benzylamino-substituted pyridopyrimidinones and derivatives as sos1 inhibitors

专利摘要:
The present invention relates to compounds of formula (I), in which the groups R1 to R4, A and p have the meanings provided in the claims and specification, their use as SOS1 inhibitors, pharmaceutical compositions containing compounds of this type and their use as medicines / medical uses, especially as agents for treatment and / or prevention of oncological diseases.
公开号:BR112020010123A2
申请号:R112020010123-0
申请日:2018-12-20
公开日:2020-11-10
发明作者:Juergen RAMHARTER；Markus Ostermeier；Markus Frank；Annika GILLE；Stefan Goepper；Marco Santagostino；Julian WIPPICH；Christiane Kofink；Heinz Stadtmueller；Tobias Wunberg；Marco Hans Hofmann；Anke Baum；Michael Gmachl；Dorothea Ingrid RUDOLPH；Fabio SAVARESE
申请人:Boehringer Ingelheim International Gmbh；
IPC主号:

专利说明:

[0001] [0001] The present invention relates to pyridopyrimidinones substituted by benzylamino and derivatives of formula (I) (R 4) p THE
[0002] [0002] in which the groups R1 to R4, A and p have the meanings provided in the claims and specification, their use as SOS1 inhibitors, pharmaceutical compositions containing compounds of this type and their use as medicines / medical uses, especially as agents for the treatment and / or prevention of oncological diseases. BACKGROUND OF THE INVENTION
[0003] [0003] Proteins of the RAS family, including KRAS (homologue of the Kirsten V-Ki-ras2 rat sarcoma viral oncogene), NRAS (homologue of the neuroblastoma RAS viral oncogene) and HRAS (Harvey murine sarcoma viral oncogene) and any mutants thereof are small GTPases existing in cells in the states bound to GTP or bound to GDP (McCormick et al., J. Mol. Med. (Berl)., 2016, 94 (3): 253-8; Nim - nual et al., Sci. STKE., 2002, 2002 (145): pe36). Proteins of the RAS family have weak intrinsic GTPase activity and low nucleotide exchange rates (Hunter et al., Mol. Cancer Res., 2015, 13 (9): 1325- 35). The binding of GTPase-activating proteins (GAPs), such as NF1, increases the GTPase activity of proteins of the RAS family. The binding of guanine nucleotide exchange factors (GEFs), such as
[0004] [0004] Cancer-associated mutations in proteins of the RAS family suppress its GAPase-induced and intrinsic GTPase activity, leading to an increase in the population of GTP-activated / linked RAS 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 persistent activation of effector pathways (eg MEK / ERK, PI3K / AKT / mTOR, RalGDS pathways) downstream of the RAS family proteins. KRAS mutations (eg, amino acids G12, G13, Q61, A146) are found in a variety of human cancers, including lung cancer, colorectal cancer and pancreatic cancer (Cox et al., Nat. Rev. Drug Discov., 2014, 13 (11): 828-51). Mutations in HRAS (for example, amino acids G12, G13, Q61) and NRAS (for example, amino acids G12, G13, Q61, A146) are also found in a variety of types of human cancer, but generally with a lower frequency compared to KRAS mutations (Cox et al., Nat. Rev. Drug Discov., 2014, 13 (11): 828-
[0005] [0005] Son of Sevenless 1 (SOS1) is a human homologue of the Drosophila Son de Sevenless protein originally identified (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 N-terminal histone (HD) domains followed by the Dbl homology domain (DH), a plecstrin homology domain (PH), a helical ligand (HL), RAS exchange motif ( REM), CDC25 homology domain and a C-terminal proline (PR) domain. SOS1 has two binding sites for proteins of the RAS family; a catalytic site that binds GDP-linked RAS family proteins to promote guanine nucleotide exchange; and an allosteric site that binds GTP-bound RAS family proteins that causes an additional increase in 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 the activation of mutant KRAS and oncogenic signaling in cancer (Jeng et al., Nat. Commun., 2012, 3: 1168). The depletion of SOS1 levels decreased the rate of proliferation and survival of tumor cells carrying a KRAS mutation, while no effect was observed in wild-type KRAS cell lines. The effect of the loss of SOS1 could not be rescued by the introduction of a mutated catalytic site in SOS1, demonstrating the essential role of the GEF activity of SOS1 in KRAS mutant cancer cells.
[0006] [0006] SOS1 is critically involved in activating the signaling of proteins of the RAS family in cancer through mechanisms other than mutations in proteins of the RAS family. SOS1 interacts with the adapter protein Grb2 and the resulting SOS1 / Grb2 complex binds to activated / phosphorylated Receptor Tyrosine Kinases (eg EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A / B, FGFR1 / 2/3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2/3, AXL) (Pierre et al., Biochem. Pharmacol., 2011, 82 (9): 1049-56). SOS1 is also recruited to other cell surface phosphorylated 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 location of SOS1 in the plasma membrane, proximal to proteins of the RAS family, allows SOS1 to promote the activation of proteins of the RAS family. The activation of SOS1 of proteins in the RAS family can also be mediated by the interaction of SOS1 / Grb2 with the BCR-ABL oncoprotein 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).
[0007] [0007] In addition, changes in SOS1 have been implicated in cancer. SOS1 mutations are found in embryonic rhabdomyosarcomas, Sertoli cell testicular tumors, granular skin cell tumors (Denayer et al., Genes Chromosomes Cancer, 2010, 49 (3): 242-52) and adenocarcinoma of lung (Cancer Ge- name Atlas Research Network., Nature. 2014, 511 (7511): 543-50). In the meantime, 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, hereditary mutations of SOS1 are implicated in the pathogenesis of RASopathies such as, for example, Noonan syndrome (NS),
[0008] [0008] SOS1 is also a GEF for the activation of RTP1 GTPases (Ras-related botulinum toxin C3 substrate 1) (Innocenti et al., J. Cell Biol., 2002, 156 (1): 125-36). RAC1, like proteins in the RAS family, is implicated in the pathogenesis of a variety of human cancers and other diseases (Bid et al., Mol. Cancer Ther. 2013, 12 (10): 1925-34).
[0009] [0009] Son of Sevenless 2 (SOS2), a SOS1 homologue 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 no-mouse models suggest a redundant role for SOS1 and SOS2 in adult mouse homeostasis. While the germ knockout of SOS1 in mice results in lethality during middle embryonic pregnancy (Qian et al., EMBO J., 2000, 19 (4): 642-54), adult mice with systemic conditional SOS1 are viable (Baltanás et al., Mol. Cell. Biol., 2013, 33 (22): 4562-78). The targeting of the SOS2 gene did not result in any evident phenotype in mice (Esteban et al., Mol. Cell. Biol., 2000, 20 (17): 6410-3). In contrast, SOS1 and SOS2 double knockout leads to rapid lethality in adult mice (Baltanás et al., Mol. Cell. Biol., 2013, 33 (22): 4562-78). These published data suggest that the selective targeting of individual SOS isoforms (eg, selective targeting of SOS1) may be adequately tolerated to achieve a therapeutic index among cancers activated by the SOS1 / RAS family protein (or other protein pathologies of the SOS1 family) / RAS) and normal cells and tissues.
[0010] [0010] Selective pharmacological inhibition of SOS1 catalytic site binding to proteins of the RAS family is expected to prevent SOS1-mediated activation of proteins of the RAS family to the GTP-bound form. Such SOS1 inhibitor compounds are expected to consequently inhibit signaling in cells downstream of proteins of the RAS family (eg ERK phosphorylation). In cancer cells associated with dependence on proteins of the RAS family (eg KRAS mutant cancer cell lines), SOS1 inhibitory compounds are expected to offer anticancer efficacy (eg, inhibition of proliferation, survival, metastasis, etc. .). High potency for inhibiting the binding of proteins of the SOS1 family: RAS (IC 50 values at the nanomolar level) and ERK phosphorylation in cells (IC 50 values at the nanomolar level) are desirable characteristics for an SOS1 inhibiting compound. In addition, a desirable characteristic of the SOS1 inhibiting compound would be the selective inhibition of SOS1 over SOS2. This conclusion is based on the viable phenotype of SOS1 knockout mice and lethality of double SOS1 / SOS2 knockout mice, as described above.
[0011] [0011] These characteristics have not been fully achieved in the SOS1 inhibitor compounds described above. In recent decades, the RAS-protein SOS1 protein interaction has gained increasing recognition. To date, several efforts have been made to identify and optimize binders, which target the RAS effector binding site or the SOS1 catalytic binding site (for a selected review, see: Lu et al., ChemMedChem. 2016, 11 (8): 814-21), were made with limited success.
[0012] [0012] Recently, small activating molecules have been identified, which bind to a lipophilic bag of SOS1 near the RAS binding site (Burns et al., Proc. Natl. Acad. Sci. 2014, 111 (9) : 3401 -6). However, the binding of these molecules seems to lead to an increase in nucleotide exchange and, thus, to RAS activation instead of deactivation.
[0013] [0013] In an effort to stabilize the protein-protein interaction of proteins in the RAS family with SOS1 and to prevent the reloading of proteins in the RAS family with GTP, several different fragments were subsequently identified (Winter et al., J Med. Chem. 2015, 58 (5): 2265-74). However, the reversible binding of fragments to SOS1 did not translate into a measurable effect on nucleotide exchange and only a weak effect was observed for fragments covalently linked to RAS.
[0014] [0014] Still recently, studies were conducted to combine screening platforms and rational design to identify inhibitors of small molecules of SOS1 (Evelyn et al., Chem. Biol. 2014, 21 (12): 1618-28; Evelyn et al., J. Biol. Chem. 2015, 290 (20): 12879-98; Zheng et al., WO 2016/077793), that is, compounds that bind to SOS1 and inhibit protein-protein interaction with proteins from RAS family. Although compounds with a mild inhibitory effect on SOS1 have been identified, the effects on guanine nucleotide exchange and modulation of cellular signal transduction (eg, ERK phosphorylation) are weak.
[0015] [0015] WO 2018/115380 and WO 2018/172250 disclose quinazoline-based SOS inhibitors.
