103(45):16692-7; Pierre et al., Biochem. Pharmacol., 2011, 82(9):1049-56). Published data indicate a critical involvement of SOS1 in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al., Nat. Commun., 2012, 3:168). Depletion of SOS1 levels reduced the growth rate and survival of tumor cells with KRAS mutations, but no effect was observed in KRAS wild-type cell lines. Introduction of SOS1 mutated at its catalytic site could not rescue the effects of SOS1 loss, demonstrating an essential role for SOS1 GEF activity in KRAS mutant cancer cells.

[0005] SOS1 is critically involved in the activation of RAS family protein signaling in cancer by mechanisms other than mutations in RAS family proteins. SOS1 interacts with the adaptor protein Grb2, and the resulting SOS1 / Grb2 complex binds to activated / phosphorylated receptor tyrosine kinases (e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A / B, FGFR1 / 2 / 3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2 / 3, AXL) (e.g., Pierre et al., Biochem. Pharmacol., 2011, 82(9):1049-56). SOS1 is also recruited to other phosphorylated cell surface receptors, such as the T cell receptor (TCR), B cell receptor (BCR) and monocyte colony-stimulating factor receptor (Salojin et al., J. Biol. Chem. 2000, 275(8):5966-75). This localization of SOS1 to the plasma membrane in close proximity to RAS family proteins allows SOS1 to promote RAS family protein activation. SOS1 activation of RAS family proteins can also be mediated by SOS1 / Grb2 interaction with the BCR-ABL oncoprotein, which is commonly found in chronic myeloid leukemia (Kardinal et al., 2001, Blood, 98:1773-81; Sini et al., Nat. Cell Biol. 2004, 6(3):268-74). Moreover, alterations in SOS1 are associated with cancer. SOS1 mutations have been found in embryonal rhabdomyosarcomas, testicular Sertoli cell tumors, granular cell tumors of the skin (Denayer et al., Genes Chromosomes Cancer, 2010, 49(3):242-52), and lung adenocarcinoma (Cancer Genome Atlas Research Network. Nature. 2014, 511(7511):543-50).On the other hand, overexpression of SOS1 has been described in bladder cancer (Watanabe et al., IUBMB Life., 2000, 49(4):317-20) and prostate cancer (Timofeeva et al., Int. J. Oncol., 2009, 35(4):751-60). In addition to cancer, inherited SOS1 mutations are implicated in the pathogenesis of RASopathies such as Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC) and hereditary gingival fibromatosis type 1 (Pierre et al., Biochem. Pharmacol., 2011, 82(9):1049-56).

[0006] SOS1 is also a GEF for the activation of the GTPase RAC1 (Ras-related C3 botulinum toxin substrate 1) (Innocenti et al., J. Cell Biol., 2002, vol. 156(1):125-36). RAC1, like the RAS family proteins, is involved in the pathogenesis of various human cancers and other diseases (Bid et al., Mol. Cancer Ther., 2013, vol. 12(10):1925-34).

[0007] Son of Sevenless 2 (SOS2), the homolog of SOS1 in mammalian cells, also acts as a GEF for the activation of RAS family proteins (Pierre et al., Biochem. Pharmacol., 2011, 82(9):1049-56; Buday et al., Biochim. Biophys. Acta., 2008, 1786(2):178-87). Published data from mouse knockout models suggest redundant roles for SOS1 and SOS2 in homeostasis in adult mice. Germline knockout of SOS1 in mice results in lethality during mid-embryonic gestation (Qian et al., EMBO J., 2000, 19(4):642-54), whereas systemic conditional SOS1 knockout adult mice are viable (Baltanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78). SOS2 gene targeting did not result in any overt phenotype in mice (Esteban et al., Mol. Cell. Biol., 2000, 20(17):6410-3). In contrast, double knockout of SOS1 and SOS2 results in rapid lethality in adult mice (Baltanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78). These published data suggest that selective targeting of individual SOS isoforms (e.g., selective SOS1 targeting) may be adequately tolerated to achieve a therapeutic index between SOS1 / RAS family protein-driven cancers (or other SOS1 / RAS family protein pathologies) and normal cells and tissues.

[0008] Selective pharmacological inhibition of the binding of the SOS1 catalytic site to RAS family proteins is expected to prevent SOS1-mediated activation of RAS family proteins to their GTP-bound forms. Such SOS1 inhibitor compounds are expected to result in inhibition of cellular signaling downstream of RAS family proteins (e.g., ERK phosphorylation). In cancer cells associated with a dependency on RAS family proteins (e.g., KRAS mutant cancer cell lines), SOS1 inhibitor compounds are expected to achieve anti-cancer efficacy (e.g., inhibition of proliferation, survival, metastasis, etc.). SOS1:RAS family protein binding (nanomolar IC 50 value) and ERK phosphorylation in cells (nanomolar levels of IC 50 High potency for inhibition of SOS1 (value) is a desirable feature for an SOS1 inhibitor compound. Additionally, a desirable feature of an SOS1 inhibitor compound would be selective inhibition of SOS1 versus SOS2. This conclusion is based on the viable phenotype of SOS1 knockout mice and the lethality of SOS1 / SOS2 double knockout mice, as described above.

[0009] These characteristics are not fully achieved by the previously described SOS1 inhibitor compounds. In the last decades, RAS family protein-SOS1 protein interactions have been increasingly recognized. To date, several efforts to identify and optimize binders target either the effector binding site of RAS or the catalytic binding site of SOS1 (for a selective review, see Lu et al., ChemMedChem. 2016, 11(8):814-21), but have had limited success.

[0010] Recently, activating small molecules have been identified that bind to a lipophilic pocket of SOS1 that is close to the RAS binding site (Bums et al., Proc. Natl. Acad. Sci. 2014, 111(9):3401-6). However, binding of these molecules appears to increase nucleotide exchange, thereby causing activation of RAS instead of inactivation.

[0011] In an effort to stabilize the protein-protein interaction of RAS family proteins with SOS1 and prevent the reloading of RAS family proteins with GTP, several different fragments were subsequently identified (Winter et al., J. Med. Chem. 2015, 58(5):2265-74). However, the reversible binding of the fragments to SOS1 did not translate into a measurable effect of nucleotide exchange, and only a weak effect was observed with the fragments covalently bound to RAS.

[0012] Recently, there have also been studies combining rational design and screening platforms to identify small molecule inhibitors of SOS1, i.e. compounds that bind to SOS1 and inhibit protein-protein interactions with RAS family proteins (Evelyn et al., Chem. Biol. 2014, vol. 21(12):1618-28; Evelyn et al., J. Biol. Chem. 2015, vol. 290(20):12879-98; Zheng et al., WO2016 / 077793). Compounds with slight inhibitory effects on SOS1 have been identified, but with weak effects on guanine nucleotide exchange and regulation of cell signaling (e.g., ERK phosphorylation). WO2018 / 115380 and WO2018 / 172250 disclose quinazoline-based SOS inhibitors.

[0013] Thus, there is a need for new compounds that modulate SOS1 activity for the treatment of diseases and disorders, such as neoplastic diseases. Summary of the Invention [Means for solving the problem]

[0014] The present disclosure provides SOS1 inhibitors, such as compounds of structural formula (I), (II), (III-A) or (III-B), pharma- ceutically acceptable salts, stereoisomers and pharmaceutical compositions thereof. Surprisingly, it has been found that the compounds disclosed herein significantly improve human liver microsome stability and effectively inhibit SOS1 activity.

[0015] [ka]

[0016] The present disclosure further provides methods of using the compounds disclosed herein (e.g., compounds of structural formula (I), (II), (III-A) or (III-B)), pharma- ceutically acceptable salts, stereoisomers, or pharmaceutical compositions thereof, to inhibit the activity of SOS1.

[0017] The present disclosure further provides methods for using the compounds disclosed herein (e.g., compounds of structural formula (I), (II), (III-A) or (III-B)), pharma- ceutically acceptable salts, stereoisomers or pharmaceutical compositions thereof, for treating conditions, diseases or disorders in which inhibition of the interaction of SOS1 with RAS family proteins or RAC1 would be of therapeutic benefit, particularly in the treatment of oncological diseases.

[0018] In one aspect, the disclosure provides a compound of any one of the formulas described herein (e.g., structural formulas (I), (II), (III-A) or (III-B)), a pharma- ceutically acceptable salt or stereoisomer thereof.

[0019] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of any one of the formulas described herein (e.g., structural formulas (I), (II), (III-A) or (III-B)), a pharma- ceutically acceptable salt or stereoisomer thereof, as defined in any one of the embodiments described herein, in a mixture with at least one pharma- ceutically acceptable carrier.

[0020] In another aspect, the disclosure provides a compound of any one of the formulas described herein (e.g., structural formulas (I), (II), (III-A) or (III-B)), a pharma- ceutically acceptable salt or stereoisomer thereof, as defined in any one of the embodiments described herein, for use as a medicament.

[0021] In another aspect, the disclosure provides a compound of any one of the formulas described herein (e.g., structural formulas (I), (II), (III-A) or (III-B)), a pharma- ceutically acceptable salt or stereoisomer thereof, as defined in any one of the embodiments described herein, for use in the treatment of a condition, disease or disorder in which inhibition of the interaction of SOS1 with a RAS family protein or RAC1 would be of therapeutic benefit, in particular in the treatment of a neoplastic disease.

[0022] In another aspect, the present disclosure provides the use of a compound of any one of the formulas described herein (e.g., structural formulas (I), (II), (III-A) or (III-B)), a pharma- ceutically acceptable salt or stereoisomer thereof, as defined in any one of the embodiments described herein, for the manufacture of a medicament for treating a condition, disease or disorder in which inhibition of the interaction of SOS1 with a RAS family protein or RAC1 would be of therapeutic benefit, in particular in the treatment of a neoplastic disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] 1.Compound In a first embodiment, the present disclosure provides a compound of formula (I):

[0024] [ka]

[0025] A compound represented by the formula: Ring A is a 3- to 12-membered carbocyclyl, a 3- to 12-membered heterocyclyl, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; R 1 is hydrogen, halogen, C 1~6 Alkyl or C 3~6 cycloalkyl, R 1 The C represented by 1~6 Alkyl or C 3~6 cycloalkyl is optionally substituted with one to more groups selected from halogen and -OH; V is N or CR 2 and; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -OR 2a , -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -SO2R 2a , -SO2NR 2a R 2b , -P(O)R 2a R 2b , -NR 2a C(O)R 2b , -NR 2a C(O)OR 2b , -NR 2a SO2R 2b , -NR 2a SO2NR 2b R 2c , 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; R 2 The C represented by 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl may be selected from one or more R 2d is optionally substituted by; R 2a , R 2b and R 2c are independently hydrogen, C 1~6 selected from the group consisting of alkyl, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; or R 2a and R 2b Or R 2b and R 2c together with the N or P atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl; R 2a , R 2b Or R 2c or R 2a , R 2b Or R 2c In the group represented by 1~6 Alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl may optionally be one or more R 2d Replaced by; R 2d is, at each occurrence, hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 2e , -NR 2e R 2f , -C(O)R 2e , -C(O)OR 2e , -C(O)NR 2e R 2f , -SO2R 2e , -SO2NR 2e R 2f , -P(O)R 2e R 2f , -NR 2e C(O)R 2f , -NR 2e C(O)OR 2f , -NR 2e SO2R 2f , -NR 2e SO2NR 2f R 2g , 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; R 2e , R 2f and R 2g are independently hydrogen and C 1~6 selected from the group consisting of alkyl; X is N or CR 3 and; R 3 is hydrogen, halogen or C 1~3 is alkyl; R 4 is hydrogen or C 1~6 is alkyl; R 5 is hydrogen, C 1~6 alkyl, 3- to 6-membered monocyclic carbocyclyl, or 4- to 6-membered monocyclic heterocyclyl; R 5 The C represented by 1~6 The alkyl, 3- to 6-membered monocyclic carbocyclyl, or 4- to 6-membered monocyclic heterocyclyl is optionally substituted with one or more groups selected from halogen and -OH; R 6 is hydrogen, -OH, halogen, -CN, oxo, C 1~6 Alkyl, C 1~6 Alkoxy, -SO2R 6a , -SO2NR 6a R 6b , -P(O)R 6a R 6b , -C(O)NR 6a R 6b , -NR 6a C(O)R 6a , -NR 6a C(O)NR 6a R 6b , -(CH2) s NR 6a R 6b , -O(CH2) t NR 6a R 6b , 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; R 6 The C represented by 1~6 Alkyl, C 1~6Alkoxy, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl may be one to more R 6c is optionally substituted by; R 6a and R 6b are independently hydrogen or C 1~6 alkyl or R 6a and R 6b together with the N or P atom to which they are attached form a 4- to 7-membered heterocyclyl; s is an integer from 0 to 3; t is an integer from 2 to 4; R 6c is hydrogen, -OH, halogen, -CN, oxo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, -NR 6a R 6b , -SO2R 6a , -SO2NR 6a R 6b , -C(O)NR 6a R 6b , -P(O)R 6a R 6b , -NR 6a C(O)R 6a , -NR 6a C(O)NR 6a R 6b , -(CH2) s NR 6a R 6b or -O(CH2) t NR 6a R 6b ;R 6c The C represented by 1~6 Alkyl or C 3~6 Cycloalkyl is substituted with halogen, -OH and -NR 6a R 6b and optionally substituted with one to more groups selected from; R 7 and R 8 are independently hydrogen, C 1~6 Alkyl, C 3~6 Alkenyl, C3~6 Alkynyl, C 2~6 alkoxy, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; R 7 Or R 8 The C represented by 1~6 Alkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 2~6 Alkoxy, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl may be one or more R 7a or R 7 and R 8 together with the N atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl; said 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl may be selected from the group consisting of one or more R 7b and optionally substituted; R 7a is hydrogen, halogen, -CN, C 1~6 Alkyl, -OR 7c , -NR 7c R 7d , -C(O)R 7c , -C(O)OR 7c , -C(O)NR 7c R 7d , -SO2R 7c , -P(O)R 7c R 7d , -SO2NR 7c R 7d , -NR 7c C(O)R 7d , -NR 7c C(O)OR 7d , -NR 7c SO2R 7d , -NR 7c SO2NR 7d R 7e , 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; R 7a The C represented by1~6 Alkyl, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl may be one or more R 7f is optionally substituted by; R 7b is hydrogen, halogen, -CN, oxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, -OR 7c , -NR 7c R 7d , -C(O)R 7c , -C(O)OR 7c , -C(O)NR 7c R 7d , -SO2R 7c , -P(O)R 7c R 7d , -SO2NR 7c R 7d , -NR 7c C(O)R 7d , -NR 7c C(O)OR 7d , -NR 7c SO2R 7d , -NR 7c SO2NR 7d R 7e , 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; R 7b C represented by 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl may be selected from one or more R 7f is optionally substituted by; R 7c , R 7d and R 7e are independently hydrogen, C 1~6 selected from the group consisting of alkyl, 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; or R7c and R 7d together with the N or P atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl; R 7c , R 7d Or R 7e or R 7c , R 7d Or R 7e The C in the group represented by 1~6 Alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is one or more R 7f is optionally substituted by; R 7f is, at each occurrence, hydrogen, halogen, -CN, or OH; n is 0, 1, 2, or 3; The heterocyclyl contains 1 to 4 heteroatoms selected from O, N, and S; the heteroaryl contains 1 to 4 heteroatoms selected from O, N, and S. to provide.

[0026] In a second embodiment, the present disclosure provides a compound according to the first embodiment, comprising the compound of formula II

[0027] [ka]

[0028] or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the definitions of the variables are provided in the first embodiment. In a third embodiment, the present disclosure provides a compound according to the first and second embodiments, a pharma- ceutically acceptable salt or stereoisomer thereof. (In the formula, Ring A is a 3- to 10-membered carbocyclyl, a 4- to 10-membered heterocyclyl, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; R 1 is hydrogen, C 1~4 Alkyl or C 3~6 is cycloalkyl; R 2 is hydrogen, halogen, -CN, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, -OR 2a , -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -NR 2a C(O)R 2b , -NR 2a C(O)OR 2b , 3-6 membered monocyclic carbocyclyl, 3-6 membered monocyclic heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; R 2 The C represented by 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is selected from 1 to 3 R 2d is optionally substituted by; R 2a and R 2b are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 hydroxyalkyl; or R 2a and R 2b together with the N atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl; R 2d is, at each occurrence, hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, -OR 2e , -NR 2e R 2f , -SO2R 2e , -P(O)R 2e R 2f , COOR 2e ,CONR 2eR 2f , a 3- to 6-membered monocyclic carbocyclyl, a 3- to 6-membered monocyclic heterocyclyl, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; R 2e and R 2f are independently hydrogen and C 1~6 selected from the group consisting of alkyl; R 5 is hydrogen, C 1~4 alkyl, 3- to 5-membered monocyclic carbocyclyl, or 4- to 5-membered monocyclic heterocyclyl; R 6 is hydrogen, -OH, halogen, -CN, oxo, C 1~6 Alkyl, -(CH2) s NR 6a R 6b , 3-6 membered monocyclic carbocyclyl, 3-6 membered monocyclic heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; R 6 The C represented by 1~6 Alkyl, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl may optionally be further optionally joined by one or more R 6c Replaced by; R 6a and R 6b are independently hydrogen or C 1~4 is alkyl; s is an integer from 0 to 2; R 6c is hydrogen, -OH, halogen, -CN, oxo, C 1~6 Alkyl, -NR 6a R 6b or -(CH2) s NR 6a R 6b ;R 6c The C represented by 1~6 The alkyl is optionally substituted with one to more groups selected from halogen and -OH; R 7 and R 8 are independently hydrogen, C 1~4 Alkyl, C 3~4 Alkenyl, C3~4 Alkynyl, C 2~4 alkoxy, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R 7 Or R 8 The C represented by 1~4 Alkyl, C 3~4 Alkenyl, C 3~4 Alkynyl, C 2~4 Alkoxy, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl may be one or more R 7a or R 7 and R 8 together with the N atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl; said 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl may be selected from the group consisting of 1 to 3 R 7b and optionally substituted; R 7a is hydrogen, halogen, -CN, C 1~6 Alkyl, -OR 7c , or -NR 7c R 7d and; R 7b is hydrogen, halogen, -CN, oxo, C 1~6 Alkyl, C 1~6 Alkoxy, -OR 7c , -NR 7c R 7d , -C(O)R 7c , -C(O)OR 7c , -SO2R 7c or 5-10 membered heteroaryl, R 7b C represented by 1~6 Alkyl, C 1~6 Alkoxy, or 5-10 membered heteroaryl, may be one or more R 7f is optionally substituted by; R 7c Or R 7d are independently hydrogen, C 1~4selected from the group consisting of alkyl, 3-6 membered monocyclic carbocyclyl, 4-8 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl; or R 7c and R 7d together with the N atom to which they are attached form a 4- to 8-membered heterocyclyl or a 5- to 10-membered heteroaryl; R 7c or R 7d The C represented by 1~4 Alkyl, 3-6 membered monocyclic carbocyclyl, 4-8 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is 1-3 R 7f and optionally substituted; R 7f is hydrogen, halogen, -CN or OH at each occurrence. to provide.