[0016] [0016] Here, new SOS1 inhibitor compounds are described, which bind to the catalytic site of SOS1 (confirmed by crystallography) and simultaneously prevent interactions and activation of proteins of the RAS family. This results in a marked inhibitory effect on the interaction of SOS1 with proteins of the RAS family, in particular, KRAS (with low single-digit nanomolar IC50 activity) and, consequently, a significant reduction in ERK phosphorylation in cell lines cancer mutants for KRAS.
[0017] [0017] The selective SOS1 inhibitor compounds described in this document are expected to provide a pharmacological benefit to cancer patients that are associated with dependence on protein signaling from the RAS family. Those channels that are expected to be targets of an SOS1 inhibiting compound include those that require changes (mutations, gene amplification, overexpression) of components (proteins, genes) in the RAS family protein pathway, such as KRAS, NRAS , HRAS, 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), GAPs (e.g., NF1) and SOS1. In addition, given the role of SOS1 in the activation of RAC1, cancers that demonstrate RAC1 dependence are expected to be targets of SOS1 inhibitory compounds. In addition, in other diseases associated with dysregulation of the RAS family protein pathway, such as neurofibromatosis, Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC) and type 1 hereditary gingival fibromatosis, it is expected SOS1 inhibitor compounds are also expected to provide a pharmacological benefit.
[0018] [0018] In addition to the inhibitory effect and potency, the compounds disclosed here show good solubility, adjusted DMPK properties and good selectivity over human cytoma kinases. In addition, these structurally and synthetically new pyridopyrimidinone-based compounds show good metabolic stability, a time-dependent decrease in the risk of cytochrome inhibition and, presumably, a general decrease in off-target risk.
[0019] [0019] It has now been found that, surprisingly, compounds of formula (I), in which the groups R1 to R4, A and p have the meanings provided in this document, act as inhibitors of the interaction of the catalytic site of SOS1 with proteins of the RAS family that is involved in the control of cell proliferation. In this way, the compounds according to the invention can be used, for example, for the treatment of diseases characterized by excessive or abnormal cell proliferation.
[0020] The present invention, therefore, relates to a compound of formula (I) (R 4) p THE
[0021] [0021] In one aspect [A1], the invention relates to a compound of formula (I) or a salt thereof, where R1 is Ra1; Ra1 is selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, where C1-6alkyled, C1 -6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted by one or more identical or different Rb1 and / or Rc1; each Rb1 is independently selected from the group consisting of -ORc1, -NRc1Rc1, halogen, -CN, -C (O) Rc1, -C (O) ORc1 and -C (O) NRc1Rc1; each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, where o C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted by one or more identical Rd1 and / or Re1 or different; each Rd1 is independently selected from the group consisting of –ORe1, -NRe1Re1, halogen, -CN, -C (O) Re1, -C (O) ORe1 and -C (O) NRe1Re1; each Re1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl.
[0022] [0022] In another aspect [A2], the invention relates to a compound of formula (I) or a salt thereof, where R1 is Ra1; Ra1 is selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl and he-
[0023] [0023] In another aspect [A3], the invention relates to a compound of formula (I) or a salt thereof, where R1 is Ra1; Ra1 is selected from the group consisting of C3-10cycloalkyl and C4-10cycloalkenyl, where C3-10cycloalkyl and C4-10cycloalkenyl are both optionally substituted by one or more identical or different Rb1 and / or Rc1; each Rb1 is independently selected from the group consisting of -ORc1, -NRc1Rc1, halogen, -CN, -C (O) Rc1, -C (O) ORc1 and -C (O) NRc1Rc1; each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, where o C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and heteroaryl
[0024] [0024] In another aspect [A4], the invention relates to a compound of formula (I) or a salt thereof, wherein R1 is C3-8cycloalkyl optionally substituted by one or more identical or different Rb1 and / or Rc1 ; each Rb1 is independently selected from the group consisting of -ORc1, halogen and -C (O) NRc1Rc1; each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, where C1-6alkyl, C1-6haloalkyl, heterocyclyl 3-8 membered, 5-6 membered phenyl and heteroaryl are all optionally substituted by one or more, identical or different Rd1 and / or Re1; each Rd1 is independently selected from the group consisting of –ORe1 and halogen; each Re1 is independently selected from the group consisting of hydrogen and C1-6alkyl.
[0025] [0025] In another aspect [A5], the invention relates to a compound of formula (I) or a salt thereof, wherein R1 is C3-8cycloalkyl optionally substituted by one or more identical or different substitutes selected from the group consisting of C1-4alkyl, C1-4haloalkyl, C1-4alkoxy-C1-4alkyl, 5-6 membered heteroaryl, phenyl, halophenyl, halogen, 3-6 membered heterocyclyl, -C (O) N (C1 -4alkyl) 2 and hydroxy.
[0026] [0026] In another aspect [A6], the invention relates to a compound of formula (I) or a salt thereof, in which R1 is selected from among F F F F F F *, *, *, *, *, F F F F * * *,,, *, *, F F F *, * * *, *,,, OH OH OH F * F * F * *, *,,,, F F F F F * * *,, *, *,, O N O O N N N * * * * *,,,,, F OH OH The F
[0027] [0027] In another aspect [A7], the invention relates to a compound of formula (I) or a salt thereof, wherein R1 is selected from the group consisting of C1-6alkyl and C1-6haloalkyl.
[0028] [0028] In another aspect [A8], the invention relates to a compound of formula (I) or a salt thereof, wherein R1 is selected from the group consisting of C1-4alkyl and C1-4haloalkyl.
[0029] [0029] In another aspect [A9] the invention relates to a compound of formula (I) or a salt thereof, wherein R1 is 3-10 membered heterocyclyl optionally substituted by one or more, identical or different Rb1 and / or Rc1; each Rb1 is independently selected from the group consisting of -ORc1, -NRc1Rc1, halogen, -CN, -C (O) Rc1, -C (O) ORc1 and -C (O) NRc1Rc1; each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, where o C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted by one or more identical Rd1 and / or Re1 or different; each Rd1 is independently selected from the group consisting of –ORe1, -NRe1Re1, halogen, -CN, -C (O) Re1, -C (O) ORe1 and -C (O) NRe1Re1; each Re1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl.
[0030] [0030] In another aspect [A10], the invention relates to a compound of formula (I) or a salt thereof, wherein
[0031] [0031] In another aspect [A11], the invention relates to a compound of formula (I) or a salt thereof, wherein R1 is 3-8 membered heterocyclyl optionally substituted by a substituent selected from the group consisting of C1-6alkyl, C1-6haloalkyl and C6-10aryl.
[0032] [0032] In another aspect [A12], the invention relates to a compound of formula (I) or a salt thereof, in which R1 is selected from among O O O O O *, *, *, *, *, F F O F F O AT THE F F O *, *, *, *, *, O F F O F F N N O F F *, *, *, *, *
[0033] [0033] In another aspect [A13], the invention relates to a compound of formula (I) or a salt thereof, wherein R1 is 5-6 membered heteroaryl optionally substituted by C1-4alkyl.
[0034] [0034] In another aspect [B1], the invention relates to a compound of formula (I) or a salt thereof, where R2 is hydrogen.
[0035] [0035] In another aspect [B2], the invention relates to a compound of formula (I) or a salt thereof, where R2 is C1-4alkyl.
[0036] [0036] In another aspect [B3], the invention relates to a compound of formula (I) or a salt thereof, where R2 is methyl.
[0037] [0037] In another aspect [B4], the invention relates to a compound of formula (I) or a salt thereof, where R2 is halogen.
[0038] [0038] In another aspect [B5], the invention relates to a compound of formula (I) or a salt thereof, wherein R2 is selected from the group consisting of fluorine and bromine.
[0039] [0039] In another aspect [B6], the invention relates to a compound of formula (I) or a salt thereof, where R2 is fluorine.
[0040] [0040] In another aspect [B7], the invention relates to a compound of formula (I) or a salt thereof, wherein R2 is C3-5cycloalkyl.
[0041] [0041] In another aspect [B8] the invention relates to a compound of formula (I) or a salt thereof, wherein R2 is cyclopropyl.
[0042] [0042] In another aspect [C1], the invention relates to a compound of formula (I) or a salt thereof, where R3 is hydrogen.
[0043] [0043] In another aspect [C2], the invention relates to a compound of formula (I) or a salt thereof, wherein R3 is C1-4alkyl.
[0044] [0044] In another aspect [C3], the invention relates to a compound of formula (I) or a salt thereof, where R3 is methyl.
[0045] [0045] In another aspect [D1], the invention relates to a compound of formula (I) or a salt thereof, in which ring system A is selected from the group consisting of C6-10aryl, heteroaryl of 5 -10 members and 9-10 membered bicyclic heterocyclyl; p denotes 1 or 2; each R4 is independently selected from the group consisting of C1-4alkyl, C2-4alkynyl, C1-4haloalkyl, hydroxy-C1-4haloalkyl, C1-4haloalkyl substituted by a 3-6 membered heterocyclyl, halogen and the bivalent substituent = O , while = O can only be a substitute for a non-aromatic ring.
[0046] [0046] In another aspect [D2], the invention relates to a compound of formula (I) or a salt thereof, in which ring system A is selected from the group consisting of C6-10aryl and bicyclic heterocyclic of 9-10 members; p denotes 1 or 2; each R4 is independently selected from the group consisting of C1-4alkyl, C2-4alkynyl, C1-4haloalkyl, hydroxy-C1-4haloalkyl, C1-4haloalkyl substituted by a 3-6 membered heterocyclyl, halogen and the bivalent substituent = O , while = O can only be a substitute for a non-aromatic ring.
[0047] [0047] In another aspect [D3], the invention relates to a compound of formula (I) or a salt thereof, where A together with the substituent p R4 has the substructure A B R R Ç
[0048] [0048] In another aspect [D4], the invention relates to a compound of formula (I) or a salt thereof, where A together with the substituent p R4 has the substructure A B R R Ç
[0049] [0049] In another aspect [D5], the invention relates to a compound of formula (I) or a salt thereof, where A together with the substituent p R4 has the substructure A B R R Ç
[0050] [0050] In another aspect [D6], the invention relates to a compound of formula (I) or a salt thereof, where A together with the substituent p R4 has the substructure A B R R Ç
[0051] [0051] In another aspect [D7], the invention relates to a compound of formula (I) or a salt thereof, in which A together with the p substituents R4 are selected from among F F F F F F F F F F *, *, *, *, F F F F F F F F F F F F *, *, *, *, F F F F F F F F HO HO OFF * , * , * , * , F F F F O F O O F O * , * , * , * F F
[0052] [0052] In another aspect [D8], the invention relates to a compound of formula (I) or a salt thereof, in which A together with the p substituents R4 are selected from among F F F F F F F F F F *, *, *, *, F F F F F F F F F F F F *, *, *, *, F F F F F F F F HO HO OFF * , * , * , * , F F F F O O O
[0053] [0053] All the structural aspects mentioned above [A1] to [A13], [B1] to [B8], [C1] to [C3] and [D1] to [D8] are preferred modalities of the corresponding aspects [A0], [B0], [C0] and [D0], respectively. The structural aspects [A0] to [A13], [B0] to [B8], [C0] to [C3] and [D0] to [D8] referring to different molecular parts of the compounds (I) according to the invention can be combined together as desired in combinations [A] [B] [C] [D] to obtain preferred compounds (I). Each combination [A] [B] [C] [D] represents and defines individual modalities or generic subsets of compounds (I) according to the invention.
[0054] [0054] Preferred embodiments of the invention having structure (I) are exemplary compounds I-1 to I-179 and any subset thereof.
[0055] [0055] All generically defined synthetic intermediates, as well as specifically disclosed in this document and their salts are also part of the invention.
[0056] [0056] All individual synthetic reaction steps, as well as reaction sequences comprising these individual synthetic reaction steps, both generically defined or specifically disclosed in this document, are also part of the invention.
[0057] [0057] The present invention also relates to hydrates, solvates, polymorphs, metabolites, derivatives, isomers and prodrugs of a compound of formula (I) (including all its modalities).
[0058] [0058] The present invention also relates to a hydrate of a compound of formula (I) (including all its modalities).
[0059] [0059] The present invention also relates to a solvate of a compound of formula (I) (including all its modalities).
[0060] [0060] Compounds of formula (I) (including all their modalities) that, for example, carry ester groups are potential prodrugs, the ester being cleaved under physiological conditions and are also part of the invention.
[0061] [0061] The present invention also relates to a pharmaceutically acceptable salt of a compound of formula (I) (including all its modalities).
[0062] [0062] The present invention also relates to a pharmaceutically acceptable salt of a compound of formula (I) (including all its modalities) with organic or inorganic bases or acids. Medical Uses - Treatment Methods
[0063] The present invention relates to SOS1 inhibiting compounds, in particular compounds of formula (I) (including all their modalities), which are useful in the treatment and / or prevention of a disease and / or associated condition with or modulated by SOS1, especially in which the inhibition of the interaction of SOS1 and a protein from the RAS and / or RAC1 family is of therapeutic benefit, including, but not limited to, the treatment and / or prevention of cancer .
[0064] [0064] In another aspect, the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use as a medicament.
[0065] [0065] In another aspect, the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use in a method of treating the human or animal body.
[0066] [0066] In another aspect, the invention relates to an SOS1-inhibiting compound, in particular a compound of formula (I), - or a pharmaceutically acceptable salt thereof - for use in the treatment and / or prevention of a disease and / or condition, in which the inhibition of the interaction of SOS1 and a protein of the RAS and / or RAC1 family is of therapeutic benefit, including, but not limited to, the treatment and / or prevention of cancer.
[0067] [0067] In another aspect, the invention relates to an SOS1-inhibiting compound, in particular a compound of formula (I), - or a pharmaceutically acceptable salt thereof - for use in the treatment and / or prevention of cancer .
[0068] [0068] In another aspect, the invention relates to an SOS1-inhibiting compound, in particular a compound of formula (I), - or a pharmaceutically acceptable salt thereof - for use in a treatment method and / or prevention of cancer in the human or animal body.
[0069] [0069] In another aspect, the invention relates to an SOS1-inhibiting compound, in particular a compound of formula (I), - or a pharmaceutically acceptable salt thereof - for use in a treatment method and / or prevention of cancer in the human or animal body.
[0070] [0070] In another aspect, the invention relates to an SOS1-inhibiting compound - or a pharmaceutically acceptable salt thereof - for use as defined above in this document, wherein said SOS1-inhibiting compound is administered before , after or in conjunction with at least one other pharmacologically active substance.
[0071] [0071] In another aspect, the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use as defined above in this document, wherein said compound is administered before, after or together with at least one other pharmacologically active substance.
[0072] [0072] In another aspect, the invention relates to an SOS1-inhibiting compound - or a pharmaceutically acceptable salt thereof - for use as defined above in this document, wherein said SOS1-inhibiting compound is administered in combination with at least one other pharmacologically active substance.
[0073] [0073] In another aspect, the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use as defined above in this document, wherein said compound is administered in combination with at least one another pharmacologically active substance.
[0074] [0074] In another aspect, the invention relates to a pharmacologically active substance prepared to be administered before, after or in conjunction with an SOS1-inhibiting compound - or a pharmaceutically acceptable salt thereof - for use as defined above in this document for the use of the compound of formula (I).
[0075] [0075] In another aspect, the invention relates to a pharmacologically active substance prepared to be administered before, after or in conjunction with a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use as defined above in this document for the use of the compound of formula (I).
[0076] [0076] In another aspect, the invention relates to an SOS1-inhibiting compound, in particular a compound of formula (I), - or a pharmaceutically acceptable salt thereof - for use in treatment or in a treatment method as defined above in this document.
[0077] [0077] In another aspect, the invention relates to the use of an SOS1 inhibiting compound, in particular a compound of formula (I), - or a pharmaceutically acceptable salt thereof - to prepare a pharmaceutical composition for the treatment and / or cancer prevention.
[0078] [0078] In another aspect, the invention relates to the use of an SOS1-inhibiting compound - or a pharmaceutically acceptable salt thereof - as defined above in this document, wherein said SOS1-inhibiting compound is administered before, after or in conjunction with at least one other pharmacologically active substance.
[0079] [0079] In another aspect, the invention relates to the use of a compound of formula (I) - or a pharmaceutically acceptable salt thereof - as defined above in this document, wherein said compound is administered before, after or together with at least one other pharmacologically active substance.
[0080] [0080] In another aspect, the invention relates to the use of an SOS1 inhibiting compound, in particular a compound of formula (I), - or a pharmaceutically acceptable salt thereof - as defined above in this document for the treatment .
[0081] [0081] In another aspect, the invention relates to a method for the treatment and / or prevention of a disease and / or condition, in which the inhibition of the interaction of SOS1 and a protein of the RAS or RAC1 family is of therapeutic benefit comprising administering a therapeutically effective amount of an SOS1 inhibiting compound, in particular a compound of formula (I), - or a pharmaceutically acceptable salt thereof - to a human.
[0082] [0082] In another aspect, the invention relates to a method for the treatment and / or prevention of cancer comprising administering a therapeutically effective amount of an SOS1 inhibiting compound, in particular a compound of formula (I), - or a pharmaceutically acceptable salt thereof - to a human.
[0083] [0083] In another aspect, the invention relates to a method as defined above in this document, in which the SOS1-inhibiting compound - or a pharmaceutically acceptable salt thereof - is administered before, after or in conjunction with at least one other pharmacologically active substance.
[0084] [0084] In another aspect, the invention relates to a method as defined above in this document, in which the compound of formula (I) - or a pharmaceutically acceptable salt thereof - is administered before, after or in conjunction with at least one other pharmacologically active substance.
[0085] [0085] In another aspect, the invention relates to a method as defined above in this document, wherein the SOS1 inhibiting compound
[0086] [0086] In another aspect, the invention relates to a method as defined above in this document, wherein the compound of formula (I) - or a pharmaceutically acceptable salt thereof - is administered in combination with a therapeutically effective amount of hair. less another pharmacologically active substance.
[0087] [0087] In another aspect, the invention relates to a method for treatment as defined above in this document.
[0088] [0088] In another aspect, the invention relates to a kit comprising  a first pharmaceutical composition or dosage form comprising an SOS1 inhibiting compound and, optionally, one or more pharmaceutical carriers, excipients and / or vehicles - acceptable, and  at least a second pharmaceutical composition or dosage form comprising another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable carriers, excipients and / or vehicles.
[0089] [0089] In another aspect, the invention relates to a kit comprising  a first pharmaceutical composition or dosage form comprising a compound of formula (I) and, optionally, one or more carriers, excipients and / or pharmaceutically acceptable vehicles, and  at least a second pharmaceutical composition or dosage form comprising another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable carriers, excipients and / or vehicles.
[0090] In another aspect, the invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of formula (I) - or a pharmaceutically acceptable salt thereof - and one or more pharmaceutically acceptable excipients.
[0091] [0091] In another aspect, the invention relates to a pharmaceutical preparation comprising a compound of formula (I) - or a pharmaceutically acceptable salt thereof - and at least one (preferably one) other pharmacologically active substance.
[0092] [0092] In another aspect, the pharmacologically active substance to be used together / in combination with the SOS1 inhibiting compound, in particular compound of formula (I) (including all individual modalities or generic subsets of compounds (I) ), or medical uses, uses, methods of treatment and / or prevention as defined in this document (above and below) may be selected from any one or more of the following (preferably there is only one additional pharmacologically active substance used in all of these modalities) :
[0093] [0093] In this invention, it should be understood that the combinations, compositions, kits, methods, uses or compounds for use in accordance with this invention may provide for simultaneous, concomitant, sequential, successive, alternate or separate administration of the ingredients or active components. It will be appreciated that the SOS1 inhibiting compound
[0094] [0094] In this context, "combination" or "combined", within the meaning of this invention, includes, without limitation, a product that results from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations (for example , free) (including kits) and uses, such as, for example, simultaneous, concomitant, sequential, successive, alternate or separate use of components or ingredients. The term "fixed combination" means that the active ingredients are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients are administered to a patient as separate entities simultaneously, concurrently or sequentially, without specific time limits, so that such administration promotes therapeutically effective levels of the two compounds in the patient's body. .
[0095] [0095] The administration of the SOS1 inhibiting compound (for example, compound of formula (I)) and at least one other pharmacologically active substance can occur by co-administering the active components or ingredients, such as, for example, administering it. either simultaneously or concurrently in a single or two or more separate formulations or dosage forms. Alternatively, the administration of the SOS1 inhibiting compound (for example, compound of formula (I)) and at least one other pharmacologically active substance can occur by administering the active components or ingredients sequentially or alternately, such as, for example , in two or more separate formulations or dosage forms.