[0029] In a fourth embodiment, the present disclosure relates to a compound according to any one of the first to third embodiments, a pharma- ceutically acceptable salt or stereoisomer thereof. (In the formula, R 2 is hydrogen, halogen, -CN, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 alkynyl, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R 2 The C represented by 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl may each be selected from 1 to 3 R 2d is optionally substituted by; R 2d is, at each occurrence, hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, -OR 2e , -NR 2e R 2f, -SO2R 2e , -P(O)R 2e R 2f , COOR 2e ,CONR 2e R 2f , a 3- to 6-membered monocyclic carbocyclyl, a 3- to 6-membered monocyclic heterocyclyl, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; R 2e and R 2f are independently hydrogen and C 1~6 alkyl) to provide.

[0030] In a fifth embodiment, the present disclosure provides a compound according to any one of the first to fourth embodiments, a pharma- ceutically acceptable salt or stereoisomer thereof. (In the formula, R 7 and R 8 are independently hydrogen, C 1~4 Alkyl, C 3~4 Alkenyl, C 3~4 Alkynyl; R 7 Or R 8 The C represented by 1~4 Alkyl, C 3~4 Alkenyl, C 3~4 Alkynyl is one or more R 7a or R 7 and R 8 together with the N atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5-membered heteroaryl, each of which is 1 to 3 R 7b and optionally substituted; R 7a is hydrogen, halogen, -CN, C 1~6 Alkyl, -OR 7c , or -NR 7c R 7d and; R 7b is hydrogen, halogen, -CN, oxo, -OH, C 1~6 Alkyl, C 1~6 Alkoxy, -NR 7c R7d , -C(O)R 7c , -C(O)OR 7c , -SO2R 7c or 5-10 membered heteroaryl, R 7b C represented by 1~6 Alkyl, C 1~6 Alkoxy, or 5-10 membered heteroaryl, may be one or more R 7f is optionally substituted by; R 7c Or R 7d are independently hydrogen, C 1~4 selected from the group consisting of alkyl, 3-6 membered monocyclic carbocyclyl, 4-8 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl; or R 7c and R 7d together with the N atom to which they are attached form a 4- to 8-membered heterocyclyl or a 5- to 10-membered heteroaryl; R 7c or R 7d The C represented by 1~4 Alkyl, 3- to 6-membered carbocyclyl, 4- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is selected from 1 to 3 R 7f and optionally substituted; R 7f is hydrogen, halogen, -CN or OH at each occurrence. to provide.

[0031] In a sixth embodiment, the present disclosure provides a compound according to the first, second, third, fourth or fifth embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof. (In the formula, Ring A is a 3- to 6-membered monocyclic cycloalkyl, a 4- to 6-membered monocyclic heterocyclyl, a phenyl, or a 5- to 10-membered heteroaryl; R 6 is hydrogen, -OH, halogen, -CN, C 1~6 Alkyl or -(CH2) s NR 6a R 6b ;R 6 The C represented by 1~6The alkyl is optionally substituted with one to more groups selected from halogen and -OH; R 6a and R 6b are independently hydrogen or C 1~4 is alkyl; (s is 0 or 1) to provide.

[0032] In a seventh embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth or sixth embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof, wherein Ring A is cyclopropyl, phenyl, thiophenyl or indole. to provide.

[0033] In an eighth embodiment, the disclosure provides a compound according to the first, second, third, fourth, fifth, sixth or seventh embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the compound has formula (III-A) or (III-B):

[0034] [ka]

[0035] It is expressed by: Definitions of the variables are provided in any one of the first to seventh embodiments. In a ninth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof, wherein R 6 is hydrogen, halogen, C 1~4 Alkyl or -(CH2)NR 6a R 6b ;R 6 The C represented by 1~4 Alkyl is optionally substituted with one to more groups selected from halogen and -OH; R 6a and R 6b are independently hydrogen or C 1~4 (It is alkyl) to provide.

[0036] In a tenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof, wherein R 5 is hydrogen, methyl or ethyl, optionally methyl).

[0037] In an eleventh embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof. (In the formula, R 2 is hydrogen, halogen, -CN, C 1~4 Alkyl, C 2~4 alkenyl, 3-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl or 5-10 membered heteroaryl; R 2 The C represented by 1~4 Alkyl, 3-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl, or 5-10 membered heteroaryl is selected from 1-3 R 2d is optionally substituted by; R 2d is, at each occurrence, hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, -OR 2e , -NR 2e R 2f , -SO2R 2e , -P(O)R 2e R 2f , COOR 2e ,CONR 2e R 2f , 3-6 membered monocyclic carbocyclyl, 3-6 membered monocyclic heterocyclyl, phenyl, or 5-10 membered heteroaryl; R 2e and R 2f are independently hydrogen and C 1~6 alkyl) to provide.

[0038] In a twelfth embodiment, the present disclosure relates to a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof. (In the formula, R 2 is phenyl or 5-10 membered heteroaryl; said phenyl or 5-10 membered heteroaryl is selected from 1-3 R 2d is optionally substituted by; R 2d represents hydrogen, halogen, -CN, C at each occurrence. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, -OR 2e , -NR 2e R 2f , -SO2R 2e , -P(O)R 2e R 2f , COOR 2e ,CONR 2e R 2f , 3-6 membered monocyclic carbocyclyl, 3-6 membered monocyclic heterocyclyl, phenyl, or 5-10 membered heteroaryl; R 2e and R 2f are independently hydrogen and C 1~6 alkyl) to provide.

[0039] In a thirteenth embodiment, the present disclosure provides a compound according to the twelfth embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof, wherein R 2 is phenyl, pyridyl, pyrimidyl, imidazolyl, pyrazolyl, imidazo[1,2-a]pyrimidine, imidazo[1,2-a]pyridine, or triazolo[4,3-a]pyridine, each of which is 1 to 3 R 2d Optionally substituted by R 2d is selected from the group consisting of hydrogen, halogen, -CN, -CH3, -CF3, -NH2, -S(O)2Me, -OCH3, COOH, CONH2, COOMe, -P(O)(CH3)2, -CH2CH2OH and -CH2CHF2. to provide.

[0040] In a fourteenth embodiment, the present disclosure provides a compound according to the thirteenth embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof, wherein R 2 is phenyl or pyridyl; each of which is 1 to 3 R 2d Optionally substituted by R 2d is selected from the group consisting of hydrogen, halogen, -CN, -CH3, -CF3, -NH2, -S(O)2Me, -OCH3, COOH, CONH2, COOMe, -P(O)(CH3)2, -CH2CH2OH and -CH2CHF2.

[0041] In a fifteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth or fourteenth embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof, wherein R 7 and R 8 together with the N atom to which they are attached form a 5- to 10-membered heterocyclyl or a 5-membered heteroaryl, each of which is halogen, -CN, oxo, -OH, C 1~6 Alkyl, C 1~6 Alkoxy, -C(O)R 7c , -C(O)OR 7c and pyridinyl optionally substituted with CN; R 7c are independently hydrogen, optionally replaced with -CN or -OH; 1~4 alkyl) to provide.

[0042] In a sixteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth or fourteenth embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof, wherein R 7 and R 8 are independently hydrogen or C 1~4alkyl, and optionally R 7 and R 8 is methyl).

[0043] In a seventeenth embodiment, the present disclosure relates to a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, fifteenth or sixteenth embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof. (In the formula, R 2 are H, F, Br, CH3, -CN,

[0044] [ka]

[0045] is selected from the group consisting of R 2d is selected from the group consisting of hydrogen, halogen, -CN, -CH3, -CF3, -NH2, -S(O)2Me, -OCH3, COOH, CONH2, COOMe, -P(O)(CH3)2, -CH2CH2OH and -CH2CHF2. to provide.

[0046] In an eighteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or seventeenth embodiment, a pharma- ceutically acceptable salt or stereoisomer thereof, wherein R 7 and R 8 together with the atoms to which they are attached,

[0047] [ka]

[0048] forming a heterocyclyl selected from the group consisting of Each of these is -F, -CN, oxo, -OH, methyl, isopropyl, methoxyl, -C(O)R 7c , -C(O)OR 7cand pyridinyl, optionally substituted with CN. to provide.

[0049] In one embodiment, the disclosure provides a compound selected from the compounds disclosed in the Examples and Table 1, a pharma- ceutically acceptable salt, or stereoisomer thereof.

[0050] [Table 1-1]

[0051] [Table 1-2]

[0052] [Table 1-3]

[0053] [Table 1-4]

[0054] [Table 1-5]

[0055] [Table 1-6]

[0056] [Table 1-7]

[0057] [Table 1-8]

[0058]

Table 1-9

[0059]

Table 1-10

[0060]

Table 1-11

[0061]

Table 1-12

[0062]

Table 1-13

[0063]

Table 1-14

[0064]

Table 1-15

[0065]

Table 1-16

[0066]

Table 1-17

[0067]

Table 1-18

[0068]

Table 1-19

[0069] [Table 1-20]

[0070] [Table 1-21]

[0071] [Table 1-22]

[0072] [Table 1-23]

[0073] [Table 1-24]

[0074] 2.Definition The term "halogen" as used herein refers to fluoride, chloride, bromide or iodide.

[0075] The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy” or “haloalkyl”, refers to a group of the formula —C n H (2n+1) Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms, i.e., C 1~6 As used herein, "C 1~6 An "alkyl" group means a group having from 1 to 6 carbon atoms in a straight or branched arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, and the like.

[0076] The term “alkylene” as used herein refers to a straight or branched chain alkyl group of the formula -C n H 2n - means a divalent hydrocarbon radical. Non-limiting examples include ethylene and propylene.

[0077] The term "alkenyl" means an alkyl group in which one or more carbon / carbon single bonds are replaced by a double bond. The term "alkynyl" means an alkyl group in which one or more carbon / carbon single bonds are replaced with a triple bond.

[0078] The term "alkoxy" refers to an alkyl group attached through an oxygen linking atom and is represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0079] The term "haloalkyl" means an alkyl optionally substituted with one or more halogen atoms. The term "hydroxyalkyl" means an alkyl optionally substituted with one or more hydroxyl groups.

[0080] The term "carbocyclyl" refers to any stable non-aromatic hydrocarbon ring having 3-12 carbocyclyl members. In one embodiment, the carbocyclyl is a 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic, or a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, or unsaturated. Any substitutable ring atom may be substituted (e.g., by one or more substituents). Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In one embodiment, carbocyclyl is intended to include bridged, fused, and spirocyclic rings. In a spirocyclic carbocyclyl, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiropentanyl. In a bridged carbocyclyl, the rings share at least two common non-adjacent atoms. Examples of bridged carbocycles include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl. In a fused ring carbocyclyl system, two or more rings may be fused together such that two rings share one common bond. Examples of 2- or 3-fused ring carbocycles include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.

[0081] The term "cycloalkyl" refers to a cyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon group having 3 to 12 ring carbons. In one embodiment, a cycloalkyl can have 3 to 7 ring carbons. Any substitutable ring atom can be substituted (e.g., by one or more substituents). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl can include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyls also include spirocyclic rings (e.g., spirocyclic bicycles in which two rings are joined through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0082] The term "heterocyclyl" or "heterocyclic" refers to a group of 3-12 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone ("3-12 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("3-7 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., bicyclic ("bicyclic heterocyclyl") or tricyclic ("tricyclic heterocyclyl"), polycyclic ring systems including fused, bridged, or spiro ring systems). Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can contain heteroatoms in one or more rings in the polycyclic ring system. Substituents may be present in one or more rings in the polycyclic ring system.

[0083] Spiroheterocyclyl refers to a 5-12 membered polycyclic heterocyclyl having rings bonded through one common carbon atom (called a spiro atom), where the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g. NO), oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms are C, and one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Representative examples of spiroheterocyclyls include, but are not limited to, the following groups:

[0084] [ka]

[0085] Examples include: Fused heterocyclyl refers to a 5-12 membered polycyclic heterocyclyl group, where each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, one or more of the rings may contain one or more double bonds, but at least one of the rings does not have a fully conjugated pi-electron system, said rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, and the remaining ring atoms are C. Representative examples of fused heterocyclyls include, but are not limited to, the following groups:

[0086] [ka]

[0087] Examples include: Bridged heterocyclyl refers to a 5-12 membered polycyclic heterocyclyl group, where any two rings in the group share two unbonded atoms, the rings may have one or more double bonds but do not have a fully conjugated pi-electron system, the rings have one or more heteroatoms as ring atoms selected from the group consisting of nitrogen, quaternary nitrogen, nitric oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, with the remaining ring atoms being C. Representative examples of bridged heterocyclyls include, but are not limited to, the following groups:

[0088] [ka]

[0089] Examples include: Generally, a carbocyclyl, cycloalkyl, or heterocyclyl may be unsubstituted or, where valence allows, substituted with one or more substituents, which may be independently selected from several groups, such as oxo, -CN, halogen, alkyl, and alkoxyl, and optionally the alkyl substituents may be further substituted.

[0090] The term "aryl" refers to a 6- to 10-membered, all-carbon, monocyclic, or polycyclic fused ring (a "fused" ring system means that each ring in the system shares adjacent pairs of carbon atoms with other rings in the system) group that has a completely conjugated pi-electron system. Representative examples of aryl are phenyl and naphthyl.

[0091] The term "heteroaryl" as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon in which at least one of the ring carbon atoms is replaced with a heteroatom independently selected from oxygen, nitrogen and sulfur. Preferably, heteroaryl is C 5~10 Based on aryl, one or more of its ring carbon atoms are replaced with heteroatoms.Heteroaryl groups can be bonded through ring carbon atoms or, if valence allows, through ring nitrogen atoms.Generally, heteroaryls can be unsubstituted or, if valence allows, substituted with one or more substituents, which are independently selected from halogen, OH, alkyl, alkoxyl and amino (e.g., NH2, NHalkyl, N(alkyl)2), and optionally alkyl can be further substituted.

[0092] As used herein, the term "treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., or the amelioration of a symptom thereof, such as alleviation, reduction, modulation, amelioration, or elimination.

[0093] The term "therapeutically effective amount" refers to an amount of an agent (e.g., a compound described herein) effective to treat at least one symptom of a disease or disorder in a patient or subject. The "therapeutically effective amount" of an agent for administration can vary based on the desired activity, the condition of the patient or subject being treated, the dosage form, the method of administration, patient factors such as the patient's sex, genotype, weight and age, the underlying cause of the condition or disease being treated, the route of administration and bioavailability, the persistence of the administered agent in the body, evidence of natriuresis and / or diuresis, the type of formulation, and the potency of the agent. Pharmaceutically acceptable salts The term "pharmaceutical acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without unnecessary toxicity, irritation and allergic reactions within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio.Pharmaceutical acceptable salts are well known in the art.For example, SM Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci., 1977, vol. 66, pp. 1-19.

[0094] Pharmaceutically acceptable salts of the compounds of any one of the above formulas include acid addition and base salts. The present teachings also include pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid) and organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid and succinic acid). Compounds of the present teachings having an acidic group, such as carboxylic acid, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (e.g., sodium and potassium salts) and alkaline earth metal salts (e.g., magnesium and calcium salts).

[0095] Pharmaceutically acceptable salts of compounds of any one of the above formulas may be prepared in three ways: (i) reacting a compound of any one of the above formulas with a desired acid or base; (ii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of any one of the above formulas, or ring-opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid or base; or (iii) converting one salt of a compound of any one of the above formulas into another by reaction with a suitable acid or base or by using a suitable ion exchange column. The composition may be prepared by one or more of the following methods.

[0096] All three reactions are typically carried out in solution. The resulting salt can be precipitated and filtered off or recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to nearly non-ionized.

[0097] Compounds of any one of the above formulas and pharma- ceutically acceptable salts thereof can exist in unsolvated and solvated forms. Stereoisomers and other variations A compound of any one of the above formulae may exhibit one or more types of isomers (e.g., optical isomers, geometric isomers, or tautomers). Such variations are implicit in the compounds of any one of the above formulae defined by reference to the structural features of the compound, and are therefore within the scope of the present disclosure.

[0098] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration, or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers with two or more chiral centers that are not identical and are not mirror images of each other.

[0099] When a compound is named by its chemical name indicating a single enantiomer (e.g., when the configuration is indicated in the chemical name by "R" or "S") or by its structure (e.g., when the configuration is indicated by a "wedge" bond), unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the mixture of the named or depicted enantiomer divided by the total weight of the mixture of both enantiomers.

[0100] When the stereochemistry of a disclosed compound is named or depicted by a structure, and when the named or depicted structure encompasses more than one stereoisomer (e.g., as a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0101] When two stereoisomers are depicted by their chemical names or structures and the chemical names or structures are connected by "and," a mixture of the two stereoisomers is intended. When two stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by "or," either one or the other of the two stereoisomers is intended, but not both.

[0102] When a disclosed compound having a chiral center is depicted by a structure without indicating the configuration at that chiral center, the structure is meant to encompass compounds having an S configuration at that chiral center, compounds having an R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without designating the configuration at that chiral center with "S" or "R," the name is meant to encompass compounds having an S configuration at that chiral center, compounds having an R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center.