[0096] [0096] For example, simultaneous administration includes administration at substantially the same time. This form of administration can also be referred to as “concomitant” administration. Simultaneous administration includes administering active agents in the same general period of time, for example, on the same day (s), but not necessarily at the same time. Alternate administration includes administering one agent over a period of time, for example, over the course of a few days or a week, followed by administering the other agent (s) over a subsequent period of time. , for example, over the course of a few days or a week, and then repeating the pattern for one or more cycles. Sequential or successive administration includes administration of an agent over a first period of time (for example, over the course of a few days or a week) using one or more doses, followed by administration of the other agent (s) (s) for an additional second period of time (for example, over the course of a few days or a week) using one or more doses. An overlapping schedule can also be employed, which includes the administration of active agents on different days during the treatment period, not necessarily according to a regular sequence. Variations in these general guidelines can also be used, for example, according to the agents used and the condition of the individual.
[0097] [0097] The elements of the combinations of this invention can be administered (dependent or independently) by methods usual to the person skilled in the art, for example, orally, enterally, parenterally (eg, intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous tissue, or implant), nasal administration routes,
[0098] [0098] Therefore, in one aspect of the invention, the invention provides a method for the treatment and / or prevention of cancer comprising administering to a patient in need thereof a therapeutically effective amount of an SOS1 inhibiting compound (for example , a compound of formula (I)) and a therapeutically effective amount of at least one other pharmacologically active substance, wherein the SOS1 inhibiting compound (for example, a compound of formula (I)) is administered simultaneously, concomitantly, sequentially, successively, alternately or separately with at least one other pharmacologically active substance.
[0099] [0099] In another aspect, the invention provides an SOS1-inhibiting compound (for example, a compound of formula (I)) for use in the treatment and / or prevention of cancer, wherein the SOS1-inhibiting compound (for example , a compound of formula (I)) is administered simultaneously, concomitantly, sequentially, successively, alternately or separately with at least one other pharmacologically active substance.
[0100] [0100] In another aspect, the invention provides a kit comprising  a first pharmaceutical composition or dosage form comprising an SOS1 inhibiting compound (for example, a compound of formula (I)), and, optionally, one or more pharmaceutically acceptable carriers, excipients and / or vehicles, and  at least a second pharmaceutical composition or dosage form comprising another pharmacologically active substance, and, optionally, one or more pharmaceutically acceptable carriers, excipients and / or vehicles, for use in the treatment and / or prevention of cancer, in which the first pharmaceutical composition must be administered simultaneously, concurrently, sequentially, successively, alternately or separately with the second and / or additional pharmaceutical composition or dosage form.
[0101] [0101] In another embodiment of the invention, the components (i.e., the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all modalities) are administered simultaneously.
[0102] [0102] In another embodiment of the invention, the components (i.e., the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all modalities) are administered concomitantly.
[0103] [0103] In another embodiment of the invention, the components (i.e., the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all modalities) are administered sequentially.
[0104] [0104] In another embodiment of the invention, the components (i.e., the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all modalities) are administered successively.
[0105] [0105] In another embodiment of the invention, the components (i.e., the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all modalities) are administered alternately.
[0106] [0106] In another embodiment of the invention, the components
[0107] [0107] The "therapeutically effective amount" of the active compound (s) to be administered is the minimum amount necessary to prevent, ameliorate or treat a disease or disorder.
[0108] [0108] The combinations of this invention can be administered in single daily doses or divided therapeutically effective. The active components of the combination can be administered in such doses that are therapeutically effective in monotherapy, or in such doses that are lower than the doses used in monotherapy, but when combined result in a desired therapeutically effective amount (joint).
[0109] [0109] In another aspect, the disease / condition / cancer to be treated / prevented with the SOS1 inhibitor compound, SOS1 inhibitor compound for use, compound of formula (I), compound of formula (I) for use, use for preparing and method for treatment and / or prevention as defined in this document (above and below) is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer rhino, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia , hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcomas.
[0110] [0110] In another aspect, the disease / condition / cancer to be treated / prevented with the SOS1 inhibitor compound, SOS1 inhibitor compound for use, compound of formula (I), compound of formula (I) for use, use for preparing and method for treatment and / or prevention as defined in this document (above and below) is selected from the group consisting of pancreatic cancer, lung cancer (preferably non-small cell lung cancer (NSCLC) ), cholangiocarcinoma and colorectal cancer.
[0111] [0111] In another aspect, the disease / condition to be treated / prevented with the SOS1 inhibitor compound, SOS1 inhibitor compound for use, compound of formula (I), compound of formula (I) for use, use for preparing and method for treatment and / or prevention as defined in this document (above and below) is a RASopathy, preferably selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan with Multiple Lentigins (NSML) (also known as LEOPARD syndrome), Capillary Malformation Syndrome-Arteriovenous Malformation (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome ( also known as NF1 syndrome) and hereditary gingival fibromatosis.
[0112] [0112] In another aspect, the disease / condition / cancer to be treated / prevented with the SOS1 inhibitor compound, SOS1 inhibitor compound for use, compound of formula (I), compound of formula (I) for use, use to prepare and method for treatment and / or prevention as defined in this document (above and below) is a disease / condition / cancer defined as having one or more of the following molecular characteristics:
[0113] [0113] Particularly preferred, the cancer to be treated / prevented with the SOS1 inhibitor compound, SOS1 inhibitor compound for use, compound of formula (I), compound of formula (I) for use, use for preparation and method for the treatment and / or prevention as defined in this document (above and below) is selected by the group consisting of:  lung adenocarcinoma with a KRAS mutation selected from the group consisting of G12C, G12V, G12D and G12R;  colorectal adenocarcinoma with a KRAS mutation selected from the group consisting of G12D, G12V, G12C, G12R and G13D; and  pancreatic adenocarcinoma with a KRAS mutation selected from the group consisting of G12D, G12V, G12R, G12C and Q61H.
[0114] [0114] Any disease / condition / cancer, medical use, use, method of treatment and / or prevention as disclosed herein (including molecular / genetic characteristics) may be treated / carried out with any compound of formula (I) as disclosed or defined in this document (including all individual modalities or generic subsets of compounds (I)). DEFINITIONS
[0115] [0115] Terms not specifically defined in this document must be given the meanings given to them by someone skilled in the art in the light of disclosure and context. However, as used in the specification, unless otherwise specified, the following terms have the indicated meaning and the following conventions are respected:
[0116] [0116] The use of the prefix Cx-y, where each of x and y represents a positive integer (x <y), indicates that the chain or ring structure or combination of chain and ring structure as a whole, especially specified and mentioned in direct association, it can consist of a maximum of y a minimum of x carbon atoms.
[0117] [0117] The indication of the number of members in groups containing one or more heteroatoms (for example, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl) refers to the total number of atoms of all ring members or the total of all members of the carbon e ring and chain.
[0118] [0118] The indication of the number of carbon atoms in groups consisting of a combination of carbon chain and carbon ring structure (for example, cycloalkylalkyl, arylalkyl) refers to the total number of carbon atoms of all members of carbon ring and carbon chain. Obviously, a ring structure has at least three members.
[0119] [0119] In general, for groups comprising two or more sub-groups
[0120] [0120] In groups such as HO, H2N, (O) S, (O) 2S, NC (cyan), HOOC, F3C or similar, the converse can see the radical binding point (s) to the molecule of free valences of the group itself.
[0121] [0121] Alkyl denotes monovalent saturated hydrocarbon chains, which can be present in either the straight (unbranched) or branched chain form. If an alkyl is substituted, the substitution can occur independently, by mono- or polysubstitution in each case, in all hydrogen-carrying carbon atoms.
[0122] [0122] The term "C1-5alkyl" includes, for example, H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH (CH3) -, H3C-CH2-CH2-CH2-, H3C-CH2 -CH (CH3) -, H3C-CH (CH3) -CH2-, H3C-C (CH3) 2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2- CH2-CH (CH3) -, H3C -CH2-CH (CH3) -CH2-, H3C-CH (CH3) -CH2-CH2-, H3C- CH2-C (CH3) 2-, H3C-C (CH3) 2-CH2-, H3C-CH (CH3 ) -CH (CH3) - and H3C-CH2-CH (CH2CH3) -.
[0123] [0123] Other examples of alkyl are methyl (Me; -CH3), ethyl (Et; - CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (i-Pr; iso- propyl; -CH (CH3) 2), 1-butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-1-propyl (iso-butyl; i-Bu; -CH2CH (CH3 ) 2), 2-butyl (sec-butyl; sec-Bu; -CH (CH3) CH2CH3), 2-methyl-2-propyl (tert-butyl; t-Bu; -C (CH3) 3), 1- pentyl (n-pentyl; -CH2CH2CH2CH2CH3), 2-pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH2CH3) 2), 3-methyl-1-butyl (iso-pentyl; -CH2CH2CH (CH3 ) 2), 2-methyl-2-butyl (-C (CH3) 2CH2CH3), 3-methyl-2-butyl (-CH (CH3) CH (CH3) 2), 2,2-dimethyl-1-propyl ( neo-pentyl; -CH2C (CH3) 3), 2-methyl-1-butyl (- CH2CH (CH3) CH2CH3), 1-hexyl (n-hexyl; -CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3) CH2CH2CH2CH3 ), 3-hexyl (-CH (CH2CH3) (CH2CH2CH3)),
[0124] [0124] By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nickel, decyl etc. without any further definition they are saturated hydrocarbon groups with the corresponding number of carbon atoms, in which all isomeric forms are included.
[0125] [0125] The above definition for alkyl also applies if alkyl is part of another (combined) group, such as, for example, Cx-yalkylamino or Cx-yalkyloxy.
[0126] [0126] The term alkylene can also be derived from alkyl. Alkylene is divalent, unlike alkyl, and requires two bonding partners. Formally, the second valence is produced by removing a hydrogen atom in an alkyl. Corresponding groups are, for example, -CH3 and -CH2-, -CH2CH3 and -CH2CH2- or> CHCH3 etc.
[0127] [0127] The term "C1-4alkylene" includes, for example, - (CH2) -, - (CH2-CH2) -, - (CH (CH3)) -, - (CH2-CH2-CH2) -, - ( C (CH3) 2) -, - (CH (CH2CH3)) -, - (CH (CH3) -CH2) -, - (CH2-CH (CH3)) -, - (CH2-CH2-CH2-CH2) - , - (CH2-CH2-CH (CH3)) -, - (CH (CH3) -CH2-CH2), - (CH2-CH (CH3) -CH2), - (CH2-C (CH3) 2) -, - (C (CH3) 2-CH2) -, - (CH (CH3) -CH (CH3)) -, - (CH2-CH (CH2CH3)) -, - (CH (CH2CH3) - CH2), - (CH (CH2CH2CH3)) -, - (CH (CH (CH3)) 2) - and -C (CH3) (CH2CH3) -.
[0128] [0128] Other examples of alkylene are methylene, ethylene, propylene, 1-methylethylene, butylene, 1 methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1 dimethylpropylene, 2,2- dimethylpropylene, 1,2-dimethylpropylene, 1,3 dimethylpropylene, hexylene etc.
[0129] [0129] By generic terms, propylene, butylene, pentylene, hexylene, etc. without any further definition, mean all conceivable isomeric forms with the corresponding number of carbon atoms, that is, propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2 -dimethylethylene.
[0130] [0130] The above definition for alkylene also applies if alkylene is part of another (combined) group such as, for example, in HO-Cx-yalkyleneamino or H2N-Cx-yalkyleneoxy.
[0131] [0131] Unlike alkyl, alkenyl consists of at least two carbon atoms, where at least two adjacent carbon atoms are joined by a C-C double bond and a carbon atom can be part of just a C-C double bond. If in an alkyl, as defined above in this document, having at least two carbon atoms, two hydrogen atoms in adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding alkenyl is formed .
[0132] [0132] Examples of alkenyl are vinyl (ethylene), prop-1-enyl, ally (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl - prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2 -enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, hex-1-enyl , hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2 -methylidene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3 -dienyl, buta-1,3-dienyl, 2,3-dimethylbut-1,3-diene etc.
[0133] [0133] By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, no-nadienyl, decadienyl, etc. without any further definition, all conceivable isomeric forms with the corresponding number of carbon atoms are represented, ie propenyl includes prop-1-enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl etc.
[0134] [0134] The alkenyl can optionally be present in the cis or trans or E or Z orientation with respect to the double bond (s).
[0135] [0135] The above definition for alkenyl also applies when alkenyl is part of another (combined) group, such as, for example, in Cx-yalkenylamino or Cx-yalkenyloxy.
[0136] [0136] Unlike alkylene, alkenylene consists of at least two carbon atoms, where at least two adjacent carbon atoms are joined by a C-C double bond and a carbon atom may only be part of a C-C double bond. If in an alkylene, as defined above in this document, having at least two carbon atoms, two hydrogen atoms in adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, the alkenylene corresponds - tooth is formed.
[0137] [0137] Examples of alkenylene are ethylene, propenylene, 1-methylethylene, butenylene, 1-methylpropenylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropylene - leno, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene etc.
[0138] [0138] By the generic terms propenylene, butenylene, pentenylene, hexenylene etc. without any further definition, all conceivable isomeric forms with the corresponding number of carbon atoms are represented, ie propenylene includes 1-methylethylene and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethyl- tenylene and 1,2-dimethylethylene.
[0139] [0139] Alkenylene can optionally be present in the cis or trans or E or Z orientation in relation to the double bond (s).
[0140] [0140] The above definition for alkenylene also applies when alkenylene is part of another (combined) group such as, for example, in HO-Cx-yalkenyleneamino or H2N-Cx-yalkenyleneoxy.
[0141] [0141] Unlike alkyl, alkynyl consists of at least two carbon atoms, where at least two adjacent carbon atoms are joined by a C-C triple bond. If in an alkyl, as defined above in this document, having at least two carbon atoms, two hydrogen atoms in each case in adjacent carbon atoms are formally removed and the free valences are secured to form two additional bonds, the corresponding alkynyl is formed.
[0142] [0142] Examples of alkynyl are ethynyl, prop-1-inyl, prop-2-inyl, but-1-inyl, but-2-inyl, but-3-inyl, 1-methyl-prop-2-inyl, pent -1-inyl, pent-2-inyl, pent-3-inyl, pent-4-inyl, 3-methyl-but-1-inyl, hex-1-inyl, hex-2-inyl, hex-3-inyl , hex-4-inyl, hex-5-inyl etc.
[0143] [0143] By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptinyl, octinyl, noninyl, decynyl etc. without any further definition, all conceivable isomeric forms with the corresponding number of carbon atoms are represented, that is, propynyl includes prop-1-inyl and prop-2-inyl, butynyl includes but-1-inyl, but- 2-inyl, but-3-inyl, 1-methyl-prop-1-inyl, 1-methyl-prop-2-inyl etc.
[0144] [0144] If a hydrocarbon chain carries at least one double bond and also at least one triple bond, by definition it belongs to the alkynyl subgroup.
[0145] [0145] The above definition for alkynyl also applies if alkynyl is part of another (combined) group, such as, for example, in Cx-yalquinylamino or Cx-yalquinyloxy.
[0146] [0146] Unlike alkylene, alkynylene consists of at least two carbon atoms, where at least two adjacent carbon atoms are linked by a C-C triple bond. If in an alkylene, as defined above in this document, it has at least two carbon atoms, two hydrogen atoms in each case in adjacent carbon atoms are formally removed and the free valences are saturated to form two additional bonds, the corresponding alkylene. It is formed.
[0147] [0147] Examples of alkynylene are ethynylene, propynylene, 1-methylethylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene , 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene etc.
[0148] [0148] By the generic terms propynylene, butynylene, pentynylene, hexynylene etc., without any further definition, all conceivable isomeric forms with the corresponding number of carbon atoms are represented, that is, propynylene includes 1-methylethylene and butyn- lene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.
[0149] [0149] The above definition for alkynylene is also applicable if alkynylene is part of another (combined) group, such as, for example, in HO-Cx-yalquinyleneamino or H2N-Cx-yalquinyleneoxy.
[0150] [0150] Heteroatoms means oxygen, nitrogen and sulfur atoms.
[0151] [0151] Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previously defined alkyl (alkenyl, alkynyl) replacing one or more hydrogen atoms in the hydrocarbon chain independently of one another by halogen atoms, which can be identical or different. If a haloalkyl (haloalkenyl, haloalkynyl) has yet to be replaced, substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all carbon atoms carrying hydrogen.
[0152] [0152] Examples of haloalkyl (haloalkenyl, haloalkynyl) are - CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, - CF2CF2CF3, -CF2CH2CH3, -C2 = CH2, -CBr = CH2, -C≡C-CF3, - CHFCH2CH3, -CHFCH2CF3 etc.
[0153] [0153] From the haloalkyl defined above (haloalkenyl, haloalkynyl), the terms haloalkylene (haloalkenylene, haloalkylene) are also derived. Haloalkylene (haloalkenylene, haloalkynylene), unlike haloalkyl (haloalkenyl, haloalkynyl), is bivalent and requires two bonding partners. Formally, the second valence is formed by the removal of a hydrogen atom from a haloalkyl (haloalkenyl, haloalkynyl).
[0154] [0154] Corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or> CFCH2F etc.
[0155] [0155] The above definitions also apply if the groups containing the corresponding halogen are part of another (combined) group.
[0156] [0156] Halogen refers to fluorine, chlorine, bromine and / or iodine atoms.
[0157] [0157] Cycloalkyl is composed of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spirohydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings, two rings are joined so that they have at least two carbon atoms in common. In spiro hydrocarbon rings, a carbon atom (spiroatom) belongs to two rings together.
[0158] [0158] If a cycloalkyl is substituted, the substitutions can occur independently of each other, in the form of mono- or po-
[0159] [0159] Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycle [2,2,0] hexyl, bicycle [3,2,0] heptyl, bicycle [3,2,1] octyl, bicycle [2,2,2] octyl, bicycles [4,3,0] nonyl (octahidroindenila), bicycles [4,4,0] decil (decahidronaftila), bicycles [2,2,1] heptil (norbornila) ), bicycle [4,1,0] heptyl (norcaranyl), bicycle [3,1,1] heptyl (pinanil), spiro [2,5] octyl, spiro [3,3] heptyla, etc.
[0160] [0160] The above definition for cycloalkyl is also applicable if cycloalkyl is part of another (combined) group, for example, in Cx-ycycloalkylamino, Cx-ycycloalkyloxy or Cx-ycycloalkylalkyl.
[0161] [0161] If the free valence of a cycloalkyl is saturated, then an alicyclic group is obtained.
[0162] [0162] The term cycloalkylene can thus be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two bonding partners. Formally, the second value is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are, for example: cyclohexyl and or or (cyclohexylene).
[0163] [0163] The above definition for cycloalkylene is also applicable if cycloalkylene is part of another (combined) group such as, for example, in HO-Cx-ycycloalkyleneamino or H2N-Cx-ycycloalkyleneoxy.
[0164] [0164] Cycloalkenyl is also made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spirohydrocarbon rings. However, the systems are unsaturated, that is, there is at least one C-C double bond, but no aromatic system. If in a cycloalkyl, as defined above in this document, two hydrogen atoms in adjacent cyclic carbon atoms are formally removed and the free valences are secured to form a second bond, the corresponding cycloalkenyl is obtained.
[0165] [0165] If a cycloalkenyl has to be replaced, the substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all carbon atoms carrying hydrogen. Cycloalkenyl itself can be attached as a substituent to the molecule through each appropriate position of the ring system.
[0166] [0166] Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex -1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobut-1,3-dienyl, cyclopenta -1,4-dienyl, cyclopenta-1,3-diamine, cyclopenta-2,4-dienyl, cyclohex-1,3-dienyl, cyclohex-1,5-dienyl, cyclohex-2,4-dienyl, cyclohex -1,4-dienyl, cyclohex-2,5-dienyl, bicycle [2,2,1] hepta-2,5-dienyl (norborna-2,5-dienyl), bicycle [2,2,1] hept-2-enyl (norbornenyl), spiro [4,5] dec-2-enyl etc.
[0167] [0167] The above definition for cycloalkenyl also applies when cycloalkenyl is part of another (combined) group such as, for example, in Cx-ycycloalkenylamino, Cx-ycycloalkenyloxy or Cx-ycycloalkenylalkyl.