[0103] A racemic mixture means 50% of one enantiomer and 50% of its corresponding enantiomer. When a compound with one chiral center is named or drawn without representing the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms of the compound (e.g., enantiomerically pure, enantiomerically enriched, or racemic). When a compound with two or more chiral centers is named or drawn without representing the stereochemistry of the chiral center, it is understood that the name or structure encompasses all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, or equimolar mixtures of one or more diastereomers (e.g., racemic mixtures)).

[0104] The term "geometric isomer" refers to a compound that contains at least one double bond, which can exist in the cis (also called syn or entgegen (E)) or trans (also called anti or zusammen (Z)) form, as well as mixtures thereof.

[0105] Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ("tautomers") can occur. This can take the form of proton tautomers in compounds of any one of the above formulae that contain, for example, an imino, keto or oxime group, or so-called valence tautomers in compounds that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomer.

[0106] When a geometric isomer is depicted by name or structure, it is understood that the named or depicted isomer is present to a greater extent than another isomer, i.e., the geometric isomeric purity of the named or depicted geometric isomer is greater than 50% by weight, e.g., at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0107] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers / diastereomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, such as an alcohol, or, if the compound of any one of the above formulas contains an acidic or basic moiety, with a base or acid, such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers are converted to the corresponding pure enantiomer by means well known to those skilled in the art. Chiral compounds of any one of the above formulas (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0-50%, typically 2%-20% by volume of isopropanol, and 0-5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate gives an enriched mixture. Chiral chromatography using subcritical and supercritical fluids can be employed. Methods for chiral chromatography useful in some embodiments of the present disclosure are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), Vol. 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249, and references cited therein). Columns can be obtained from Chiral Technologies, Inc., West Chester, Pa., USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan.

[0108] It must be emphasized that compounds of any one of the above formulas may be depicted herein in a single tautomeric form, and all possible tautomeric forms are included within the scope of the present disclosure. 3. Administration and Dosing Typically, the compound of the present disclosure is administered in an amount effective for treating the conditions as described herein.The compound of the present disclosure can be administered as the compound itself, or alternatively as pharmaceutically acceptable salt.For the purpose of administration and dosage, the compound itself or its pharmaceutically acceptable salt is simply referred to as the compound of the present disclosure.

[0109] The compounds of the present disclosure are administered by any suitable route, in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment. The compounds of the present disclosure can be administered orally, rectally, vaginally, parenterally or topically.

[0110] The compounds of the present disclosure can be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

[0111] In another embodiment, the compound of the present disclosure can also be directly administered into bloodstream, into muscle, or into internal organs.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous.Suitable devices for parenteral administration include needle (including microneedle) injector, needle-free injector and infusion technology.

[0112] In another embodiment, the compounds of the present disclosure can be administered topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the present disclosure can be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure can be administered rectally or intravaginally. In another embodiment, the compounds of the present disclosure can be administered directly to the eye or ear.

[0113] The dosage regimen of the disclosed compound and / or the composition containing said compound is based on many factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the specific compound employed. Thus, the dosage regimen may vary widely. In one embodiment, for the treatment of the indicated conditions discussed herein, the total daily dose of the disclosed compound is typically about 0.001 to about 100 mg / kg (i.e. mg of the disclosed compound per kg of body weight).

[0114] For oral administration, the composition may be provided in the form of a tablet containing 0.1 to 500 milligrams of active ingredient for symptomatic adjustment of dosage to the patient. Medicaments typically contain from about 0.01 mg to about 500 mg of active ingredient. Intravenously, doses may range from about 0.01 to 10 mg / kg / min during a constant rate infusion.

[0115] Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammals, such as primates, rodents (mouse, rats, hamsters, rabbits, etc.). In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development. 4. Pharmaceutical Compositions In another embodiment, the present disclosure includes pharmaceutical compositions. Such pharmaceutical compositions include the compounds of the present disclosure present together with a pharma- ceutically acceptable carrier or excipient. Other pharmacologically active substances may also be present.

[0116] As used herein, "a pharma- ceutically acceptable carrier or excipient" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Examples of pharma- ceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof, and isotonic agents, such as sugars, sodium chloride, or polyalcohols, such as mannitol or sorbitol, may be included in the composition. Pharmaceutically acceptable substances, such as wetting agents or minor amounts of auxiliary substances, such as wetting agents or emulsifying agents, preservatives or buffers, that enhance the shelf life or effectiveness of the antibody or antibody portion.

[0117] The compositions of the present disclosure can be in many forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0118] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those typically used for passive immunization of humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0119] The solid dosage form of oral administration can be, for example, in separate units, such as hard or soft capsules, pills, cachets, lozenges or tablets, each of which contains a predetermined amount of at least one compound of the present disclosure. In another embodiment, oral administration can be in powder or granule form. In another embodiment, oral administration form is sublingual, such as lozenges. In such solid dosage forms, the compound of any one of the above formulas is originally combined with one or more adjuvants. Such capsules or tablets can contain controlled release formulations. In the case of capsules, tablets and pills, the dosage form can also contain buffering agents or be prepared with enteric coatings.

[0120] In another embodiment, oral administration can be in liquid dosage form.The liquid dosage form for oral administration includes, for example, pharma- ceutically acceptable emulsion, solution, suspension, syrup and elixir, which contains inert diluent (e.g., water) commonly used in the art.Such compositions can also contain adjuvants, such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweeteners), and / or aromatic agents.

[0121] In another embodiment, the present disclosure comprises a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection and infusion. Injectable preparations (i.e., sterile injectable aqueous or oily suspensions) can be formulated according to the known art using suitable dispersing agents, wetting agents and / or suspending agents.

[0122] In another embodiment, the present disclosure comprises a topical dosage form. "Topical administration" includes, for example, transdermal administration, such as via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments and creams. Topical formulations can include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present disclosure are administered by a transdermal device, administration is accomplished using a patch, either of the reservoir and porous membrane type, or of the solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dustings, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated, see, eg, Finnin and Morgan, J. Pharm. Sci., 88:955-958, 1999.

[0123] Suitable formulations for topical administration to the eye include, for example, eye drops, in which the compound of the present disclosure is dissolved or suspended in a suitable carrier. Typical formulations suitable for intraocular or intraaural administration can be in the form of micronized suspension or solution drops in isotonic pH-adjusted sterile saline. Other suitable formulations for intraocular or intraaural administration include ointments, biodegradable (i.e., absorbable gel sponge, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and particulate or vesicular systems, such as niosomes or liposomes. Polymers, such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers, such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymers, such as gellan gum, can be incorporated together with preservatives, such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0124] For intranasal administration or administration by inhalation, the compounds of the present disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or in the form of an aerosol spray from a pressure container or nebulizer with the use of suitable propellants.The formulation suitable for intranasal administration is typically administered in the form of a dry powder from a dry powder inhaler (either alone or as a mixture in a dry blend with, for example, lactose, or as mixed component particles, for example mixed with phospholipids, for example phosphatidylcholine), or as an aerosol spray from a pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to generate a fine mist) or nebulizer, with or without the use of suitable propellants, for example 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.For intranasal use, the powder can contain a bioadhesive agent, for example chitosan or cyclodextrin.

[0125] In another embodiment, the present disclosure includes a rectal dosage form. Such a dosage form can be, for example, in the form of a suppository. Cocoa butter is a traditional suppository base, although various alternatives can be used as appropriate.

[0126] Other carrier materials and modes of administration known in the pharmaceutical art may also be used.The pharmaceutical compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, including effective formulation and administration procedures.

[0127] The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks.Drug formulation is discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., eds., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999. 5. Treatment Method The present disclosure is directed to SOS1 inhibitor compounds, particularly compounds of formula (I), (II), (III-A) or (III-B) (including all embodiments thereof), which are associated with or regulated by SOS1, and in particular, which are useful in the treatment and / or prevention of diseases and / or conditions in which inhibition of the interaction of SOS1 with RAS family proteins and / or RAC1 is of therapeutic benefit, including, but not limited to, the treatment and / or prevention of cancer.

[0128] In one embodiment, the present disclosure relates to a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof, for use as a medicament.

[0129] In one embodiment, the disclosure relates to a compound of (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof, for use in a method of treatment of the human or animal body.

[0130] In one embodiment, the present disclosure relates to SOS1 inhibitor compounds, in particular compounds of (I), (II), (III-A) or (III-B), pharma- ceutically acceptable salts or stereoisomers thereof, for use in the treatment and / or prevention of diseases and / or conditions in which inhibition of the interaction of SOS1 with RAS family proteins and / or RAC1 is of therapeutic benefit, including but not limited to the treatment and / or prevention of cancer.

[0131] In one embodiment, the present disclosure relates to SOS1 inhibitor compounds, in particular compounds of formula (I), (II), (III-A) or (III-B), pharma- ceutically acceptable salts or stereoisomers thereof, for use in the treatment and / or prevention of cancer.

[0132] In one embodiment, the present disclosure relates to SOS1 inhibitor compounds, in particular compounds of formula (I), (II), (III-A) or (III-B), pharma- ceutically acceptable salts or stereoisomers thereof, for use in methods for the treatment and / or prevention of cancer in the human or animal body.

[0133] In one embodiment, the present disclosure relates to an SOS1 inhibitor compound, in particular a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof, administered before, after or together with at least one other pharmacologically active substance, for use as previously defined.

[0134] In one embodiment, the present disclosure relates to an SOS1 inhibitor compound, or a pharma- ceutically acceptable salt thereof, for use as previously defined, wherein the SOS1 inhibitor compound, or a pharma- ceutically acceptable salt thereof, is administered in combination with at least one other pharmacologically active substance.

[0135] In one embodiment, the present disclosure relates to a compound of formula (I), (II), (III-A) or (III-B), or a pharma- ceutically acceptable salt or stereoisomer thereof, for use as previously defined, wherein the compound, or a pharma- ceutically acceptable salt or stereoisomer thereof is administered in combination with at least one other pharmacologically active substance.

[0136] In one embodiment, the present disclosure relates to a pharmacologically active substance prepared for administration before, after, or together with an SOS1 inhibitor compound or a pharma- ceutically acceptable salt thereof for uses as defined above for the use of a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt thereof or a stereoisomer thereof.

[0137] In one embodiment, the present disclosure relates to a pharmacologically active substance prepared for administration before, after, or together with a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof, for the uses as previously defined for the use of the compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof.

[0138] In one embodiment, the present disclosure relates to an SOS1 inhibitor compound, in particular a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof, for use in a treatment or method of treatment as previously defined.

[0139] In one embodiment, the present disclosure relates to the use of an SOS1 inhibitor compound, in particular a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof, for the preparation of a pharmaceutical composition for the treatment and / or prevention of cancer.

[0140] In one embodiment, the present disclosure relates to the use of an SOS1 inhibitor compound, or a pharma- ceutically acceptable salt thereof, as previously defined, wherein said SOS1 inhibitor compound is administered before, after or together with at least one other pharmacologically active substance.

[0141] In one embodiment, the present disclosure relates to the use of a compound of formula (I), (II), (III-A) or (III-B) as previously defined, a pharma- ceutically acceptable salt or stereoisomer thereof, wherein said compound is administered before, after or together with at least one other pharmacologically active substance.

[0142] In one embodiment, the present disclosure relates to the use of an SOS1 inhibitor compound as defined previously, in particular a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof, for treatment.

[0143] In one embodiment, the present disclosure relates to a method for the treatment and / or prevention of a disease and / or condition in which inhibition of the interaction of SOS1 with a RAS family protein or RAC1 would be therapeutically beneficial, comprising administering to a human a therapeutically effective amount of an SOS1 inhibitor compound, in particular a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof.

[0144] In one embodiment, the present disclosure relates to a method for the treatment and / or prevention of cancer, comprising the step of administering to a human a therapeutically effective amount of an SOS1 inhibitor compound, in particular a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof.

[0145] In one embodiment, the present disclosure relates to a method as previously defined, wherein an SOS1 inhibitor compound, or a pharma- ceutically acceptable salt thereof, is administered before, after or together with at least one other pharmacologically active substance.

[0146] In one embodiment, the present disclosure relates to a method as previously defined, wherein a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof is administered before, after or together with at least one other pharmacologically active substance.

[0147] In one embodiment, the present disclosure relates to a method as previously defined, wherein an SOS1 inhibitor compound, or a pharma- ceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of at least one other pharmacologically active substance.

[0148] In one embodiment, the present disclosure relates to a method as previously defined, wherein a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof is administered in combination with a therapeutically effective amount of at least one other pharmacologically active substance.

[0149] In one embodiment, the present disclosure relates to a method for treatment as previously defined. In one embodiment, the disease / condition / cancer to be treated / prevented using the SOS1 inhibitor compound, the SOS1 inhibitor compound for use, the compound of formula (I), the compound of formula (I) for use, the use for preparation, and the method for treatment and / or prevention as defined herein (above or below) is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[0150] In one embodiment, the disease / condition / cancer to be treated / prevented using the SOS1 inhibitor compound, the SOS1 inhibitor compound for use, the compound of formula (I), the compound of formula (I) for use, the use for preparation, and the method for treatment and / or prevention as defined herein (above or below) is selected from the group consisting of pancreatic cancer, lung cancer (preferably non-small cell lung cancer (NSCLC)), cholangiocarcinoma and colorectal cancer.

[0151] In one embodiment, the disease / condition treated / prevented with the SOS1 inhibitor compound, the SOS1 inhibitor compound for use, the compound of formula (I), the compound of formula (I) for use, the use for preparation, and the method for treatment and / or prevention as defined herein (above or below) is a rasopathy, which in one embodiment is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML) (also called LEOPARD syndrome), Capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Regius syndrome (also known as NF1-like syndrome), and hereditary gingival fibromatosis.

[0152] In one embodiment, the pharmacologically active substance used in conjunction / combination with an SOS1 inhibitor compound as defined herein (above or below), in particular a compound of formula (I), (II), (III-A) or (III-B), a pharma- ceutically acceptable salt or stereoisomer thereof, or in a method of medical use, use, treatment and / or prophylaxis, may be selected from one or more of the following:

[0153] 1. EGFR and / or its mutant inhibitors a. For example, afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, EGF-816; b. Afatinib, osimertinib, and cetuximab; or C.Afatinib; 2. Inhibitors of ErbB2 (Her2) and / or its mutants a. For example, afatinib, lapatinib, trastuzumab, pertuzumab; b. Afatinib and trastuzumab; C.Trastuzumab; 3. ALK and / or its mutant inhibitors a. For example, crizotinib, alectinib, entrectinib, brigatinib; b. Crizotinib and alectinib; C. Crizotinib; 4. Inhibitors of MEK and / or its mutants a. For example, trametinib, cobimetinib, binimetinib, selumetinib, refametinib; b. Trametinib and cobimetinib; C.Trametinib; 5. Inhibitors of GDP-bound KRAS and / or its mutants a.Irreversible inhibitor of KRAS G12C i. For example, ARS-853 (compound V-64 in WO2014 / 152588), Example I-272 in WO2016 / 044772; b. Reversible inhibitors of GDP-bound KRAS and / or its mutants 6. Inhibitors of BCR-ABL and / or its mutants a. For example, imatinib, dasatinib, nilotinib; b. Imatinib and nilotinib; C. Imatinib; 7. Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or mutants thereof a. For example, nintedanib; 8. Inhibitors of ROS1 and / or its mutants a. For example, crizotinib, entrectinib, lorlatinib, ceritinib, and merestinib; b. Crizotinib and entrectinib; C. Crizotinib; 9. Inhibitors of c-MET and / or its mutants 10. Inhibitors of AXL and / or its mutants 11. Inhibitors of NTRK1 and / or its mutants 12. Inhibitors of RET and / or its mutants 13. Taxanes a. For example, paclitaxel, nab-paclitaxel, docetaxel; B. Paclitaxel; 14.Platinum-containing compounds a. For example, cisplatin, carboplatin, oxaliplatin; 15. Antimetabolites a. For example, a combination of 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, trifluridine and tipiracil (=TAS102); B. Gemcitabine; 16. Mitotic kinase inhibitors a. For example, CDK4 / 6 inhibitors i. For example, palbociclib, ribociclib, abemaciclib; ii. Palbociclib and abemaciclib; iii. Abemaciclib; 17. Immunotherapeutic agents a. For example, immune checkpoint inhibitors i. For example, anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, anti-TIM3 mAb; ii. Anti-PD1 mAb; iii. For example, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab); iv. Nivolumab, pembrolizumab and PDR-001 (= spartalizumab); v. Pembrolizumab; 18. Antiangiogenic drugs a. e.g. bevacizumab, nintedanib; B. Bevacizumab; 19. Topoisomerase inhibitors a. For example, irinotecan, irinotecan liposomal, topotecan; b. Irinotecan; 20. Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or mutants thereof a. For example, RAF-709 (= Example 131 in WO2014 / 151616), LY-3009120 (= Example 1 in WO2013 / 134243); 21. Inhibitors of ERK and / or its mutants a. For example, ulixertinib; 22. Apoptosis regulators For example, inhibitors of the interaction between p53 (functional p53, wtp53) and MDM2 ("MDM2 inhibitors"); i. For example, HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-1 15; ii. HDM-201, RG-7388 and AMG-232 b. For example, PARP inhibitors; c. For example, MCL-1 inhibitors; 23. mTOR inhibitors a. For example, rapamycin, temsirolimus, everolimus, ridaforolimus; 24. Epigenetic Modulators a. For example, BET inhibitors i. For example, JQ-1, GSK525762, OTX015 (=MK8628), CPI0610, TEN-010 (=R06870810); b. For example, CDK9 inhibitors; 25. IGF1 / 2 and / or IGF1-R Inhibitors a. For example, Zentuzumab (antibody 60833 in WO2010 / 066868), MEDI-573 (=Dusigitumab); 26. Inhibitors of RAS GEF and / or its mutants a. Inhibitors of, for example, SOS2 and / or its mutants 27. Inhibitors of PI3K and / or its mutants 28. Inhibitors of SHP2 and / or its mutants In one embodiment, non-drug therapy can be used together / combined with SOS1 inhibitor compounds, particularly compounds of formula (I), (II), (III-A) or (III-B), their pharma- ceutically acceptable salts or stereoisomers, or in methods of medical use, use, treatment and / or prevention, as described herein (above or below). Examples of non-drug therapy include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical removal of tumor tissue) and T cell adoptive transfer (ACT) therapy.

[0154] In one embodiment, the compounds of the present disclosure can be used as adjuvant therapy after surgery. In some embodiments, the compounds of the present disclosure can be used as neoadjuvant therapy after surgery.

[0155] Radiation therapy can be used to inhibit abnormal cell growth or treat hyperproliferative disorders, such as cancer, in a subject (e.g., a mammal (e.g., a human)). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered through one or a combination of several methods, including, but not limited to, external beam radiation therapy, internal radiation therapy, interstitial irradiation, stereotactic radiosurgery, total body radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. The term "brachytherapy" as used herein refers to radiation therapy delivered by inserting spatially localized radioactive material into or near the site of a tumor or other proliferative tissue disease in the body. The term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Suitable radiation sources for use as cell conditioners of the present disclosure include both solid and liquid. As non-limiting examples, the radiation source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can be a fluid made from a solution of any radionuclide, for example a solution of I-125 or I-131, or the radioactive fluid can be produced using a slurry of a suitable fluid containing fine particles of a solid radionuclide, for example Au-198 or Y-90. Additionally, the radionuclide can be incorporated into a gel or radioactive microspheres.

[0156] In one embodiment, the compounds of the present disclosure can make abnormal cells more sensitive to treatment with radiation for the purpose of killing or inhibiting the growth of such cells.Thus, the present disclosure relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation, comprising administering to the mammal an amount of the compounds of the present disclosure that is effective for sensitizing the abnormal cells to treatment with radiation.The amount of the compound in this method can be determined by the means for ascertaining the effective amount of the compound described herein.In some embodiments, the compounds of the present disclosure can be used as adjuvant therapy after radiation therapy or as neoadjuvant therapy before radiation therapy.

[0157] In one embodiment, the non-drug treatment is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells may be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. Prior to the expansion and genetic modification of T cells, a source of T cells is obtained from the subject. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. Certain embodiments of the present disclosure may use any number of T cell lines available in the art. In some embodiments, the T cells are autologous T cells. Either before or after genetic modification of the T cells to express a desired protein (e.g., a CAR), the T cells can be activated and expanded generally using methods such as those described in, for example, U.S. Patent Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041.

[0158] In one embodiment, an additional therapeutic agent may be used together / in combination with the SOS1 inhibitor compounds, particularly compounds of formula (I), (II), (III-A) or (III-B), their pharma- ceutically acceptable salts or stereoisomers, as described herein (above or below), or in methods of medical use, use, treatment and / or prophylaxis.

[0159] In one embodiment, the additional therapeutic agent may be a steroid. Thus, in some embodiments, the one or more additional treatments include a steroid. Suitable steroids include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, Examples of such agents include fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednibar, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof.

[0160] Further examples of therapeutic agents that can be used in combination therapy with the compounds of the present disclosure include those described in the following patents: U.S. Pat. Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and International Patent Application W WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089 and WO00 / 02871.

[0161] The therapeutic agent may be a biologic (e.g., a cytokine (e.g., an interferon or an interleukin, e.g., IL-2)) used in the treatment of cancer or a condition related thereto. In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof), that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer. Antibody-drug conjugates are also included.

[0162] The therapeutic agent may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, e.g., a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, e.g., an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, e.g., an antibody, that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitor antibody or a small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitor antibody or a small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitor antibody or a small molecule inhibitor) of PDL-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitor antibody or an Fc fusion or small molecule inhibitor) of PDL-2 (e.g., a PDL-2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitor antibody or a small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, a B-7 family ligand, or a combination thereof.In some embodiments, the checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibodies, such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene&Celgene), or other antibodies, including but not limited to and checkpoint inhibitors disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0163] The therapeutic agent may be an agent that treats cancer or a condition related thereto (e.g., a cytotoxic agent, a non-peptide small molecule or other compound useful in treating cancer or a condition related thereto, collectively "anti-cancer agent"). The anti-cancer agent can be, for example, a chemotherapeutic agent or a targeted therapy agent.

[0164] Anticancer drugs include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenal cortical suppressants, adrenal cortical steroids, progesterones, estrogens, antiestrogens, androgens, antiandrogens, gonadotropin-releasing hormone analogs. Additional anticancer drugs include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, the one or more additional treatments include two or more anticancer drugs. Two or more anticancer drugs can be used in a cocktail that is administered in combination or separately.Appropriate dosing regimens of combined anticancer drugs are known in the art, and are described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0165] Non-limiting examples of other anti-cancer drugs include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents such as thiotepa, cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, piposulfan; aziridines such as benzodopa, carboquone, metholedopa, uredopa; ethylenimines and methylamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its adzelesin, carzelesin and and synthetic analogs of bizelesin; cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eluterobin; pancratistatin; sarcodictin A; spongiostatins; nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicins, such as calicheamicin gamma 1I and calicheamicin omega 11 (see, e.g., Agnew, Chem. Intl., ed. Engl. 33:183-186 (1994)); dynemycins, such as dynemycin A; bisphosphonates, such as clodronate; esperamicin;Neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyano nomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins, e.g. mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, keramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, e.g. methotrexate, 5-fluorouracil (5-FU); folic acid analogues, e.g. deno Pterin, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as floric acid. ;Aceglatone;Aldophosphamide glycosides;Aminolevulinic acid;Eniluracil;Amsacrine;Bestravcil;Bisantrene;Edatraxate;Defofamine;Demecolcine;Diazicon;Elformitin;Elliptinium acetate;Epothilones, e.g. epothilone B;Etoglucide;Gallium nitrate;Hydroxyurea;Lentinan;Lonidamine;Maytansinoids, e.g. maytansine and ansamitocin;Mitoguazone;Mitoxantrone;Mopidamol;Nitracrine;Pentostatin;Phenamet;Pirarubicin;Rosoxantrone;Podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; schizophyllan; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; trichothecenes, such as T-2 toxin, veracrine A, roridin A, and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphatase amides; thiotepa; taxoids such as Taxol® (paclitaxel), Abraxane® (cremophor-free, albumin engineered nanoparticle formulation of paclitaxel), Taxotere® (docetaxel); chlorambucil; tamoxifen (Nolvadex®); raloxifene; aromatase inhibitor 4(5)-imidazoles; 4-hydroxytamoxifen; trioxyphene; ketoxifene; LY 117018; Onapristone; Toremifene (Fareston®); Flutamide, nilutamide, bicalutamide, leuprolide, goserelin; Chlorambucil; Gemzar® gemcitabine; 6-thioguanine; Mercaptopurine; Platinum coordination complexes, such as cisplatin, oxaliplatin and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Navelbine® (vinorelbine); Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Ibandronate; Irinotecan (e.g. CPT-11); Topoisomerase inhibitors RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; esperamicin; capecitabine (e.g., Xeloda®); and pharma- ceutically acceptable salts of any of the above.

[0166] Non-limiting examples of additional anti-cancer drugs include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicin, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17 -demethoxygeldanamycin, alpharazine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastic agents (e.g., non-cell cycle specific antineoplastic agents, and other antineoplastic agents described herein), antitumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricoder, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, lanicuidar, larotaxel, lenalidomide, lucantone, lurtotecan, mafosfamide, mitozolomide, These include nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0167] Non-limiting examples of additional anti-cancer agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase, which metabolizes L-asparagine systemically and depletes cells that do not have the ability to synthesize their own asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and its analogs, melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (CDK 4 / 6 inhibitors, such as ribociclib, abemaciclib, or palbociclib), seliclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazenes-dacarbazine (DTIC), antiproliferative / antiproliferative antimetabolites, such as folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxacil, bromocriptine ... lysine and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid,acid), vorinostat, LBH589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array520), DNA binders (e.g., Zalypsis®), PI3K inhibitors, e.g., PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3 K delta and gamma inhibitors (e.g. CAL-130), copanlisib, alpelisib and idelalisib; multikinase inhibitors (e.g. TG02 and sorafenib), hormone (e.g. estrogen) and hormone agonists such as luteinizing hormone releasing hormone (LHRH) agonists (e.g. goserelin, leuprolide and triptorelin), BAFF neutralising antibodies (e.g. LY2127399), IKK inhibitors, p38MAPK inhibitors agents, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN163L), Aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., E. These include anti-cancer drugs such as cyclophosphamide, cyclophosphamide (Cyclohexyl 1-phosphate dehydrogenase), anti-cancer drugs such as ...

[0168] In some embodiments, the anticancer drug is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or an analog or derivative variant of any of the foregoing.

[0169] In some embodiments, the anticancer drug is an ALK inhibitor.Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011; CT-707; TPX-0005 and AP26113.Additional examples of ALK kinase inhibitors are described in Example 3-39 of WO05016894.

[0170] In some embodiments, the anti-cancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., an SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068), another SOS1 inhibitor (e.g., BI-1701963), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., an mTORC1 inhibitor or an mTORC2 inhibitor). In some embodiments, the anti-cancer agent is JAB-3312. In some embodiments, the anti-cancer agent is a Ras inhibitor (e.g., AMG510, MRTX1257, LY349946, MRTX849, ARS-3248 (JNJ-74699157) or ARS-1620) or a Ras vaccine, or another therapy designed to directly or indirectly reduce the oncogenic activity of Ras.

[0171] In some embodiments, the Ras protein is wild type. In some embodiments, the cancer comprises a Ras mutation. In some embodiments, the mutation is (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12f, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V, and combinations thereof; (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R and combinations thereof; and (c) the following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, and combinations thereof; or any combination of the foregoing (e.g., both K-Ras G12C and K-Ras G13C). In some embodiments, the cancer comprises a Ras mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V.

[0172] In some embodiments, therapeutic agents that may be combined with compounds of the present disclosure are inhibitors of the MAP kinase (MAPK) pathway (or "MAPK inhibitors"). MAPK inhibitors include, but are not limited to, one or more of the MAPK inhibitors described in Cancers (Basel) 2015 September;7(3):1758-1784. For example, MAPK inhibitors include trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA119 / BAY86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche, PLoS One. 2014 Nov. 25; 9(11)); and GSK1120212 (or JTP-74057, Clin Cancer Res. 2011 Mar. 1; 17(5):989-1000).

[0173] In some embodiments, the anti-cancer agent is a disruptor or inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway. The PI3K / AKT inhibitor can include, but is not limited to, one or more of the PI3K / AKT inhibitors described in Cancers (Basel) September 2015; 7(3):1758-1784. For example, the PI3K / AKT inhibitor can be selected from one or more of NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[0174] In some embodiments, the anti-cancer agent is a PD-1 or PD-L1 antagonist. In some embodiments, the additional therapeutic agents include EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapy.

[0175] IGF-1R inhibitors include linsitinib, or a pharma- ceutically acceptable salt thereof. EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs.Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab and matuzumab.Further antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. The EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra) or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0176] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®) and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. Further non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and all pharma- ceutically acceptable salts of such EGFR inhibitors: EP 0520722; EP 0566226; WO 96 / 33980; U.S. Patent No. 5,747,498; WO 96 / 30347; EP 0787772; WO 97 / 30034; WO 97 / 30044; WO 97 / 38994; WO 97 / 49688; EP 837063; WO 98 / 02434; WO 97 / 38983; WO 95 / 19774; WO 95 / 19970; WO 97 / 13771; WO 98 / 02437; WO 98 / 024 38;WO97 / 32881;DE19629652;WO98 / 33798;WO97 / 32880;WO97 / 32880;EP682027;WO9 7 / 02266;WO97 / 27199;WO98 / 07726;WO97 / 34895;WO96 / 31510;WO98 / 14449;WO98 / 144 50; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; U.S. Patent No. 5,789,427; U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and WO92 / 20642.Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. In some embodiments, the EGFR inhibitor is osimertinib.

[0177] MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®) and binimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets MEK mutations, i.e., class I MEK1 mutations selected from D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a class II MEK1 mutation selected from DE51-Q58; DF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N.

[0178] PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs described in WO06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (BEZ 235 or NVP-BEZ 235, also known as 235 and described in WO06 / 122806; (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, described in WO08 / 070740; LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, available from Axon Medchem; PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride, available from Axon Medchem); PIK 75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione (available from Axon available from Medchem);TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one (available from Axon Medchem);XL-765;and XL-147. Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0179] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem. J. 2005, vol. 385(Pt. 2): 399-408); Akt-1-1,2 (inhibits Akl and 2) (Barnett et al., Biochem. J. 2005, vol. 385(Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, vol. 91: 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05 / 011700); indole-3-carbinol and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(Suppl 12):3493S-3498S); perifosine (e.g., disrupts Akt membrane localization; Dasmahapatra et al., Clin. Cancer Res. 2004, 10(15):5242-52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9).

[0180] mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin1; FKBP12 potentiators; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO 94 / 09010); ridahololimus (also known as dehololimus or AP23573); rapalogs, such as those disclosed in WO 98 / 02441 and WO 01 / 14387, such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolium phosphate)-rapamycin (also known as CC1779); 16-pentynyloxy-32(S)-dihydrorapamycin; derivatives disclosed in WO 05 / 005434; U.S. Patent Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and the like. No. 5,256,790, and derivatives disclosed in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, e.g., WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552.

[0181] The BRAF inhibitors that can be used in combination with the compounds of the present disclosure include, for example, vemurafenib, dabrafenib and encorafenib.BRAF may comprise class 3 BRAF mutation.In some embodiments, class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R and A762E.

[0182] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665 and S63845.Myeloid cell leukemia-1 (MCL-1) protein is one of the important anti-apoptotic members of B-cell lymphoma-2 (BCL-2) protein family.Overexpression of MCL-1 is closely related to tumor progression and resistance to targeted therapy, including not only conventional chemotherapy but also BCL-2 inhibitors, such as ABT-263.

[0183] In some embodiments, the additional therapeutic agent is a SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions, including proliferation, differentiation, cell cycle maintenance and migration. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP) and a C-terminal tail. The two SH2 domains regulate the intracellular localization and functional control of SHP2. The molecule exists in an inactive autoinhibited conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. Stimulation, for example by cytokines or growth factors acting through receptor tyrosine kinases (RTKs), results in the exposure of the catalytic site, resulting in the enzymatic activation of SHP2.

[0184] SHP2 is involved in signal transduction through the RAS-mitogen-activated protein kinase (MAPK), JAK-STAT or phosphoinositol 3-kinase-AKT pathways. Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human developmental disorders, such as Noonan syndrome and Leopard syndrome, as well as human cancers, such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung and colon cancer. Some of these mutations destabilize the autoinhibitory configuration of SHP2, promoting autoactivation or enhanced growth factor activation of SHP2. Thus, SHP2 represents a very attractive target for the development of new therapies for the treatment of various diseases, including cancer. SHP2 inhibitors (e.g. RMC-4550 or SHP099) in combination with RAS pathway inhibitors (e.g. MEK inhibitors) have been shown to inhibit the growth of multiple cancer cell lines in vitro (e.g. pancreatic, lung, ovarian and breast cancer). Thus, combination therapy involving SHP2 inhibitors together with RAS pathway inhibitors may be a general strategy to prevent tumor resistance in a wide range of malignancies and may form the basis of triple inhibitor combinations with SOS1 inhibitors.

[0185] Non-limiting examples of such SHP2 inhibitors known in the art include those disclosed in Chen et al., Mol Pharmacol. 2006, 70, 562; Sarver et al., J. Med. Chem. 2017, 62, 1793; Xie et al., J. Med. Chem. 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; and PCT applications: WO2015107493; WO2015107494; WO201507495; WO2016203404; WO2016203405; WO2016203406; WO201102244 0;WO2017156397;WO2017079723;WO2017211303;WO2012041524;WO2017211303;WO2019051084 ;WO2017211303;US20160030594;US20110281942;WO2010011666;WO2014113584;WO2014176488 ;WO2017100279;WO2019051469;US8637684;WO2007117699;WO2015003094;WO2005094314;WO2 008124815;WO2009049098;WO2009135000;WO2016191328;WO2016196591;WO2017078499;WO201 7210134; WO2018013597; WO2018129402; WO2018130928; WO20181309928; WO2018136264; WO2018136265; WO2018160731; WO2018172984; and WO2010121212, each of which is incorporated by reference herein.

[0186] In some embodiments, the SHP2 inhibitor binds in the active site. In some embodiments, the SHP2 inhibitor is a mixed type irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, e.g., a non-covalent allosteric inhibitor. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor, e.g., an inhibitor that targets a cysteine ​​residue (C333) outside the active site of the phosphatase. In some embodiments, the SHP2 inhibitor is a reversible inhibitor. In some embodiments, the SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RCM-4630. In some embodiments, the SHP2 inhibitor is JAB-3068.

[0187] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0188] Immunotherapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically modified T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents.

[0189] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that modify the immune response) that contain an imide group. The IMiD class includes thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0190] Exemplary anti-PD-1 antibodies and methods for their use are described in Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168 A1, as well as elsewhere herein.

[0191] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Pat. No. 6,111,090, U.S. Pat. No. 8,586,023, WO2010 / 003118 and WO2011 / 090754; or those described in, for example, U.S. Pat. No. 7,025,962, EP No. 1947183, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886, U.S. Pat. No. 7,618,632, EP 1866339 and the anti-GITR antibodies described in WO 2011 / 028683, WO 2013 / 039954, WO 05 / 007190, WO 07 / 133822, WO 05 / 055808, WO 99 / 40196, WO 01 / 03720, WO 99 / 20758, WO 06 / 083289, WO 05 / 115451 and WO 2011 / 051726.

[0192] Another example of a therapeutic agent that can be used in combination with the compounds of the present disclosure is an antiangiogenic agent.Antiangiogenic agents include, but are not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof.Antiangiogenic agents can be agonists, antagonists, allosteric regulators, toxins, or more generally act to inhibit or stimulate their targets (e.g., activate or inhibit receptors or enzymes), thereby promoting cell death or stopping cell growth.In some embodiments, one or more additional treatments include antiangiogenic agents.