[0168] [0168] If the free valence of a cycloalkenyl is saturated, then an unsaturated alicyclic group is obtained.
[0169] [0169] The term cycloalkenylene can thus be derived from the previously defined cycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires two bonding partners. Formally, the second valence is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are, for example:
[0170] [0170] The above definition for cycloalkenylene is also applicable if cycloalkenylene is part of another group (combined) as, for example, in HO-Cx-ycycloalkenyleneamino or H2N-Cx-ycycloalkenyloxy.
[0171] [0171] Arila denotes mono-, bi- or tricyclic carbocycles with at least one aromatic carbocycle. Preferably, it denotes a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or a six-membered ring with a five-membered ring), in which the a second ring can also be aromatic or, however, it can also be partially saturated.
[0172] [0172] If an aryl must be replaced, the substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all carbon atoms that carry hydrogen. Aryl itself can be attached as a substituent to the molecule through all the appropriate positions of the ring system.
[0173] [0173] Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphile (1,2,3,4-tetrahydroonaptyl, tetralinyl), dihydronaphile (1,2 -dihydronaftila), fluorenyl etc. Most preferred is phenyl.
[0174] [0174] The above definition of aryl is also applicable if aryl is part of another (combined) group, for example, in arylamino, aryloxy or arylalkyl.
[0175] [0175] If the free valence of an arila is saturated, then an aromatic group is obtained.
[0176] [0176] The term arylene can also be derived from the previously defined aryl. Arylene, unlike aryl, is divalent and requires two bonding partners. Formally, the second valence is formed by removing a hydrogen atom from an aryl. Corresponding groups are, for example: phenyl and or or (o, m, p-phenylene), naphthyl and or or etc.
[0177] [0177] The above definition for arylene is also applicable if arylene is part of another (combined) group, for example, in HO-arylenamino or H2N-aryleneoxy.
[0178] [0178] Heterocyclyl denotes ring systems, which are derived from the previously defined cycloalkyl, cycloalkenyl and aryl replacing one or more of the -CH2- groups independently of each other in the hydrocarbon rings with the -O-, -S- or -NH- groups or replacing one or more of the = CH- groups with the = N- group, where a total of no more than five heteroatoms can be present, at least one carbon atom must be present between two oxygen atoms and between two atoms sulfur or between an oxygen and sulfur atom and the ring as a whole must have chemical stability. Hetero atoms can optionally be present in all possible oxidation stages (sulfur  sulfoxide -SO-, sulfone -SO2-; nitrogen  N-oxide). In a heterocyclyl, there is no heteroaromatic ring, that is, no heteroatom is part of an aromatic system.
[0179] [0179] A direct result of the cycloalkyl, cycloalkyl and aryl derivation is that heterocyclyl is composed of the monocyclic hetero-rings, bicyclic hetero-rings, tricyclic hetero-rings and spiro-hetero-rings, which may be present in saturated or unsaturated form .
[0180] [0180] By unsaturated, it is understood that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In bicyclic hetero rings, two rings are linked together so that they have at least two (hetero) atoms in common. In spiro-hetero rings, a carbon atom (spiroatom) belongs to two rings together.
[0181] [0181] If a heterocyclyl is substituted, substitutions can occur independently of one another, in the form of mono- or polysubstitutions in each case, in all hydrogen and carbon atoms and nitrogen. The heterocyclyl itself can be attached as a substituent to the molecule through each suitable position of the ring system. Substituents in the heterocyclyl do not count towards the number of members of a heterocyclyl.
[0182] [0182] Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxolamine, 1,4-dioxolamine , homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S, S-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4] -oxaziline, -dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydroxy-dihydroxy-2-hydroxy, 3-dihydro-oxide -pyrrolyl, 4H-pyranyl, 1,4-dihydropyridinyl, 8- aza-bicyclo [3,2,1] octyl, 8-aza-bicyclo [5,1,0] octyl, 2-oxa-5-azabici-clo [2,2,1] heptyl, 8-oxa-3-aza-bicyclo [3,2,1] octyl, 3,8-diaza-bicyclo [3,2 , 1] octyl, 2,5-diaza-bicycle [2,2,1] heptyl, 1-aza-bicycle [2,2,2] octyl, 3,8-diaza-bicycle [3,2,1] octyl , 3,9-diaza-bicycles [4,2,1] nonila, 2,6-diaza-bi- cycle [3,2,2] nonila, 1,4-dioxa-spiro [4,5] decila, 1 -oxa-3,8-diaza-espiro [4,5] decila, 2,6-diaza-espiro [3,3] heptila, 2,7-diaza-espiro [4,4] nonila,
[0183] [0183] Other examples are the structures illustrated below, which can be linked through each hydrogen-carrying atom (exchanged for hydrogen): The H H O N Y Y Y Y H The N H O S O O N S S N NH H H H N N The H N O O S S O N H S O O O S O O O O S H AT THE s S S O S O O O S O H O N H H N N S S O O s s Y N O O O H O O O H H O S N N S s S S O S O O S O O O H O O N O S S The S H O O O O O N O S Y s N N N N N H H H H H O O O O O S O S S S S s O O O O O S O H H N N O O S S O O N N O O O O Y Y Y N N H H H N H N N N O O N N NH NH H N N O H N N N N N N S S H S S S O O H H N N N N O O S S O S O S O O O O O S O O H H H N N N N S S O O O H N N O O O H H H N N N N N NH H H H H N N N O N N N N N N H H H N H O S S N N NH H O O O H O O O S s O S NH S O Y N O O H BONE O S O O H N H H The N N Y Y N O H O S H H N N O O O S S S O O O O S O O O H O S N H N s S S O O N O S O H O H N H H N N O O s s S O O O S O O O O S s S S S O O O S O O
[0184] [0184] Preferably, heterocyclics are monocyclic with 4 to 8 members and have one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.
[0185] [0185] Preferred heterocyclyl are: piperazinyl, piperidinyl, morpho-linyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl.
[0186] [0186] The above definition of heterocyclyl is also applicable if heterocyclyl is part of another (combined) group such as, for example, heterocyclylamino, heterocyclyloxy or heterocyclylalkyl.
[0187] [0187] If the free valence of a heterocyclyl is saturated, then a heterocyclic group is obtained.
[0188] [0188] The term heterocyclyl is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is divalent and requires two binding partners. Formally, the second value is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups are, for example: NH NH
[0189] [0189] The above definition of heterocyclylene is also applicable if heterocyclylene is part of another (combined) group, for example, in HO-heterocyclyleneamino or H2N-heterocyclyloxyoxy.
[0190] [0190] Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring, which
[0191] [0191] If a heteroaryl has to be replaced, substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all hydrogen and carbon atoms and nitrogen. The heteroaryl itself can be attached as a substituent to the molecule through each appropriate position of the ring, carbon and nitrogen system. Heteroaryl substituents do not count for the number of members of a heteroaryl.
[0192] [0192] Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridinyl, pyridzinyl, pyridzinyl, pyridazinyl, pyridazine , pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide , oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benziszazole, benziszazole , quinoxalinyl, cyino-linyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, pyrimidopyridyl, imidine, pyridine, benzylzolazole -oxide, isoquinolyl-N-o oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide, inzolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide etc.
[0193] [0193] Other examples are the structures illustrated below, which can be linked through each hydrogen-carrying atom (exchanged for hydrogen): O O H O H H N O Y Y Y N N O N N N N N H H O O Y N N Y Y N N N N N N N N N N N N N N N N N N N N
[0194] [0194] Preferably, heteroaryls are monocyclic 5-6 members or bicyclic 9-10 members, each with 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.
[0195] [0195] The above definition of heteroaryl is also applicable if heteroaryl is part of another (combined) group, for example, in heteroarylamino, heteroaryloxy or heteroarylalkyl.
[0196] [0196] If the free valence of a heteroaryl is saturated, a heteroaromatic group is obtained.
[0197] [0197] The term heteroarylene is also derived from the previously defined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are, for example:
[0198] [0198] The above definition of heteroarylene is also applicable if heteroarylene is part of another (combined) group, for example, in HO-heteroaryleneamino or H2N-heteroaryleneoxy.
[0199] [0199] By "substituted", it is understood that a hydrogen atom that is attached directly to the atom under consideration is replaced by another atom or another group of atoms (substituent). Depending on the initiation conditions (number of hydrogen atoms), mono- or polysubstitution can occur in an atom. Substitution by a specific substituent is only possible if the permitted valences of the substituent and the atom to be replaced correspond to each other and the substitution leads to a stable compound (ie, a compound that is not spontaneously converted, for example , by rearrangement, cyclization or elimination).
[0200] [0200] Bivalent substituents, such as = S, = NR, = NOR, = NNRR, = NN (R) C (O) NRR, = N2 or similar, can only be substituents on carbon atoms, while bivalent substituents = E = NR can also be a sulfur substituent. Usually, the substitution can be carried out by a bivalent substituent only in ring systems and requires the replacement of two basic hydrogen atoms, that is, hydrogen atoms that are bonded to the same carbon atom that is saturated before replacement. Substitution by a bivalent substituent is therefore only possible in the group - CH2- or sulfur atoms (group = O or group = NR only, one or two groups = O possible or, for example, a group = O and a group = NR, each group replacing a free electron pair) of a ring system.
[0201] [0201] Stereochemistry / solvates / hydrates: Unless specifically indicated, throughout the specification and attached claims, a given name or chemical formula must cover tautomers and all stereo, optical and geometric isomers (for example, enantiomers- rosins, diastereomers, E / Z isomers etc.) and their racemates, as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers or mixtures of any of the previous forms, when these isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts and solvates thereof, such as, for example, hydrates including solvates and hydrates of the free compound or solvates and hydrates of a salt of the compound.
[0202] [0202] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the art, for example, by separating corresponding mixtures, using stereochemically pure starting materials and / or by stereoselective tests. It is known in the art to prepare optically active forms, such as by resolving racemic forms or by synthesis, for example, starting from optically active starting materials and / or using chiral reagents.
[0203] [0203] Enantiomerically pure compounds of this invention or intermediates can be prepared by asymmetric analysis, for example, by the preparation and subsequent separation of appropriate diastereomeric compounds or intermediates that can be used by known methods (for example, by chromatographic separation or crystallization) ) and / or using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.