[0193] Antiangiogenic agents can be MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors and COX-II (cyclooxygenase II) inhibitors. Non-limiting examples of antiangiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 528 89, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578 and US20090012085, as well as U.S. Patent Nos. 5,863,949 and 5,861,510. In some embodiments, the MMP-2 and MMP-9 inhibitors have little or no activity inhibiting MMP-1. In some embodiments, the MMP-2 and MMP-9 inhibitors selectively inhibit MMP-2 or AMP-9 relative to other matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Examples of some specific MMP inhibitors are AG-3340, RO32-3555, and RS13-0830.

[0194] Further representative anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind to VEGF or a soluble VEGF receptor or its ligand binding region), such as VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind to it), EGFR inhibitors (e.g., antibodies or antigen binding regions that specifically bind to it) such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen binding regions that specifically bind to it or its receptors, such as Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind to it). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g. specific binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM disintegrin domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), specific binding anti-eph receptor or anti-ephrin antibodies or Antigen binding regions (U.S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and patent family members) and anti-PDGF-BB antagonists (e.g., specific binding antibodies or antigen binding regions), as well as antibodies or antigen binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto). Additional antiangiogenic agents include SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium, (Gilead Sciences, USA); alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, US 5712291);Ilomastat, (Arriva, USA, US5892112); Emaxanib, (Pfizer, USA, US5792783); Vatalanib, (Novartis, Switzerland); 2-Methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); Anecortave acetate (Alcon, USA); Alpha-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); Anti-Vn Mab (Crucell, Netherlands), DAC antiangiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070);ARGENT technology (Ariad, USA);YIGSR-Stealth (Johnson&Johnson, USA);Fibrinogen-E fragment (BioActa, UK);Angiogenesis inhibitors (Trigen, UK);TBC-1635 (Encysive Pharmaceuticals, USA);SC-236 (Pfizer, USA);ABT-567 (Abbott, USA);Metastatin (EntreMed, USA);Maspin (Sosei, Japan);2-Methoxyestradiol (Oncology Sciences Corporation, USA);ER-68203-00 (IV AX, USA);Benefin (Lane Labs, USA);Tz-93 (Tsumura, Japan);TAN-1120 (Takeda, Japan);FR-111142 (Fujisawa, Japan, JP 02233610);Platelet factor 4 (RepliGen, USA, EP 407122);vascular endothelial growth factor antagonists (Borean, Denmark);bevacizumab (pINN) (Genentech, USA);angiogenesis inhibitors (SUGEN, USA);XL 784 (Exelixis, USA);XL 647 (Exelixis, USA);MAb, alpha5beta3 integrin second generation (Applied Molecular Evolution, USA and MedImmune, USA); enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and antiangiogenic agents derived from BPI (XOMA, USA); PI 88 (Progen, Australia); cilengitide (Merck KGaA, German; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292, (Telios, USA); endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); 2-Methoxyestradiol (Boston Children's Hospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (Angiogene Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); Vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); Tissue factor pathway inhibitor (EntreMed, USA); Pegaptanib (Pinn), (Gilead Sciences, USA); Xanthorrhizol, (Yonsei University, South Korea); Vaccine, Gene-Based VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University of California at San Diego, USA);PX 478, (ProlX, USA); metastatin, (EntreMed, USA); troponin I, (Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); motuporamine C, (British Columbia University, Canada); CDP 791, (Celltech Group, UK); atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna, Canada); Vaccines, Angiogenesis (EntreMed, USA); Urokinase Plasminogen Activator Inhibitor (Dendreon, USA); Oglufanide (pINN), (Melmotte, USA); HIF-1 alpha inhibitor, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES 2622, (Bayer, Germany); Angiocidin (InKine, USA); A6, (Angstrom, USA); KR 31372, (Korea Research Institute of Chemical Technology, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery, Japan); drug delivery system, intraocular, 2-methoxyestradiol; Anginex (Maastricht University, Netherlands, and University of Minnesota, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor-alpha inhibitor;SU 11248 (Pfizer, USA and SUGEN USA); ABT 518, (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, alpha5beta (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (University of South Florida, USA and Yale University, USA); CS 706 (Sankyo, Japan); Combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA) CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); irsogladine (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); squalamine (Genaera, USA); RPI 4610 (Sirna, USA); heparanase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VE-cadherin-2 antagonist (ImClone Systems, USA); vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); tumstatin (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck&Co, USA); Tie-2 ligand (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA.

[0195] Further examples of therapeutic agents that can be used in combination with the compounds of the present disclosure include agents (e.g., antibodies, antigen binding regions, or soluble receptors) that specifically bind and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor) and antibodies or antigen binding regions that specifically bind to its receptor, c-Met.

[0196] Another example of therapeutic agent that can be used in combination with the compounds of the present disclosure is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-suppressing algal toxins that inhibit type 2A or type 1 protein phosphatases, analogs of cAMP, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside and vinblastine. In addition, antisense or siRNA that inhibits the expression of proteins (related to autophagy), including, but not limited to, ATG5, can also be used. In some embodiments, one or more additional treatments include an autophagy inhibitor.

[0197] Another example of a therapeutic agent that can be used in combination with the compounds of the present disclosure is an anti-cancer agent.In some embodiments, one or more additional treatments include an anti-cancer agent.Non-limiting examples of an anti-cancer agent include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, aruglavin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emiteflu, epirubicin, epoetin beta, etoposide phosphate, exemestane, extract Lind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination drug, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin, (imiquimod, interferon alpha, interferon alpha, natural, interferon alpha-2, interferon alpha-2a, interferon interferon alpha-2b, interferon alpha-nl, interferon alpha-n3, interferon alphacon-1, interferon alpha, natural, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, natural interferon gamma-la, interferon gamma-lb, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinansul phenotype, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein preparations, NSC631570 Octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alpha-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alpha-2a, porfimer sodium, raloxifene, raltitrexed, rasbriembodiment, rhenium Re186 etidronate, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonel amine, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, native tumor necrosis factor alpha, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulidin, zinostatin stimalamer or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diazicon, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxifen, LDI200 (Milk House), religistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and FcMAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techni clone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitsumomab, motexafine gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA Examples of vaccines that may be used include 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, ethyl etiopropyl prionase, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), melanoma cell virus lysate vaccine (Royal Newcastle Hospital), or valspodar.

[0198] Additional examples of therapeutic agents that can be used in combination with compounds of the disclosure include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services;huMAbOX40L;Atacicept;CP-870893;Lucatumumab;Dacetuzumab;Muromonab-CD3;Ipilumumab;MEDI4736 (Imfinzi®);MSB0010718C;AMP 224;Adalimumab (Humira®);ado-Trastuzumab Emtansine (Kadcyla®);Aflibercept (Eylea®);Alemtuzumab (Campath®);Basiliximab (Simulect®);Belimumab (Benlysta®);Basiliximab (Simulect®);Belimumab (Benlysta®);Brentuximab Vedotin (Adcetris®); Canakinumab (Ilaris®); Certolizumab pegol (Cimzia®); Daclizumab (Zenapax®); Daratumumab (Darzalex®); Denosumab (Prolia®); Eculizumab (Soliris®); Efalizumab (Raptiva®); Gemtuzumab ozogamicin (Mylotarg®); Golimumab (Simponi®); Ibritumomab tiuxetan (Zevalin®); Infliximab (Remicade®); Motavizumab (Numax®); Natalizumab (Tysabri®); Obinutuzumab (Gazyva®); Ofatumumab (Arzerra®); Omalizumab (Xolair®);Palivizumab (Synagis®); pertuzumab (Perjeta®); pertuzumab (Perjeta®); ranibizumab (Lucentis®); raxibacumab (Abthrax®); tocilizumab (Actemra®); tositumomab; tositumomab-i-131; tositumomab and tositumomab-i-131 (Bexxar®); ustekinumab (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0199] In some embodiments, the additional compound used in combination therapy with the compound of the disclosure is selected from the group consisting of a CDK4 / 6 inhibitor (e.g., abemaciclib, palbociclib, or ribociclib), a KRAS:GDPG12C inhibitor (e.g., AMG510, MRTX1257) or other mutant Ras:GDP inhibitor, a KRAS:GTPG12C inhibitor or other mutant Ras:GTP inhibitor, a MEK inhibitor (e.g., refametinib, selumetinib, trametinib, or cobimetinib), a SHP2 inhibitor (e.g., TNO155, RMC-4630), an ERK inhibitor, and a RTK inhibitor (e.g., an EGFR inhibitor).

[0200] In some embodiments, the additional compound used in combination therapy with the compound of the present disclosure is selected from the group consisting of ABT-737, AT-7519, carfilzomib, cobimetinib, danusertib, dasatinib, doxorubicin, GSK-343, JQ1, MLN-7243, NVP-ADW742, paclitaxel, palbociclib and volasertib. In some embodiments, the additional compound used in combination therapy with the compound of the present disclosure is selected from the group consisting of neratinib, acetinib and reversine.

[0201] The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure are co-administered with other treatments as described herein. When used in combination therapy, the compounds described herein can be administered simultaneously or separately with the second agent. The administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure and any of the treatments described herein can be administered simultaneously, where both agents are in separate formulations. As another alternative, the compounds of the present disclosure can be administered followed by any of the treatments described herein, or vice versa. In some embodiments of the separate administration protocol, the compounds of the present disclosure and any of the treatments described herein are administered minutes apart, hours apart, or days apart.

[0202] In some embodiments, the combination therapeutic regimen employs two therapeutic agents, one selected from a compound of the present disclosure and a second selected from the therapeutic agents described herein. In some embodiments, the combination therapeutic regimen employs three therapeutic agents, one selected from a compound of the present disclosure and two selected from the therapeutic agents described herein. In some embodiments, the combination therapeutic regimen employs four or more therapeutic agents, one selected from a compound of the present disclosure and three selected from the therapeutic agents described herein.

[0203] In some embodiments of any of the methods described herein, the first treatment (e.g., a compound of the present disclosure) and the one or more additional treatments are administered simultaneously or sequentially in any order. The first treatment can be administered up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days before or immediately after the one or more additional treatments.

[0204] In this section, all references to the agents described are incorporated by reference, whether or not expressly stated as such. 6. Kit Another aspect of the present disclosure provides a kit comprising a compound of any one of the above formulas or a pharmaceutical composition comprising a compound of any one of the above formulas of the present disclosure. The kit may comprise a diagnostic or therapeutic agent in addition to a compound of any one of the above formulas of the present disclosure or a pharmaceutical composition thereof. The kit may also comprise instructions for use in diagnosis or therapy. In some embodiments, the kit comprises a compound of any one of the above formulas or a pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit comprises a compound of any one of the above formulas or a pharmaceutical composition thereof.

[0205] In yet another embodiment, the present disclosure comprises a kit suitable for use in carrying out the method of treatment described herein.In one embodiment, the kit comprises a first dosage form that comprises one or more of the compounds of the present disclosure in an amount sufficient to carry out the method of the present disclosure.In another embodiment, the kit comprises one or more of the compounds of the present disclosure in an amount sufficient to carry out the method of the present disclosure and a container for administration and a container for administration. 7. Preparation The compound of any one of the above formulas can be prepared by the following general and specific methods using the general knowledge of a person skilled in the art of synthetic organic chemistry.Such general knowledge can be found in standard references, such as Comprehensive Organic Chemistry, Barton and Ollis, eds., Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, volumes I-XII (published by Wiley-Interscience).The starting materials used herein are commercially available or can be prepared by conventional methods known in the art.

[0206] It should be noted that in the preparation of the compounds of any one of the above formulas, some of the preparation methods described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in any one of the above precursor formulas). The need for such protection varies depending on the nature of the remote functionality and the conditions of the preparation method. The need for such protection is easily determined by those skilled in the art. The use of such protection / deprotection methods is also within the skill of the art. For a general description of protecting groups and their use, see Greene, Protective Groups in Organic Synthesis, John Wiley&Sons, New York, 1991.

[0207] For example, certain compounds contain primary amine or carboxylic acid functionalities that may prevent reaction at other sites of the molecule if left unprotected. Therefore, such functionalities may be protected by suitable protecting groups that can be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include the protecting groups commonly used in peptide synthesis (e.g., Nt-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids), which are not chemically reactive under the reaction conditions generally described and can typically be removed without chemically changing other functionalities in any one of the above compound formulas.

[0208] The following scheme is intended to provide a general description of the methodology employed in the preparation of the compounds of the present disclosure. Some of the compounds of the present disclosure may contain single or multiple chiral centers with stereochemical designations (R) or (S). It is clear to those skilled in the art that all synthetic transformations can be carried out in a similar manner, regardless of whether the material is enantiomerically enriched or racemic. Furthermore, the resolution of the desired optically active material can be carried out at any desired point in the sequence, using methods as described herein and well known in the chemical literature. EXAMPLES

[0209] Abbreviation: Ar Argon DAST Diethylaminosulfur trifluoride DCM Dichloromethane DIEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMF-DMA N,N-Dimethylformamide Dimethyl Acetal DMSO Dimethyl sulfoxide Dppf 1,1'-Bis(diphenylphosphino)ferrocene EA Ethyl acetate EtOH Ethanol EtOAc Ethyl acetate HATU N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N Methylmethanaminium Hexafluorophosphate N-Oxide HPLC High Performance Liquid Chromatography i-PrOH Isopropyl alcohol LC-MS Liquid Chromatography Mass Spectrometry MeOH Methanol Pd(dppf)Cl2 Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium PE Petroleum Ether TEA Triethylamine THF Tetrahydrofuran Tf Triflate Ts Tosil Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Synthesis Example 1. Synthetic Process for Preparing Intermediates Intermediate 1

[0210] [ka]

[0211] Step 1: To a stirred solution of 2-MeTHF (75 mL) at 4° C. was added dimethyl 3-oxopentanedioate (10 g, 57.4 mmol) and DMF-DMA (6.8 g, 57.4 mmol). The mixture was stirred for 3 h. The reaction mixture was warmed to room temperature and aqueous hydrochloric acid (4N, 26 mL) was added slowly. After stirring at room temperature for 3 h, the organic layer was separated, washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give dimethyl 2-formyl-3-oxo-pentanedioate (11 g, 95% yield) as a pale yellow liquid, which was used directly without further purification. LC-MS: m / z 202.9 [M+H] + .

[0212] Step 2: A mixture of dimethyl 2-formyl-3-oxo-pentanedioate (2.3 g, 11.5 mmol), morpholin-4-amine (1.1 g, 10.4 mmol) in MeOH (15 mL) was stirred at room temperature for 12 h. MeONa (647.9 mg, 12.0 mmol) was added to the mixture and stirred for 6 h. The mixture was quenched with H2O (15 mL) and acidified to pH 1-2 with aq. HCl (1 N). The resulting solid was filtered, washed with MeOH and H2O (1:1, V:V) and dried in vacuum to give methyl 4-hydroxy-1-morpholino-6-oxo-pyridine-3-carboxylate as a white solid (2 g, 75% yield). LC-MS: m / z 254.9 [M+H] + .

[0213] Step 3: To a stirred solution of methyl 4-hydroxy-1-morpholino-6-oxo-pyridine-3-carboxylate (2.0 g, 7.9 mmol) and TEA (1.2 g, 11.8 mmol) in CH3CN (50 mL) was added 4-methylbenzenesulfonyl chloride (1.5 g, 7.9 mmol). The mixture was stirred at room temperature for 1 h. The resulting solid was filtered and washed with CH3CN to give methyl 1-morpholino-6-oxo-4-(p-tolylsulfonyloxy)pyridine-3-carboxylate (2.6 g, 81% yield). LC-MS: m / z 408.8 [M+H] + .

[0214] Step 4: A mixture of methyl 1-morpholino-6-oxo-4-(p-tolylsulfonyloxy)pyridine-3-carboxylate (2.0 g, 5.0 mmol), acetamide (590.1 mg, 10 mmol), palladium(π-cinnamyl)chloride dimer (129.4 mg, 249.7 μmol), XantPhos (289.2 mg, 499.5 μmol) and K3PO4 (2.7 g, 12.5 mmol) in dioxane (50 mL) was stirred at 100° C. for 12 h. The mixture was purified by flash column chromatography to give methyl 4-acetamido-1-morpholino-6-oxo-pyridine-3-carboxylate (1.0 g, 68% yield). LC-MS: m / z 295.9 [M+H] + .

[0215] Step 5: A mixture of methyl 4-acetamido-1-morpholino-6-oxo-pyridine-3-carboxylate (295 mg, 1.0 mmol) and a solution of NH3 in MeOH (7 M, 5 mL) was heated to 60° C. for 16 h. The mixture was concentrated and filtered to give 2-methyl-6-morpholino-3H-pyrido[4,3-d]pyrimidine-4,7-dione (200 mg, 76% yield), which was used in the next step without further purification. LC-MS: m / z 262.9 [M+H] + .

[0216] Additional intermediates of the present disclosure were prepared by using the corresponding derivatives in a similar manner to the representative procedure described for Intermediate 1. Selected compounds and their corresponding characterization data are shown in the table below.

[0217] [Table 2-1]

[0218] [Table 2-2]

[0219] Intermediate 10

[0220] [ka]

[0221] Step 1: To a solution of (2S,6R)-2,6-dimethylmorpholine (2.0 g, 17.4 mmol) in water (25 mL) was added sodium nitrite (1.8 g, 26.1 mmol) and acetic acid (1.4 g, 22.5 mmol) at 0° C. The mixture was stirred at 20° C. for 2 h. The mixture was diluted with CHCl (80 mL) and then washed with aq. NaHCO (30 mL). The organic layer was dried over NaSO, filtered and concentrated to give (2S,6R)-2,6-dimethyl-4-nitroso-morpholine as a yellow oil (2.5 g, 99% yield).

[0222] Step 2: To a solution of (2S,6R)-2,6-dimethyl-4-nitroso-morpholine (2.5 g, 17.4 mmol) in CH3OH (25 mL) was added acetic acid (3.1 g, 52.1 mmol) and zinc (3.4 g, 52.1 mmol) at 0° C. The mixture was stirred at 20° C. for 4 h. The mixture was filtered and the filtrate was concentrated to give (2S,6R)-2,6-dimethylmorpholin-4-amine (7 g) as a white solid.

[0223] The following compounds were prepared similarly to the representative procedure described for Intermediate 10.

[0224] [Table 3]

[0225] Intermediate 15

[0226] [ka]

[0227] A mixture of 2-methyl-6-morpholino-3H-pyrido[4,3-d]pyrimidine-4,7-dione (26.2 mg, 99.9 μmol) and 1-bromopyrrolidine-2,5-dione (17.8 mg, 99.9 μmol) in CH3CN (2 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated and washed with MeOH (5 mL) to give 8-bromo-2-methyl-6-morpholinopyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione (25 mg). LC-MS: m / z 341.7 [M+H] + .

[0228] Intermediate 16

[0229] [ka]

[0230] Step 1: To a solution of 5-bromobenzene-1,3-dicarboxaldehyde (5 g, 23.5 mmol) in CHCl (70 mL) was added DAST (22.7 g, 140.8 mmol) slowly at 0° C. The mixture was stirred at 20° C. for 8 h. The solution was poured into ice (120 mL) and saturated sodium bicarbonate (100 mL) was added. The mixture was extracted with CHCl (3×200 mL). The organic layers were combined, dried over NaSO, filtered, concentrated, and purified by silica gel column chromatography to give 1-bromo-3,5-bis(difluoromethyl)benzene (3.8 g, 63% yield) as a colorless oil.

[0231] Step 2: To a solution of 1-vinyloxybutane (779.3 mg, 7.7 mmol), 1-bromo-3,5-bis(difluoromethyl)benzene (1 g, 3.9 mmol), Pd(OAc)2 (87.3 mg, 389.1 μmol), potassium phosphate (1.6 g, 7.7 mmol) and dppf (431.4 mg, 778.1 μmol) in n-BuOH (15 mL) was added LiOTf (606.9 mg, 3.9 mmol). The mixture was degassed three times with a stream of N2. The mixture was stirred at 110 °C for 16 h. The mixture was purified by silica gel column chromatography to give a colorless oil. The oil was then dissolved in EtOAc (5 mL) and HCl / EtOAc (5 mL) was added. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated and purified by silica gel column chromatography to give 1-[3,5-bis(difluoromethyl)phenyl]ethanone as a white solid (260 mg, 30% yield).

[0232] Step 3: To a solution of 1-[3,5-bis(difluoromethyl)phenyl]ethanone (260 mg, 1.2 mmol) and 2-methylpropane-2-sulfinamide (286.2 mg, 2.4 mmol) in THF (8 mL) was added Ti(OEt)4 (538.7 mg, 2.4 mmol). The mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with THF (50 mL) and then quenched with water. The mixture was filtered, and the filtrate was dried over Na2SO4, filtered, and concentrated to give N-[1-[3,5-bis(difluoromethyl)phenyl]ethylidene]-2-methyl-propane-2-sulfinamide (400 mg) as a yellow solid, which was used directly in the next step without further purification.

[0233] Step 4: To a solution of N-[1-[3,5-bis(difluoromethyl)phenyl]ethylidene]-2-methyl-propane-2-sulfinamide (400 mg, 1.2 mmol) in THF (8 mL) was added NaBH4 (140.4 mg, 3.7 mmol). The mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give N-[1-[3,5-bis(difluoromethyl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (400 mg, 99% yield) as a yellow solid.

[0234] Step 5: A solution of N-[1-[3,5-bis(difluoromethyl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (400 mg, 1.2 mmol) in HCl / EtOAc (8 mL, 4N) was stirred at 20° C. for 16 h. The reaction mixture was concentrated. The residue was suspended in EtOAc (50 mL) and washed with aq. NaHCO3 (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give 1-[3,5-bis(difluoromethyl)phenyl]ethanamine as an oil (150 mg, 55% yield).

[0235] Intermediate 17

[0236] [ka]

[0237] Step 1: To a solution of 3-bromo-2-fluorobenzaldehyde (200 g, 956 mmol) in dichloromethane (3000 mL) under N2 at 0 °C, DAST (308 g, 1912 mmol) was added and the mixture was stirred at 0 °C for 1 h. The mixture was warmed to room temperature and stirred for 1 h. The reaction was carefully quenched with saturated sodium bicarbonate solution. The reaction mixture was then diluted with ethyl acetate (3000 mL) and the organic layer was washed with saturated sodium bicarbonate solution and brine, then concentrated to dryness and purified by chromatography (0-50% ethyl acetate in PE, 20 min) to give l-bromo-3-(difluoromethyl)-2-fluorobenzene as an oil (135 g, 61% yield).

[0238] Step 2: l-Bromo-3-(difluoromethyl)-2-fluorobenzene (125 g, 556 mmol) was dissolved in anhydrous 1,4-dioxane (1.2 L). Triethylamine (140 mL, 1389 mmol) and tributyl(1-ethoxyvinyl)tin (241 g, 667 mmol) were added and the resulting solution was purged with argon for 15 min. Bis(triphenylphosphine)palladium(II) chloride (3.9 g, 5.6 mmol) was added. The reaction mixture was heated to 100° C. in an autoclave for 16 h. After complete conversion of the starting material, the reaction mixture was cooled to room temperature, treated with 1N HCl and stirred for an additional 16 h. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (SiO2, hexane / ethyl acetate 10:1) to give 1-(3-(difluoromethyl)-2-fluorophenyl)ethanone (78 g, 76% yield). LC-MS: m / z 189.0 [M+H] + .

[0239] Step 3: 1-(3-(difluoromethyl)-2-fluorophenyl)ethanone (70 g, 372 mmol) was dissolved in THF (1.0 L). (R)-(+)-2-methyl-2-propanesulfinamide (68.3 g, 564 mmol) and titanium tetraethoxide (257.5 g, 1129 mmol) at room temperature were added. The resulting reaction mixture was heated to 80° C. for 16 h. After complete conversion of the starting material, ice water and EtOAc were added and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure to give (R,E)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide, which was used in the next step without further purification. LC-MS: m / z 292.0 [M+H] + .

[0240] Step 4: A solution of (R,E)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (100 g, 343.6 mmol) was dissolved in THF (1.2 L) and cooled to 0° C. Sodium borohydride (12.7 g, 343.2 mmol) was added and the resulting reaction mixture was stirred at room temperature for 6 h. After complete conversion of the starting material, ice water and EtOAc were added. The aqueous layers were extracted with EtOAc, combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography (gradient elution: 33% ethyl acetate in petroleum ether) to give isomer 1: (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide as a yellow oil, LC-MS: m / z 294.0[M+H]+ (65 g, 64% yield); isomer 2: (R)-N-((S)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide as a yellow oil, LC-MS: m / z 294.0[M+H] + Obtained as.

[0241] Step 5: To a solution of (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (65 g, 221.8 mmol) in EA (600 mL) was added 4N HCl in dioxane (300 mL) and stirred for 1.5 h at room temperature under N2. After completion of the reaction, the solution was removed in vacuo and the solid was collected and diluted with water. The mixture was adjusted to pH=8 with aq.NaHCO3 and extracted with EA (3×300 mL). The combined organic layers were concentrated to give (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine as a pale yellow oil (31 g, 73% yield). LC-MS: m / z 191.1 [M+H] + . ee value = 99%, RT = 0.88 min (column: Cellulose-SC, 4.6 × 100 mm, 5 μm).

[0242] (S)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine was prepared by the same procedure using (R)-N-((S)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide as the starting material. LC-MS: m / z 191.1 [M+H] + Room temperature = 1.12 min (column: Cellulose-SC, 4.6 × 100 mm, 5 μm).

[0243] Synthetic Example 2. Synthetic Processes for Preparing the Exemplary Compounds Synthesis Examples Example 1

[0244] [ka]

[0245] To a stirred solution of 2-methyl-6-morpholino-3H-pyrido[4,3-d]pyrimidine-4,7-dione (52.4 mg, 199.8 μmol) in CH3CN (10 mL) was added K3PO4 (105.9 mg, 499.5 μmol) and 2,2,4,4,6,6-hexachloro-1,3,5-triaza-2,4,6-triphosphacyclohexa-1,3,5-triene (69.5 mg, 199.8 μmol). The mixture was stirred at room temperature for 2 hours. (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (37.8 mg, 199.8 μmol) was added and the mixture was stirred for 2 hours. The reaction mixture was concentrated and purified by prep-HPLC to give 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-morpholino-pyrido[4,3-d]pyrimidin-7-one (20 mg, 24% yield). LC-MS: m / z 433.8[M+H] + .

[0246] The following compounds were prepared similarly to the representative procedures described for Example 1.

[0247] [Table 4-1]

[0248] [Table 4-2]

[0249] Example 10

[0250] [ka]

[0251] A solution of tert-butyl 4-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-7-oxo-pyrido[4,3-d]pyrimidin-6-yl]piperazine-1-carboxylate (500 mg, 938.8 μmol) (4N) in HCl / EtOAc (10 mL) was stirred at 20° C. for 1.5 h. The mixture was concentrated and purified by prep-HPLC to give 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-piperazin-1-yl-pyrido[4,3-d]pyrimidin-7-one as a pale yellow solid (110 mg, 27% yield). LC-MS: m / z 432.8 [M+H] + .

[0252] Example 11

[0253] [ka]

[0254] To a solution of 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-piperazin-1-yl-pyrido[4,3-d]pyrimidin-7-one (60 mg, 127.9 μmol) in CHCl (4 mL) was added TEA (38.8 mg, 383.8 μmol) and acetyl chloride (10.0 mg, 127.9 μmol) at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was diluted with CHCl (50 mL) and then washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by prep-HPLC to give 6-(4-acetylpiperazin-1-yl)-4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-pyrido[4,3-d]pyrimidin-7-one (14.1 mg, 23% yield). LC-MS: m / z 474.8[M+H] + .

[0255] Example 12

[0256] [ka]

[0257] A solution of 2-iodopropane (39.9 mg, 234.8 μmol), potassium carbonate (40.6 mg, 293.5 μmol) and 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6-(4-isopropylpiperazin-1-yl)-2-methyl-pyrido[4,3-d]pyrimidin-7-one (60 mg, 117.4 μmol) in DMF (3 mL) was stirred for 16 h at 40° C. The mixture was diluted with EtOAc (100 mL) and then washed with brine (3×320 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6-(4-isopropylpiperazin-1-yl)-2-methyl-pyrido[4,3-d]pyrimidin-7-one (1.9 mg, 3% yield) as a pale yellow solid. LC-MS: m / z 474.9[M+H] + .

[0258] Example 13

[0259] [ka]

[0260] To a solution of 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-piperazin-1-yl-pyrido[4,3-d]pyrimidin-7-one (60 mg, 127.9 μmol), TEA (38.8 mg, 383.9 μmol) and 2-hydroxyacetic acid (9.7 mg, 127.9 μmol) in DMF (3 mL) was added HATU (73.4 mg, 191.9 μmol). The mixture was stirred at 20° C. for 2 h. The mixture was diluted with EtOAc (100 mL) and then washed with brine (3×20 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6-[4-(2-hydroxyacetyl)piperazin-1-yl]-2-methyl-pyrido[4,3-d]pyrimidin-7-one as a pale yellow solid (2.1 mg, 3% yield). LC-MS: m / z 490.8[M+H] + .

[0261] The following compounds were prepared similarly to the representative procedures described for Example 13.

[0262] [Table 5]

[0263] Example 15

[0264] [ka]

[0265] A solution of 6-fluoropyridine-3-carbonitrile (28.6 mg, 234.8 μmol), NaHCO3 (16.7 mg, 199.6 μmol) and 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-piperazin-1-yl-pyrido[4,3-d]pyrimidin-7-one (50.7 mg, 117.4 μmol) in DMSO (3 mL) was stirred for 6 h at 100° C. The mixture was diluted with EtOAc (100 mL) and then washed with brine (3×20 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give 6-[4-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-7-oxo-pyrido[4,3-d]pyrimidin-6-yl]piperazin-1-yl]pyridine-3-carbonitrile as a pale yellow solid (2 mg, 3% yield). LC-MS: m / z 534.8[M+H] + .

[0266] Example 16

[0267] [ka]

[0268] Step 1: To a stirred solution of 2-methyl-6-morpholino-3H-pyrido[4,3-d]pyrimidine-4,7-dione (100 mg, 381.3 μmol) and KPO (202.1 mg, 953.2 μmol) in CHCN (15 mL) was added phosphonitrilic chloride trimer (132.7 mg, 381.3 μmol). The mixture was stirred at room temperature for 2 h. (1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethanamine (89.3 mg, 381.3 μmol) was added. The mixture was stirred for 2 h. The reaction mixture was concentrated and purified by flash column chromatography to give 2-methyl-6-morpholino-4-[[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]amino]pyrido[4,3-d]pyrimidin-7-one (50 mg, 27% yield). LC-MS: m / z 478.8 [M+H] + .

[0269] Step 2: A mixture of 2-methyl-6-morpholino-4-[[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]amino]pyrido[4,3-d]pyrimidin-7-one (10 mg, 20.9 μmol), iron (5.8 mg, 104.5 μmol) and NH4Cl (11.2 mg, 209.0 μmol) in EtOH (2 mL) and HO (2 mL) was stirred at 75° C. for 3 h. The reaction mixture was concentrated and purified by prep-HPLC to give 4-[[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]-2-methyl-6-morpholino-pyrido[4,3-d]pyrimidin-7-one (2 mg, 21% yield). LC-MS: m / z 448.8 [M+H] + .

[0270] Example 17

[0271] [ka]

[0272] A mixture of 2-methyl-6-morpholinopyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione (52.4 mg, 0.2 mmol), K3PO4 (106 mg, 0.5 mmol) and phosphonitrilic chloride trimer (70 mg, 0.2 mmol) in CH3CN (10 mL) was stirred at room temperature for 3 h. (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (45 mg, 0.22 mmol) was added. The mixture was stirred at 80° C. for 2 h. The solvent was removed. DCM (100 mL) and water (20 mL) were added. The mixture was stirred for 20 min. The organic phase was dried over Na2SO4, filtered, concentrated and purified by prep-HPLC to give (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-morpholinopyrido[4,3-d]pyrimidin-7(6H)-one (15 mg). LC-MS: m / z 447.8 [M+H] + .

[0273] The following compounds were prepared similarly to the representative procedures described for Example 17.

[0274] [Table 6-1]

[0275] [Table 6-2]

[0276] [Table 6-3]

[0277] Example 29

[0278] [ka]

[0279] Step 1: To a stirred solution of 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde (5.0 g, 26 mmol) in toluene (150 mL) was added ethylene glycol (8.0 g, 131.0 mmol) and TsOH (0.5 g, 2.5 mmol). The reaction mixture was refluxed in a water segregator until complete conversion of the starting material was observed. The solvent was evaporated under reduced pressure. The residue was diluted with DCM (150 mL) and washed with aqueous sodium bicarbonate. The organic layers were combined, dried over Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine (4.0 g). LC-MS: m / z 457.2 [M+H] + .

[0280] Step 2: A mixture of 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine (1.5 g, 6.4 mmol), dimethyl 2-fluoromalonate (960 mg, 6.4 mmol) and Cs2CO3 (2.1 g, 6.4 mmol) in DMF was stirred at 0° C. for 1 h. The mixture was diluted with EtOAc (200 mL) and H2O (30 mL). The mixture was stirred at room temperature for 10 min. The organic phase was washed with water (3×200 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to give dimethyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)-2-fluoromalonate (1.2 g). LC-MS: m / z 348.8 [M+H] + .

[0281] Step 3: A mixture of dimethyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)-2-fluoromalonate (370 mg, 1.1 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (200 mg, 1.1 mmol) and DIEA (410 mg, 3.2 mmol) in DMF was stirred at 80° C. for 5 h. The mixture was diluted with EtOAc (100 mL) and H2O (20 mL). The mixture was stirred at room temperature for 10 min. The organic phase was washed with water (3 x 200 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to give dimethyl (R)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)-2-fluoromalonate (400 mg). LC-MS: m / z 501.8 [M+H] + .

[0282] Step 4: Dimethyl (R)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)-2-fluoromalonate (320 mg, 0.6 mmol) was dissolved in DMSO (5 mL). Aqueous sodium hydroxide (20%, 384 mg) was added and the resulting mixture was stirred for 1 h until complete conversion of the starting material was observed. Triethylamine (130 mg, 1.3 mmol), morpholin-4-amine (85 mg, 0.8 mmol) and HATU (360 mg, 1.5 mmol) were added and the resulting mixture was stirred for 1 h. Water was added and the mixture was diluted with DCM. The aqueous layer was extracted with DCM. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography to give 2-(6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)-2-fluoro-N-morpholinoacetamide (260 mg). LC-MS: m / z 513.8[M+H] + .

[0283] Step 5: 2-(6-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)-2-fluoro-N-morpholinoacetamide (50 mg, 0.1 mmol) was dissolved in 2-propanol (2 mL). 5N aqueous HCl (100 μL, 0.5 mmol) was added and the resulting mixture was stirred for 1 h at 50° C. until complete conversion of the starting material was observed. The solvent was removed to give the crude product, which was purified by prep-HPLC to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-fluoro-2-methyl-6-morpholinopyrido[4,3-d]pyrimidin-7(6H)-one (20 mg). LC-MS: m / z 451.8 [M+H] + .

[0284] The following compounds were prepared similarly to the representative procedures described for Example 29.

[0285] [Table 7]

[0286] Example 34

[0287] [ka]

[0288] Step 1: To a solution of diethylpropanedioate (613.2 mg, 3.8 mmol) in THF (15 mL) was added NaH (122.2 mg, 2.5 mmol, 48%) at 0° C. The mixture was stirred at 0° C. for 0.5 h. Then 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-methyl-pyrimidine (600 mg, 2.5 mmol) was added. The mixture was stirred at 20° C. for 10 h. The reaction mixture was quenched with aq. NH4Cl (20 mL). The mixture was extracted with EtOAc (3×35 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give diethyl 2-[6-chloro-5-(1,3-dioxolan-2-yl)-2-methyl-pyrimidin-4-yl]propanedioate as a pale yellow solid (220 mg, 24% yield).