[0204] [0204] Furthermore, it is known to the person skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures in the chiral stationary phases, or by solving a racemic mixture using an agent appropriate resolution, for example, through diastereomeric salt formation of the racemic compound with optically active acids or bases, subsequent resolution of the salts and release of the desired compound from the salt or by derivatization of the corresponding racemic compounds with chiral auxiliary reagents optically active, subsequent separation of di-asteromers and removal of the chiral auxiliary group, or by kinetic resolution of a racemate (for example, by enzymatic resolution); by enantioselective crystallization of a conglomerate of enantiomorphic crystals under suitable conditions, or by crystallization (fractionated) from a suitable solvent in the presence of an optically active chiral auxiliary.
[0205] [0205] Salts: The phrase “pharmaceutically acceptable” is used here to refer to compounds, materials, compositions and / or dosage forms that are, within the scope of good medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and proportional to a reasonable benefit / risk ratio.
[0206] [0206] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds, wherein the parent compound is modified to produce acidic or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines; alkaline or organic salts of acid residues, such as carboxylic acids; and the like.
[0207] [0207] For example, these salts include benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid , methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid.
[0208] [0208] Other pharmaceutically acceptable salts can be formed with ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris ( hydroxymethyl) -aminomethane.
[0209] [0209] The pharmaceutically acceptable salts of the present invention can be synthesized by the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, these salts can be prepared by reacting the acid or free base form of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile or mixture of the themselves.
[0210] [0210] Salts of other acids, in addition to those mentioned above, which, for example, are useful for purifying or isolating the compounds of the present invention (for example, trifluoro acetate salts), also comprise the part of the invention.
[0211] [0211] In a representation, such as, for example 3
[0212] [0212] For bivalent groups where it is crucial to determine which adjacent groups it links and with which valence, the corresponding liaison partners are indicated in square brackets where necessary for clarity purposes, as in the following representations: (R 1)
[0213] [0213] In a representation, such as, for example H
[0214] [0214] Groups or substituents are often selected from among several alternative groups / substituents with a corresponding group designation (for example, Ra, Rb, etc.). If this group is used repeatedly to define a compound according to the invention in different parts of the molecule, it is pointed out that the various uses must be considered as totally independent from each other.
[0215] [0215] By a therapeutically effective amount for the purposes of this invention, we mean an amount of substance that is capable of preventing symptoms of diseases or preventing or alleviating those symptoms, or prolonging the survival of a treated patient.
[0216] [0216] Proteins of the RAS family are intended to include KRAS
[0217] [0217] An SOS1 inhibiting compound is a compound that binds to SOS1 and thus prevents SOS1-mediated nucleotide exchange and subsequently reduces RAS levels in their GTP-bound form. More specifically, an SOS1 inhibitory compound shows a pharmacological inhibition of the binding of the SOS1 catalytic site to proteins of the RAS family. In this way, this compound interacts with SOS1, for example, the catalytic site in SOS1, and reduces the level of binding to the RAS family protein in relation to said binding without adding an SOS1 inhibiting compound. Therefore, an SOS1 inhibitor compound is expected to at least reduce the level of binding to the RAS family protein by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100% when compared to the bond that is achieved without the addition of said inhibitor compound. Suitable test systems for measuring binding to the SOS1 catalytic site are disclosed in this document. Said compound can be chemically synthesized (for example, a small molecule) or produced microbiologically (for example, a monoclonal antibody) and / or comprised in, for example, samples, for example, cell extracts of, for example , plants, animals or microorganisms. Preferably, the SOS1 inhibiting compound is a small molecule. List of Abbreviations Ac acetyl ACN acetonitrile amphos bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) aq. aqueous, aqueous ATP adenosine triphosphate
[0218] [0218] The features and advantages of the present invention will become evident from detailed examples that illustrate the principles of invention, for example, without restricting its scope: Preparation of the compounds according to the General invention
[0219] [0219] Unless otherwise stated, all reactions are performed on commercially available devices, using methods that are commonly used in chemical laboratories. Materials that are sensitive to air and / or moisture are stored under shielding gas and the corresponding reactions and manipulations are performed under shielding gas (nitrogen or argon).
[0220] [0220] The compounds according to the invention are named according to CAS rules, using the Autonom software (Beilstein). If a compound is represented by both a structural formula and its nomenclature, in the event of a conflict, the structural formula is decisive.
[0221] [0221] Microwave reactions are carried out in an initiator / reactor manufactured by Biotage or in an Explorer manufactured by CEM or in Synthos 3000 or Monowave 3000 manufactured by Anton Paar in sealed containers (preferably 2, 5 or 20 ml ), preferably with agitation. Chromatography
[0222] [0222] Thin layer chromatography is performed on 60 TLC silica gel plates ready in glass (with fluorescence indicator F-254) manufactured by Merck.
[0223] [0223] Preparative high pressure chromatography (RP HPLC) of the exemplary compounds according to an invention is carried out in Agilent or Gilson systems with columns produced by Waters (names: SunFire ™ Prep C18, OBD ™ 10 µm, 50 x 150 mm or SunFire ™ Prep C18 OBD ™ 5 µm, 30 x 50 mm or XBridge ™ Prep C18, OBD ™ 10 µm, 50 x 150 mm or XBridge ™ Prep C18, OBD ™ 5 µm, 30 x 150 mm or XBridge ™ Prep C18, OBD ™ 5 µm, 30 x 50 mm) and YMC (names: Actus-Triart Prep C18, 5 µm, 30 x 50 mm).
[0224] [0224] Different H2O / acetonitrile gradients are used to elute the compounds, while for Agilent systems, 5% acid modifier (20 ml HCOOH to 1 L H2O / acetonitrile (1/1)) is added to the water (conditions acidic). For Gilson systems, water is added, 0.1% HCOOH.
[0225] [0225] For chromatography under basic conditions for Agilent systems, H2O / acetonitrile gradients are also used, while water is made alkaline by the addition of 5% basic modifier (50 g NH4HCO3 + 50 ml NH3 (25% in H2O ) to 1 L with H2O). For Gilson systems, the water is made alkaline as follows: 5mL of NH4HCO3 solution (158 g in 1 L of H2O) and 2 ml of NH3 (28% in H2O) are reconstituted to 1 L with H2O.
[0226] [0226] The supercritical fluid chromatography (SFC) of the exemplary intermediates and compounds according to the invention is carried out in a JASCO SFC system with the following columns: Chiralcel OJ (250 x 20 mm, 5 µm), Chiralpak AD (250 x 20 mm, 5 µm), Chiralpak AS (250 x 20 mm, 5 µm), Chiralpak IC (250 x 20 mm, 5 µm), Chiralpak IA (250 x 20 mm, 5 µm), Chiralcel OJ (250 x 20 mm, 5 µm), Chiralcel OD (250 x 20 mm, 5 µm), Phenomenex Lux C2 (250 x 20 mm, 5 µm).
[0227] [0227] Analytical HPLC (reaction control) of intermediate and final compounds is performed using columns produced by Waters (names: XBridgeTM C18, 2.5 µm, 2.1 x 20 mm or XBridgeTM C18, 2.5 µm, 2 , 1 x 30 mm or Aquity UPLC BEH C18, 1.7 µm, 2.1 x 50 mm) and YMC (names: Triart C18, 3.0 µm, 2.0 x 30 mm) and Phenomenex (names: Luna C18, 5.0 µm, 2.0 x 30 mm). The analytical equipment is also equipped with a mass detector in each case. HPLC-mass spectroscopy / UV spectrometry
[0228] [0228] The retention times / MS-ESI + to characterize the exemplary compounds according to the invention are produced using an HPLC-MS device (high performance liquid chromatography with mass detector). Compounds that elute at the peak of injection have the retention time tRet. = 0.00. HPLC (preparative) methods HPLC1 prep. HPLC: Pumps 333 and 334 Waters X-Bridge C18 OBD, 10 µm, 30 x 100 mm, Part. No. 186003930 A: 10 mM NH4HCO3 in H2O; B: Acetonitrile (HPLC grade) UV / Vis-155 50 ml / min 0.00 - 1.50 min: 1.5% B 1.50 - 7.50 min: variable 7.50 - 9.00 min: 100 % B prep. HPLC2 Pumps 333 and 334 Waters Sunfire C18 OBD, 10 µm, 30 x 100 mm, Part. No. 186003971 A: H2O + 0.2% HCOOH; B: Acetonitrile (HPLC Grade) + 0.2%
[0229] [0229] The compounds according to the invention and the intermediates are prepared by the synthetic methods described below, in which the substituents of the general formulas have the meanings given previously. These methods are intended as an illustration of the invention, without restricting the subject and scope of the claimed compounds to these examples. In cases where the preparation of starting compounds is not described, they can be obtained commercially or their synthesis is described in the prior art, or they can be prepared in a manner analogous to compounds or methods known in the prior art described herein, ie , is within the abilities of an organic chemist to synthesize these compounds. The substances described in the literature can be prepared according to the published synthetic methods. General reaction scheme and summary of synthesis routes for compounds (I) according to the invention Scheme 1:
[0230] [0230] Compounds (I) according to the invention can be prepared in stages with synthesis routes shown in scheme 1.
[0231] [0231] Acetal A-2 can be prepared by acetalizing the corresponding aldehyde A-1.
[0232] [0232] A-7 can be prepared through different routes:
[0233] [0233] One approach starts with nucleophilic aromatic substitution of A-2 with a substituted or unsubstituted malonic ester to provide intermediate A-3 (introduction of R2). Decarboxylation of intermediate A-3 leads to A-4, which is converted with building block B-5 (see below) into a nucleophilic aromatic substitution. Saponification of the resulting ester A-5 and subsequent amidation with building block C-1 (introduction of R1) provides intermediate A-7 in a single step.
[0234] [0234] In an alternative approach, compound A-2 is converted with a substituted or unsubstituted malonic ester (introduction of R2) and then treated with building block B-5 (see below) to provide compound A -5 in one step. Saponification of the resulting ester A-5 and subsequent amidation with building block C-1 (introduction of R1) provides intermediate A-7.