[0289] Step 2: To a solution of diethyl 2-[6-chloro-5-(1,3-dioxolan-2-yl)-2-methyl-pyrimidin-4-yl]propanedioate (220 mg, 613.2 μmol) and CsF (186.3 mg, 1.23 mmol) in DMSO (6 mL) was added (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (116 mg, 613.2 μmol). The mixture was stirred at 120° C. for 5 h. The mixture was diluted with EtOAc (60 mL) and then washed with brine (4×20 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give diethyl 2-[6-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-5-(1,3-dioxolan-2-yl)-2-methyl-pyrimidin-4-yl]propanedioate as a pale yellow solid (110 mg, 35% yield).

[0290] Step 3: To a solution of diethyl 2-[6-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-5-(1,3-dioxolan-2-yl)-2-methyl-pyrimidin-4-yl]propanedioate (70 mg, 136.8 μmol) in water (0.5 mL) and ethanol (2 mL) was added sodium hydroxide (82.1 mg, 410.5 μmol, 20%). The mixture was stirred at 100° C. for 2 h. The mixture was concentrated. CH3OH (4 mL) was added and the mixture was filtered. The filtrate was concentrated to give (R)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)acetic acid (100 mg) as a yellow solid, which was used directly in the next step without further purification.

[0291] Step 4: To a solution of (R)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)acetic acid (30 mg, 69 μmol), TEA (17.8 mg, 138.1 μmol) and HATU (52.8 mg, 138.1 μmol) in DMF (1.5 mL) was added isopropylhydrazine (15.3 mg, 138.1 μmol). The mixture was stirred at 20° C. for 0.5 h. The mixture was diluted with EtOAc (60 mL) and then washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give 2-[6-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-5-(1,3-dioxolan-2-yl)-2-methyl-pyrimidin-4-yl]-N',N'-dimethyl-acetohydrazide (10 mg) as a yellow solid.

[0292] Step 5: To a solution of 2-[6-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-5-(1,3-dioxolan-2-yl)-2-methyl-pyrimidin-4-yl]-N',N'-dimethyl-acetohydrazide (10 mg, 22 μmol) in i-PrOH (2 mL) was added HCl (5N, 10 μL). The mixture was stirred at 50° C. for 1 h. The mixture was concentrated and purified by prep-HPLC to give 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6-(dimethylamino)-2-methyl-pyrido[4,3-d]pyrimidin-7-one as a pale yellow solid (1.2 mg, 14% yield). LC-MS: m / z 391.8 [M+H] + .

[0293] The following compounds were prepared similarly to the representative procedures described for Example 34.

[0294] [Table 8-1]

[0295] [Table 8-2]

[0296] Example 40

[0297] [ka]

[0298] A mixture of 8-bromo-2-methyl-6-morpholino-3H-pyrido[4,3-d]pyrimidine-4,7-dione (25 mg, 73.3 μmol), 2,2,4,4,6,6-hexachloro-1,3,5-triaza-2,4,6-triphosphacyclohexa-1,3,5-triene (25.5 mg, 73.3 μmol) and potassium phosphate (38.9 mg, 183.2 μmol) in CH3CN (8 mL) was stirred at room temperature for 3 hours. (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (13.9 mg, 73.3 μmol) was added. The mixture was stirred for 3 hours. The reaction mixture was concentrated and purified by flash column chromatography to give 8-bromo-4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-morpholino-pyrido[4,3-d]pyrimidin-7-one (25 mg, 67% yield). LC-MS: m / z 511.7[M+H] + .

[0299] Example 41

[0300] [ka]

[0301] A mixture of zinc disyanide (23.5 mg, 200 μmol) and 8-bromo-4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-morpholino-pyrido[4,3-d]pyrimidin-7-one (25.6 mg, 50 μmol) in DMF (3 mL) was stirred in a microwave reactor for 2 h at 130° C. The mixture was diluted with EA (100 mL) and water (15 mL). The organic phase was washed with brine (3×20 mL), dried over Na2SO4, filtered, concentrated and purified by prep-HPLC to give 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-morpholino-7-oxo-pyrido[4,3-d]pyrimidine-8-carbonitrile (2 mg, 9% yield). LC-MS: m / z 458.8 [M+H] + .

[0302] Example 42

[0303] [ka]

[0304] A mixture of 8-bromo-4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-morpholino-pyrido[4,3-d]pyrimidin-7-one (51.2 mg, 99.9 μmol), cyclopropylboronic acid (12.9 mg, 149.9 μmol), Pd(dppf)Cl2 (8.2 mg, 10 μmol) and K2CO3 (27.6 mg, 199.9 μmol) in dioxane (8 mL) was stirred under Ar at 100 °C for 6 h. The mixture was diluted with DCM (150 mL) and HO (20 mL). The organic phase was dried over Na2SO4, filtered, concentrated and purified by prep-HPLC to give 8-cyclopropyl-4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-morpholino-pyrido[4,3-d]pyrimidin-7-one (7 mg, 15% yield). LC-MS: m / z 473.8[M+H] +.

[0305] Example 43

[0306] [ka]

[0307] To a mixture of 8-bromo-4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-morpholino-pyrido[4,3-d]pyrimidin-7-one (30 mg, 58 μmol), (4-methylsulfonylphenyl)boronic acid (15 mg, 75 μmol) and cesium carbonate (60 mg, 184 μmol) in dioxane (2 mL) and water (0.5 mL) was added Pd(dppf)Cl2-DCM (5 mg, 6 μmol) under nitrogen. The reaction was stirred at 100 °C for 1 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-8% MeOH in DCM to give 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-8-(4-methylsulfonylphenyl)-6-morpholino-pyrido[4,3-d]pyrimidin-7-one as a pale yellow solid (2.1 mg, 6% yield). LC-MS: m / z 587.6[M+H] + .

[0308] The following compounds were prepared similarly to the representative procedures described for Example 42 and Example 43.

[0309] [Table 9-1]

[0310] [Table 9-2]

[0311]

Table 9-3

[0312]

Table 9-4

[0313]

Table 9-5

[0314]

Table 9-6

[0315]

Table 9-7

[0316]

Table 9-8

[0317]

Table 9-9

[0318]

Table 9-10

[0319]

Table 9-11

[0320]

Table 9-12

[0321] Example 74

[0322] [ka]

[0323] A mixture of 8-bromo-4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-morpholino-pyrido[4,3-d]pyrimidin-7-one (30 mg, 59 μmol), 2-(tributylstannyl)pyridine (32 mg, 88 μmol) and Pd(PPh3)4 (14 mg, 12 μmol) in toluene (6 mL) was stirred under Ar at 110° C. for 2 h. The mixture was diluted with EA (150 mL) and HO (20 mL). The organic phase was dried over Na2SO4, filtered, concentrated and purified by prep-HPLC to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-morpholino-8-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-7(6H)-one as a yellow solid (2.5 mg, 8% yield). LC-MS: m / z 510.7 [M+H] + .

[0324] Example 75

[0325] [ka]

[0326] Step 1: A mixture of 8-bromo-2-methyl-6-morpholinopyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione (136.4 mg, 0.4 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (138.0 mg, 0.6 mmol), Pd(dppf)Cl2 (74 mg, 0.1 mmol) and Cs2CO3 (260.0 mg, 0.8 mmol) in dioxane (10 mL) and water (2 mL) was stirred under Ar at 100° C. for 5 h. The mixture was diluted with DCM (150 mL) and water (10 mL). The organic phase was dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to give 5-(2-methyl-6-morpholino-4,7-dioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-8-yl)picolinonitrile (110 mg, 75% yield). LC-MS: m / z 364.8 [M+H] + .

[0327] Step 2: A mixture of 5-(2-methyl-6-morpholino-4,7-dioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-8-yl)picolinonitrile (36.4 mg, 0.1 mmol), K3PO4 (63.6 mg, 0.3 mmol) and phosphonitrilic chloride trimer (34.8 mg, 0.1 mmol) in CH3CN (10 mL) was stirred at room temperature for 3 h. (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (18.9 mg, 0.1 mmol) was added and the mixture was stirred at 80° C. for 2 h. The solvent was removed. DCM (150 mL) and water (20 mL) were added. The mixture was stirred for 10 min. The organic phase was dried over Na2SO4, filtered, concentrated and purified by prep-HPLC to give (R)-5-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-morpholino-7-oxo-6,7-dihydropyrido[4,3-]pyrimidin-8-yl)picolinonitrile (15 mg, 28% yield). LC-MS: m / z 535.7 [M+H] + .

[0328] The following compounds were prepared similarly to the representative procedures described for Example 75.

[0329] [Table 10]

[0330] Example 77

[0331] [ka]

[0332] Step 1: A mixture of 2-methyl-6-morpholino-3H-pyrido[4,3-d]pyrimidine-4,7-dione (16 mg, 61 μmol), phosphonitrilic chloride trimer (21.2 mg, 61 μmol) and K3PO4 (32.3 mg, 152.5 μmol) in CH3CN (3 mL) was stirred at room temperature for 3 h. Tert-butyl N-[[2-[5-[(1R)-1-aminoethyl]-3-thienyl]phenyl]methyl]-N-methyl-carbamate (23.3 mg, 67.1 μmol) was added. The mixture was stirred for 3 h. The reaction mixture was concentrated and purified by prep-HPLC to give tert-butyl N-methyl-N-[[2-[5-[(1R)-1-[(2-methyl-6-morpholino-7-oxo-pyrido[4,3-d]pyrimidin-4-yl)amino]ethyl]-3-thienyl]phenyl]methyl]carbamate (5 mg, 14% yield). LC-MS: m / z 590.8[M+H] + .

[0333] Step 2: To a stirred solution of tert-butyl N-methyl-N-[[2-[5-[(1R)-1-[(2-methyl-6-morpholino-7-oxo-pyrido[4,3-d]pyrimidin-4-yl)amino]ethyl]-3-thienyl]phenyl]methyl]carbamate (5 mg, 8.5 μmol) in dioxane (1 mL) was added 4N HCl in dioxane (3 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, basified with 1N NaHCO3 (aq.), extracted with DCM (30 mL), dried over Na2SO4, filtered, concentrated and purified by prep-HPLC to give 2-methyl-4-[[(1R)-1-[4-[2-(methylaminomethyl)phenyl]-2-thienyl]ethyl]amino]-6-morpholino-pyrido[4,3-d]pyrimidin-7-one (1.5 mg, 36% yield). LC-MS: m / z 490.8 [M+H] + .

[0334] Example 3. Biological Assays a. KRAS::SOS1 AlphaScreen binding assay This assay was used to investigate the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS G12D in a defined biochemical setting. 50 The values ​​indicate high potency of SOS1 inhibitor compounds in this assay setting.

[0335] reagent: GST-TEV-SOS1(564-1049) and His-TEV-Avi-KRAS G12D(1-169) were purchased from Viva Biotech (Shanghai) Ltd.

[0336] GDP (Sigma, Catalog No. G7127) AlphaLISA glutathione acceptor beads (PerkinElmer, catalog number AL109C) AlphaScreen Streptavidin Donor Beads (PerkinElmer, Catalog No. 6760002S) Assay Plates: ProxiPlate-384 Plus, white 384 shallow well microplates (PerkinElmer, Cat. No. 6008280) Assay Buffer: PBS, pH 7.4 (Gibco, catalog number 10010023) 0.05% Tween 20 (Sigma, Catalog No. P7949-100ML) 0.1% Bovine Serum Albumin (BSA) (Sigma, Cat. No. A1933-5G) Assay Protocol: SOS1 inhibitor compounds are diluted to a final starting concentration of 1 μM. Serial dilutions of compounds are performed at 9 concentrations in 1:3 serial dilutions using a Tecan D300e digital dispenser. 100 nL of compound solution is transferred per well to a 384-well assay plate, covering the range between 1 μM and a minimum of 0.15 nM in duplicate. 10 nM (final assay concentration) of KRAS G12D, 5 nM (final assay concentration) of SOS1 and 10 μM (final assay concentration) of GDP are mixed in assay buffer and 5 μL of KRAS::SOS1 GDP mix is ​​added to the 100 nL of compound solution in the assay plate (final dilution in assay 1:100, final DMSO concentration 1%). After 30 min incubation, AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads are mixed in assay buffer at a concentration of 5 μg / mL (final assay concentration) and 5 μL of the bead mix is ​​added into the assay plate. The plate is kept at room temperature in a darkened incubator for 3 h. After 3 h incubation, the signal is determined using Envision (PerkinElmer). The excitation wavelength is 680 nm and the emission is 615 nm. IC 50 Values ​​are calculated and analyzed using GraphPad Prism.

[0337] [Table 11-1]

[0338] [Table 11-2]

[0339] b. Cell proliferation assay The purpose of the cell proliferation assay is to determine the potency of compounds to inhibit SOS1-mediated proliferation of cancer cell lines in vitro in a defined cellular setting. 50 The values ​​indicate high potency of the compounds in this assay setting. It is observed that the SOS1 inhibitor compounds exhibit strong inhibitory effects on the proliferation of KRAS mutant human cancer cell lines.

[0340] Cell proliferation assays are performed under three-dimensional (3D) ultra-low conditions using the human cell line NCI-H358, a human non-small cell lung cancer (NSCLC) cell line harboring a KRAS G12C mutation.

[0341] Materials used: ·96-well clear round-bottom ultra-low attachment microplate (Corning, Cat. No. 7007) ·96-well clear flat-bottom white polystyrene TC-treated microplate (Corning, Cat. No. 3610) RPMI-1640 medium (Gibco, catalog number 22400105) Fetal bovine serum (FBS) (Gibco, catalog number 10099141C) 0.25% Trypsin-EDTA (Gibco, catalog number 25200056) Penicillin-streptomycin (Gibco, catalog number 15140122) · CellTiter-Glo 3D Cell Viability Assay (Promega, Cat. No. G9683).

[0342] Assay Protocol: NCI-H358 cells (ATCC, Catalog No. CRL-5807) are grown in cell culture flasks using RPMI medium supplemented with 10% FBS. Cells are incubated at 37°C and 5% CO2 in a humidified atmosphere with subculture twice a week. For 3D cell viability determination, cells are trypsinized, counted, and seeded into 96-well ultra-low attachment plates. The day after seeding, serial dilutions of SOS1 inhibitor compounds are performed using a Tecan D300e digital dispenser to evaluate the concentration-dependent effect on cell viability. Test compound concentrations encompass a range between 5μM and 0.76nM at nine concentrations using 1:3 serial dilutions. 0.5μL of serial dilutions of compound are added in duplicate. After 3 days, the cell viability effect of SOS1 inhibitor compounds in 3D format is measured using the CellTiter-Glo 3D cell viability assay. Luminescence intensity is determined using Envision (PerkinElmer). Analyze the data and IC 50 Values ​​are calculated using GraphPad Prism.

[0343] [Table 12-1]

[0344] [Table 12-2]

[0345] Example 4. Comparison of biological activity and liver microsomal stability Compound I-18 disclosed in WO2019 / 122129A1 was prepared. As shown in the table below, this compound has very poor stability in human liver microsome assay and weaker activity in H358 cell assay. Surprisingly, when the CN bond between the tetrahydropyran ring and the bicyclic core in compound I-18 was replaced with an NN bond in this compound (compound I-18 vs. examples 1, 17, 29, 30, 43, 53 and 61), the human liver microsome stability of this compound was dramatically improved. Furthermore, the H358 cell activity of this compound was also significantly enhanced.

[0346] [Table 13-1]

[0347] [Table 13-2]

[0348] [Table 13-3]

Claims

1. Compounds of Formula I 【Chemistry 1】 A pharma- ceutically acceptable salt or stereoisomer thereof (In the formula, Ring A is a 3- to 12-membered carbocyclyl, a 3- to 12-membered heterocyclyl, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; R １ is hydrogen, halogen, C １～６ Alkyl or C ３～６ cycloalkyl, R １ The C represented by １～６ Alkyl or C ３～６ cycloalkyl is optionally substituted with one to more groups selected from halogen and -OH; V is N or CR ２ and R ２ is hydrogen, halogen, -CN, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, -OR ２ａ , -NR ２ａ R ２ｂ , -C(O)R ２ａ , -C(O)OR ２ａ , -C(O)NR ２ａ R ２ｂ , -SO ２ R ２ａ , -SO ２ N.R. ２ａ R ２ｂ , -P(O)R ２ａ R ２ｂ , -NR ２ａ C(O)R ２ｂ , -NR ２ａ C(O)OR ２ｂ , -NR ２ａ SO ２ R ２ｂ , -NR ２ａ SO ２ N.R. ２ｂ R ２ｃ , 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; R ２ The C represented by １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl can be selected from one or more R ２ｄ and optionally substituted with; R ２ａ , R ２ｂ and R ２ｃ are independently hydrogen, C １～６ selected from the group consisting of alkyl, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; or R ２ａ and R ２ｂ Or R ２ｂ and R ２ｃ together with the N or P atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl; R ２ａ , R ２ｂ Or R ２ｃ or R ２ａ , R ２ｂ Or R ２ｃ In the group represented by １～６ Alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl may optionally be one or more R ２ｄ is replaced by; R ２ｄ is, at each occurrence, hydrogen, halogen, oxo, -CN, C １～６ Alkyl, C １～６ Haloalkyl, -OR ２ｅ , -NR ２ｅ R ２ｆ , -C(O)R ２ｅ , -C(O)OR ２ｅ , -C(O)NR ２ｅ R ２ｆ , -SO ２ R ２ｅ , -SO ２ N.R. ２ｅ R ２ｆ , -P(O)R ２ｅ R ２ｆ , -NR ２ｅ C(O)R ２ｆ , -NR ２ｅ C(O)OR ２ｆ , -NR ２ｅ SO ２ R ２ｆ , -NR ２ｅ SO ２ N.R. ２ｆ R ２ｇ , 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; R ２ｅ , R ２ｆ and R ２ｇ are independently hydrogen and C １～６ selected from the group consisting of alkyl; X is N or CR ３ and R ３ is hydrogen, halogen or C １～３ is alkyl; R ４ is hydrogen or C １～６ is alkyl; R ５ is hydrogen, C １～６ alkyl, 3- to 6-membered monocyclic carbocyclyl, or 4- to 6-membered monocyclic heterocyclyl; R ５ The C represented by １～６ alkyl, 3- to 5-membered monocyclic carbocyclyl, or 4- to 6-membered monocyclic heterocyclyl are optionally substituted with one or more groups selected from halogen and -OH; R ６ is hydrogen, -OH, halogen, -CN, oxo, C １～６ Alkyl, C １～６ Alkoxy, -SO ２ R ６ａ , -SO ２ N.R. ６ａ R ６ｂ , -P(O)R ６ａ R ６ｂ , -C(O)NR ６ａ R ６ｂ , -NR ６ａ C(O)R ６ａ , -NR ６ａ C(O)NR ６ａ R ６ｂ , -(CH ２ ) ｓ N.R. ６ａ R ６ｂ , -O(CH ２ ) ｔ N.R. ６ａ R ６ｂ , 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; R ６ The C represented by １～６ Alkyl, C １～６ Alkoxy, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is selected from one to more R ６ｃ and optionally substituted with; R ６ａ and R ６ｂ are independently hydrogen or C １～６ alkyl or R ６ａ and R ６ｂ together with the N or P atom to which they are attached form a 4- to 7-membered heterocyclyl; s is an integer from 0 to 3; t is an integer from 2 to 4; R ６ｃ is, at each occurrence, hydrogen, -OH, halogen, -CN, oxo, C １～６ Alkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, -NR ６ａ R ６ｂ , -SO ２ R ６ａ , -SO ２ N.R. ６ａ R ６ｂ , -C(O)NR ６ａ R ６ｂ , -P(O)R ６ａ R ６ｂ , -NR ６ａ C(O)R ６ａ , -NR ６ａ C(O)NR ６ａ R ６ｂ , -(CH ２ ) ｓ N.R. ６ａ R ６ｂ or -O(CH ２ ) ｔ N.R. ６ａ R ６ｂ and R ６ｃ The C represented by １～６ Alkyl or C ３～６ Cycloalkyl includes halogen, —OH and —NR ６ａ R ６ｂ and optionally substituted with one or more groups selected from R ７ and R ８ are independently hydrogen, C １～６ Alkyl, C ３～６ Alkenyl, C ３～６ Alkynyl, C ２～６ alkoxy, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R ７ Or R ８ The C represented by １～６ Alkyl, C ３～６ Alkenyl, C ３～６ Alkynyl, C ２～６ Alkoxy, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl may be one or more R ７ａ or R ７ and R ８ together with the N atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl; said 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl may be selected from one or more R ７ｂ and optionally substituted with; R ７ａ is hydrogen, halogen, -CN, C １～６ Alkyl, -OR ７ｃ , -NR ７ｃ R ７ｄ , -C(O)R ７ｃ , -C(O)OR ７ｃ , -C(O)NR ７ｃ R ７ｄ , -SO ２ R ７ｃ , -P(O)R ７ｃ R ７ｄ , -SO ２ N.R. ７ｃ R ７ｄ , -NR ７ｃ C(O)R ７ｄ , -NR ７ｃ C(O)OR ７ｄ , -NR ７ｃ SO ２ R ７ｄ , -NR ７ｃ SO ２ N.R. ７ｄ R ７ｅ , 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; R ７ａ The C represented by １～６ Alkyl, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl can be one or more R ７ｆ and optionally substituted with; R ７ｂ is hydrogen, halogen, -CN, oxo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Alkoxy, -OR ７ｃ , -NR ７ｃ R ７ｄ , -C(O)R ７ｃ , -C(O)OR ７ｃ , -C(O)NR ７ｃ R ７ｄ , -SO ２ R ７ｃ , -P(O)R ７ｃ R ７ｄ , -SO ２ N.R. ７ｃ R ７ｄ , -NR ７ｃ C(O)R ７ｄ , -NR ７ｃ C(O)OR ７ｄ , -NR ７ｃ SO ２ R ７ｄ , -NR ７ｃ SO ２ N.R. ７ｄ R ７ｅ , 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; R ７ｂ C represented by １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Alkoxy, 3- to 12-membered carbocyclyl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl can be represented by one or more R ７ｆ and optionally substituted with; R ７ｃ , R ７ｄ and R ７ｅ are independently hydrogen, C １～６ selected from the group consisting of alkyl, 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; or R ７ｃ and R ７ｄ together with the N or P atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl; R ７ｃ , R ７ｄ Or R ７ｅ or R ７ｃ , R ７ｄ Or R ７ｅ The C in the group represented by １～６ Alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is one or more R ７ｆ and optionally substituted with; R ７ｆ is, at each occurrence, hydrogen, halogen, -CN, or -OH; n is 0, 1, 2, or 3; The heterocyclyl contains 1 to 4 heteroatoms selected from O, N and S; the heteroaryl contains 1 to 4 heteroatoms selected from O, N and S).

2. Formula II 【Chemistry 2】 2. The compound of claim 1, represented by: or a pharma- ceutically acceptable salt or stereoisomer thereof.

3. Ring A is a 3- to 10-membered carbocyclyl, a 4- to 10-membered heterocyclyl, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; R １ is hydrogen, C １～４ Alkyl or C ３～６ is cycloalkyl; R ２ is hydrogen, halogen, -CN, C １～４ Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, -OR ２ａ , -NR ２ａ R ２ｂ , -C(O)R ２ａ , -C(O)OR ２ａ , -C(O)NR ２ａ R ２ｂ , -NR ２ａ C(O)R ２ｂ , -NR ２ａ C(O)OR ２ｂ , 3-6 membered monocyclic carbocyclyl, 3-6 membered monocyclic heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; R ２ The C represented by １～４ Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R ２ｄ and optionally substituted with; R ２ａ and R ２ｂ are independently hydrogen, C １～６ Alkyl, C １～６ Haloalkyl or C １～６ hydroxyalkyl; or R ２ａ and R ２ｂ together with the N atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl; R ２ｄ is, at each occurrence, hydrogen, halogen, oxo, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, -OR ２ｅ , -NR ２ｅ R ２ｆ , -SO ２ R ２ｅ , -P(O)R ２ｅ R ２ｆ , COOR ２ｅ , C.O.R. ２ｅ R ２ｆ , a 3- to 6-membered monocyclic carbocyclyl, a 3- to 6-membered monocyclic heterocyclyl, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; R ２ｅ and R ２ｆ are independently hydrogen and C １～６ selected from the group consisting of alkyl; R ５ is hydrogen, C １～４ alkyl, 3- to 5-membered monocyclic carbocyclyl, or 4- to 5-membered monocyclic heterocyclyl; R ６ is hydrogen, -OH, halogen, -CN, oxo, C １～６ Alkyl, -(CH ２ ) ｓ N.R. ６ａ R ６ｂ , 3-6 membered monocyclic carbocyclyl, 3-6 membered monocyclic heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; R ６ The C represented by １～６ Alkyl, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl may optionally be one or more R ６ｃ is replaced by; R ６ａ and R ６ｂ are independently hydrogen or C １～４ is alkyl; s is an integer from 0 to 2; R ６ｃ is, at each occurrence, hydrogen, -OH, halogen, -CN, oxo, C １～６ Alkyl, -NR ６ａ R ６ｂ Or - (CH ２ ) ｓ N.R. ６ａ R ６ｂ and R ６ｂ The C represented by １～６ The alkyl is optionally substituted with one to more groups selected from halogen and -OH; R ７ and R ８ are independently hydrogen, C １～４ Alkyl, C ３～４ Alkenyl, C ３～４ Alkynyl, C ２～４ alkoxy, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R ７ Or R ８ The C represented by １～４ Alkyl, C ３～４ Alkenyl, C ３～４ Alkynyl, C ２～４ Alkoxy, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl may be one or more R ７ａ or R ７ and R ８ together with the N atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl; said 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl is selected from 1 to 3 R ７ｂ and optionally substituted with; R ７ａ is hydrogen, halogen, -CN, C １～６ Alkyl, -OR ７ｃ or -NR ７ｃ R ７ｄ and R ７ｂ is hydrogen, halogen, -CN, oxo, C １～６ Alkyl, C １～６ Alkoxy, -OR ７ｃ , -NR ７ｃ R ７ｄ , -C(O)R ７ｃ , -C(O)OR ７ｃ , -SO ２ R ７ｃ or 5-10 membered heteroaryl, R ７ｂ C represented by １～６ Alkyl, C １～６ Alkoxy or 5-10 membered heteroaryl can be one or more R ７ｆ and optionally substituted with; R ７ｃ Or R ７ｄ are independently hydrogen, C １～４ selected from the group consisting of alkyl, 3- to 6-membered monocyclic carbocyclyl, 4- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; or R ７ｃ and R ７ｄ together with the N atom to which they are attached form a 4- to 8-membered heterocyclyl or a 5- to 10-membered heteroaryl; R ７ｃ Or R ７ｄ The C represented by １～４ Alkyl, 3- to 6-membered monocyclic carbocyclyl, 4- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is selected from 1 to 3 R ７ｆ and optionally substituted with; R ７ｆ is, at each occurrence, hydrogen, halogen, -CN, or OH; 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt or stereoisomer thereof.

4. R ２ is hydrogen, halogen, -CN, C １～４ Alkyl, C ２～４ Alkenyl, C ２～４ alkynyl, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R ２ The C represented by １～４ Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, 3- to 6-membered monocyclic carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R ２ｄ and optionally substituted with; R ２ｄ is, at each occurrence, hydrogen, halogen, oxo, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, -OR ２ｅ , -NR ２ｅ R ２ｆ , -SO ２ R ２ｅ , -P(O)R ２ｅ R ２ｆ , COOR ２ｅ , C.O.R. ２ｅ R ２ｆ , a 3- to 6-membered monocyclic carbocyclyl, a 3- to 6-membered monocyclic heterocyclyl, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; R ２ｅ and R ２ｆ are independently hydrogen and C １～６ 4. The compound of claim 1, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of: alkyl, aryl, arylsulfates, arylalkyl, arylsulfates ...

5. R ７ and R ８ are independently hydrogen, C １～４ Alkyl, C ３～４ Alkenyl, C ３～４ alkynyl; R ７ Or R ８ The C represented by １～４ Alkyl, C ３～４ Alkenyl, C ３～４ Alkynyl is one or more R ７ａ or R ７ and R ８ together with the N atom to which they are attached form a 4- to 12-membered heterocyclyl or a 5-membered heteroaryl, each of which is represented by 1 to 3 R ７ｂ and optionally substituted with; R ７ａ is hydrogen, halogen, -CN, C １～６ Alkyl, -OR ７ｃ or -NR ７ｃ R ７ｄ and R ７ｂ is hydrogen, halogen, -CN, oxo, -OH, C １～６ Alkyl, C １～６ Alkoxy, -NR ７ｃ R ７ｄ , -C(O)R ７ｃ , -C(O)OR ７ｃ , -SO ２ R ７ｃ or 5-10 membered heteroaryl, R ７ｂ C represented by １～６ Alkyl, C １～６ Alkoxy or 5-10 membered heteroaryl can be one or more R ７ｆ and optionally substituted with; R ７ｃ Or R ７ｄ are independently hydrogen, C １～４ selected from the group consisting of alkyl, 3- to 6-membered monocyclic carbocyclyl, 4- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; or R ７ｃ and R ７ｄ together with the N atom to which they are attached form a 4- to 8-membered heterocyclyl or a 5- to 10-membered heteroaryl; R ７ｃ Or R ７ｄ The C represented by １～４ Alkyl, 3- to 6-membered monocyclic carbocyclyl, 4- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is selected from 1 to 3 R ７ｆ and optionally substituted with; R ７ｆ is, at each occurrence, hydrogen, halogen, -CN, or OH; 5. A compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt or stereoisomer thereof.

6. Ring A is a 3- to 6-membered monocyclic cycloalkyl, a 4- to 6-membered monocyclic heterocyclyl, phenyl, or a 5- to 10-membered heteroaryl; R ６ is hydrogen, -OH, halogen, -CN, C １～６ Alkyl or -(CH ２ ) ｓ N.R. ６ａ R ６ｂ and R ６ The C represented by １～６ The alkyl is optionally substituted with one to more groups selected from halogen and -OH; R ６ａ and R ６ｂ are independently hydrogen or C １～４ is alkyl; s is 0 or 1; 6. A compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt or stereoisomer thereof.

7. 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein Ring A is cyclopropyl, phenyl, thiophenyl, or indole.

8. Formula (III-A) or (III-B) 【Chemistry 3】 8. The compound of claim 1 , wherein the compound is represented by:

9. R ６ is hydrogen, halogen, C １～４ Alkyl or -(CH ２ ) N.R. ６ａ R ６ｂ and R ６ The C represented by １～４ Alkyl is optionally substituted with one or more groups selected from halogen and —OH; R ６ａ and R ６ｂ are independently hydrogen or C １～４ 9. The compound of any one of claims 1 to 8, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein: R is 1 or 2;

10. R ５ 10. The compound of claim 1, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein: is hydrogen, methyl or ethyl, optionally methyl.

11. R ２ is hydrogen, halogen, -CN, C １～４ Alkyl, C ２～４ alkenyl, 3-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl or 5-10 membered heteroaryl; R ２ The C represented by １～４ Alkyl, 3- to 6-membered monocyclic cycloalkyl, 5- to 6-membered monocyclic heterocyclyl, phenyl, or 5- to 10-membered heteroaryl is selected from 1 to 3 R ２ｄ and optionally substituted with; R ２ｄ is, at each occurrence, hydrogen, halogen, oxo, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, -OR ２ｅ , -NR ２ｅ R ２ｆ , -SO ２ R ２ｅ , -P(O)R ２ｅ R ２ｆ , COOR ２ｅ , C.O.R. ２ｅ R ２ｆ , a 3- to 6-membered monocyclic carbocyclyl, a 3- to 6-membered monocyclic heterocyclyl, phenyl, or a 5- to 10-membered heteroaryl; R ２ｅ and R ２ｆ are independently hydrogen and C １～６ 11. The compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of: alkyl.

12. R ２ is phenyl or 5-10 membered heteroaryl; said phenyl or 5-10 membered heteroaryl is selected from 1-3 R ２ｄ and optionally substituted with; R ２ｄ represents, at each occurrence, hydrogen, halogen, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, -OR ２ｅ , -NR ２ｅ R ２ｆ , -SO ２ R ２ｅ , -P(O)R ２ｅ R ２ｆ , COOR ２ｅ , C.O.R. ２ｅ R ２ｆ , a 3- to 6-membered monocyclic carbocyclyl, a 3- to 6-membered monocyclic heterocyclyl, phenyl, or a 5- to 10-membered heteroaryl; R ２ｅ and R ２ｆ are independently hydrogen and C １～６ 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of: alkyl.

13. R ２ is phenyl, pyridyl, pyrimidyl, imidazolyl, pyrazolyl, imidazo[1,2-a]pyrimidine, imidazo[1,2-a]pyridine, or triazolo[4,3-a]pyridine, each of which is one to three R ２ｄ optionally substituted with; R ２ｄ is hydrogen, halogen, -CN, -CH ３ , -CF ３ , -NH ２ , -S(O) ２ Me, -OCH ３ , COOH, CONH ２ , COOMe, -P(O)(CH ３ ) ２ , -CH ２ CH ２ OH and -CH ２ CHF ２ 13. The compound of claim 12, selected from the group consisting of: or a pharma- ceutically acceptable salt or stereoisomer thereof.

14. R ２ is phenyl or pyridyl; each of which is 1 to 3 R ２ｄ optionally substituted with; R ２ｄ is hydrogen, halogen, -CN, -CH ３ , -CF ３ , -NH ２ , -S(O) ２ Me, -OCH ３ , COOH, CONH ２ , COOMe, -P(O)(CH ３ ) ２ , -CH ２ CH ２ OH and -CH ２ CHF ２ 14. The compound of claim 13, selected from the group consisting of: or a pharma- ceutically acceptable salt or stereoisomer thereof.

15. R ７ and R ８ together with the N atom to which they are attached form a 5- to 10-membered heterocyclyl or a 5-membered heteroaryl, each of which is selected from halogen, —CN, oxo, —OH, C １～６ Alkyl, C １～６ Alkoxy, -C(O)R ７ｃ , -C(O)OR ７ｃ and pyridinyl optionally substituted with CN; R ７ｃ are independently hydrogen, optionally substituted with —CN or —OH; １～４ selected from the group consisting of alkyl, 15. A compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt or stereoisomer thereof.

16. R ７ and R ８ are independently hydrogen or C １～４ alkyl, and optionally R ７ and R ８ 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein:

17. R ２ is H, F, Br, CH ３ , -C.N., 【Chemistry 4】 Selected from the group consisting of (In the formula, R ２ｄ is hydrogen, halogen, -CN, -CH ３ , -CF ３ , -NH ２ , -S(O) ２ Me, -OCH ３ , COOH, CONH ２ , COOMe, -P(O)(CH ３ ) ２ , -CH ２ CH ２ OH and -CH ２ CHF ２ (selected from the group consisting of 17. A compound according to any one of claims 1 to 11, 15 and 16, or a pharma- ceutically acceptable salt or stereoisomer thereof.

18. R ７ and R ８ together with the atoms to which they are attached, 【Chemistry 5】 and forming a heterocyclyl selected from the group consisting of: ７ｃ , -C(O)OR ７ｃ 18. The compound of any one of claims 1 to 15 and 17, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the compound is substituted with 1 to 3 groups selected from pyridinyl, optionally substituted with CN.

19. A compound set forth in Table 1 or a pharma- ceutically acceptable salt or stereoisomer thereof.

20. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier or excipient.

21. A pharmaceutical composition for use in a subject having a disease and / or condition in which inhibition of the interaction of SOS1 with a RAS family protein or RAC1 would be therapeutically beneficial, comprising a therapeutically effective amount of a compound described in any one of claims 1 to 19 or a pharma- ceutically acceptable salt or stereoisomer thereof.

22. 20. A pharmaceutical composition for treating cancer, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt or stereoisomer thereof.

23. 23. The pharmaceutical composition of claim 21 or 22, wherein the pharmaceutical composition is administered in combination with a therapeutically effective amount of at least one other pharmacologically active substance.

24. 24. The pharmaceutical composition of claim 23, wherein said at least one other pharmacologically active substance is an inhibitor of MEK and / or a mutant thereof.

25. 23. The pharmaceutical composition of claim 22, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

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