[0235] [0235] Another route begins with nucleophilic aromatic substitution of A-2 with a substituted or unsubstituted malonic ester (introduction of R2) followed by nucleophilic aromatic substitution with building block B-5 (see below) to provide compound A -6 in one step. Direct conversion of A-6 to A-7 can be achieved by saponification of diester A-6, decarboxylation in situ and subsequent amidation with building block C-1 (introduction of R1) in a single step.
[0236] [0236] The final compounds (I) can be prepared by deprotecting acetal A-7 and cyclization. Compounds (I) can be further derivatized in optional steps (especially in R1 and R2) not shown in scheme 1 to obtain complementary / additional compounds (I).
[0237] [0237] Thus, an aspect of the invention is the manufacture of a compound (I) as defined in this document comprising ring closure of a compound A-7 as defined in this document; optionally further comprising reacting a compound A-5 as defined herein with a C-1 amine as defined in this document; optionally further comprising reacting a compound A-4 as defined herein with a compound B-5 as defined herein; optionally further comprising reacting a compound A-3 as defined herein to obtain compound A-4 as defined herein; optionally further comprising reacting a compound A-2 as defined herein to obtain compound A-3 as defined herein, optionally further comprising reacting a compound A-1 as defined herein to obtain compound A-2 as defined herein document. Scheme 2:
[0238] [0238] Alternatively, compounds (I) according to the invention can be prepared in stages with the synthetic route shown in scheme 2.
[0239] [0239] Starting from β-oxo diesters E-1, the corresponding α, β-dioxo esters E-3 can be prepared using E-2 intermediates obtained by reaction with DMF-acetal. Ring closure with C-1 amines leads to the hydroxy pyridone ring E-4. Palladium cross-coupling catalyzed after transfer of the hydroxy group to the corresponding sulfonate (eg, tosylate, triflate etc., E-5) with amides generates pyridone amides E-6, which allow for second ring closure to obtain the scaffold of desired bicyclic pyridopyrimidine-dione (E-7). E-7 thus obtained can be activated (with, for example, hexachlorocyclotri-phosphazene, SOCl2, POCl3 or similar) to be reacted with building block B-5 to reach final compounds (I) according to the invention (which can also be derivatized in additional steps).
[0240] [0240] Thus, an aspect of the invention is the manufacture of a compound (I) as defined in this document comprising activating a compound E-7 as defined in this document with a selected agent of hexachlorocyclotriphosphasene, SOCl2 and POCl3 and reacting E- 7 activated with a compound B-5 as defined in this document; optionally further comprising reacting an E-6 compound as defined in this document to obtain compound E-7 as defined herein; optionally further comprising reacting a compound E-5 as defined herein with an R3-CONH2 amide as defined herein; optionally further comprising reacting a compound E-4 as defined herein to obtain compound E-5 as defined herein; optionally further comprising reacting a compound E-3 as defined herein with a C-1 amine as defined herein; optionally further comprising reacting an E-2 compound as defined herein to obtain compound E-3 as defined herein; optionally further comprising reacting an E-1 compound as defined herein to obtain compound E-2 as defined herein.
[0241] [0241] Building blocks B-5 can be prepared in stages, starting with a synthesis presented in diagram 3.
[0242] [0242] (hetero) aryl ethylamine B-5 systems can be prepared from (hetero) arylbromides B-1, which are converted through a metal-catalyzed cross-coupling to the corresponding acetyl (hetero) aryl B-2. The formation of chiral B-3 sulfinamides is followed by stereoselective reduction to provide B-4. Finally, sulfinamide cleavage provides the desired chiral (hetero) aryl ethylamine B-5.
[0243] [0243] Alternatively, acetyl (hetero) aryls B-2 can be reduced enantioselectively to the corresponding alcohols B-6 which are then transformed into azides B-7 and can, in turn, be hydrogenated to obtain blocks chiral building blocks B-5.
[0244] [0244] Thus, an aspect of the invention is the manufacture of a compound B-5 as defined in this document comprising reducing a compound B-7 as defined in this document; optionally further comprising reacting a compound B-6 as defined in this document to obtain compound B-7 as defined in this document; optionally further comprising reducing a compound B-2 as defined herein to obtain compound B-6 as defined herein.
[0245] [0245] To a stirred solution of A-1a (150.00 g, 785.28 mmol, 1.0 equiv.) In benzene (1500 ml), ethylene glycol (48.69 g, 785.28 mm, 1.0 equiv.) And a catalytic amount of p-toluenesulfonic acid (13.51 g, 78.53 mmol, 0.1 equiv.) Are added. The reaction mixture is refluxed until full conversion of the starting material is observed. The solvent is evaporated under reduced pressure, the residue diluted with DCM and washed with an aqueous solution of sodium bicarbonate. The organic layers are combined, dried (Na2SO4) and concentrated under reduced pressure. Additional purification by flash column chromatography (eluent: 10% ethyl acetate in hexane) generates the desired product A-2a.
[0246] [0246] The following intermediates A-2 (Table 1) are available in an analogous manner starting from different A-1 pyrimidines. Crude product A-2 is purified by chromatography if necessary. Table 1: # tret structure [min] [M + H] + HPLC method Cl O A-2a N O 1.719 235 GVK_LCMS_22 N Cl Cl O A-2b N O n.a. at. - N Cl Synthesis of intermediates A-3 Experimental procedure for the synthesis of A-3a
[0247] [0247] A-2a (80.00 g, 340.33 mmoles, 1.0 equiv.) Is dissolved in DMSO (400 ml) and treated with cesium carbonate (220.53 g, 680.66 mmoles, 2, 0 equiv.) And dimethyl malonate (49.42 g, 374.36 mmol, 1.1 equiv.). The resulting mixture is heated to 80ºC for 10 h. After total conversion of the starting material, the reaction mixture is diluted with ethyl acetate and poured into ice water. The aqueous layer is extracted with ethyl acetate. The organic layers are combined and washed with an aqueous solution of 0.1 N formic acid. The organic layer is dried (Na2SO4) and concentrated under reduced pressure. Additional purification by flash column chromatography (eluent: 30% ethyl ethyl acetate in hexane) generates the desired product A-3a.
[0248] [0248] The following intermediates A-3 (Table 2) are available in an analogous manner starting from different pyrimidines A-2. Crude product A-3 is purified by chromatography if necessary. Table 2: # tret structure [min] [M + H] + HPLC Cl O method
[0249] [0249] A stirred solution of 2-fluoro-malonic acid dimethyl ester (72.30 g, 481.99 mmoles, 1.1 equiv.) In anhydrous DMF (300 ml) is cooled to 5 ° C and treated in portions with sodium hydride (20.16 g, 876.35 mmoles, 2.0 equiv.). After stirring at room temperature for 10 minutes, A-2a (103.00 g, 438.17 mmol, 1.0 equiv.) Dissolved in DMF (50 ml) is added and the resulting mixture stirred for an additional 2 h. After total conversion, the reaction mixture is poured into ice water and the aqueous layer extracted with ethyl acetate. The organic layers are combined, dried (Na2SO4) and concentrated under reduced pressure. Additional purification by flash column chromatography (eluent: 15% ethyl acetate in hexane) generates the desired product A-3c (HPLC method: GVK_LCMS_31; tret = 1.756 min; [M + H] + = 350). Synthesis of A-4 intermediates Experimental procedure for the synthesis of A-4a Cl O Cl O
[0250] [0250] A stirred solution of A-3a (40.00 g, 120.95 mmoles, 1.0 equiv.) In DMSO (120 ml) is treated with lithium chloride (20.32 g, 483.79 mmoles, 4.0 equiv.) And heated to 120ºC for 2 h. After complete conversion of the starting material, the resulting reaction mixture is diluted with diethyl ether and poured into ice water. The aqueous layer is extracted with diethyl ether, the organic layers are combined, dried (Na2SO4) and concentrated under reduced pressure. Additional purification by basic reverse phase chromatography (eluent: 20% acetonitrile in water)
[0251] [0251] The following intermediates A-4 (Table 3) are available in an analogous manner starting from different A-3 pyrimidines. Crude product A-4 is purified by chromatography if necessary. Table 3: # tret structure [min] [M + H] + HPLC Cl O method
[0252] [0252] A-4a (3135 mg, 11.50 mmoles, 1.5 equiv.) And B-5a (1450 mg, 7.67 mmoles, 1.0 equiv.) Are dissolved in anhydrous DMSO (10 ml) and
[0253] [0253] The following intermediates A-5 (Table 4) are available in an analogous manner starting from different pyrimidines A-4 and amines B-5. The crude product A-5 is purified by chromatography if necessary. Table 4: # tret structure [min] [M + H] + HPLC method F F F
[0254] [0254] A solution of A-2b (500 mg, 2.262 mmoles, 1.0 equiv.) In anhydrous DMSO (4.0 ml) is treated with 2-fluoro-malonic acid dimethyl ester (281 µL, 2.262 mmoles, 1.0 equiv.) and sodium carbonate (360 mg, 3.393 mmoles, 1.5 equiv.). The resulting mixture is stirred at room temperature for 4 d until complete conversion of the starting material is observed. Triethylamine (627 µL, 4.524 mmoles, 2.0 equiv.) And B-5a (642 mg, 3.393 mmoles, 1.5 equiv.) Are added and the reaction mixture stirred at 80ºC for another 16 h. After complete conversion, the reaction is quenched with an aqueous solution of NaHCO3 and the aqueous layer extracted with DCM. The organic layers are combined, dried (Na2SO4) and concentrated under reduced pressure. Additional purification by basic reverse phase chromatography (gradient elution: 15%
[0255] [0255] A-2a (50 mg, 0.213 mmol, 1.0 equiv.) Is dissolved in DMSO (0.5 ml) and treated with 2-fluoro-malonic acid dimethyl ester (27 µL, 0.221 mmol, 1, 0 equiv.) And potassium carbonate (58.8 mg, 0.425 mmol, 2.0 equiv.). The resulting mixture is stirred at 100ºC for 5 min until the total conversion of the starting material is observed. Triethylamine (89 µL, 0.639 mmol, 3.0 equiv.) And B-5a (60.2 mg, 0.318 mmol, 1.5 equiv.) Are added and the reaction mixture stirred at 60 ° C for another 3 h. The reaction mixture is filtered and the filtrate purified by basic reverse phase chromatography (gradient elution: 35% to 75% acetonitrile in water) to provide the desired product A-6a.
[0256] [0256] The following A-6 intermediates (Table 5) are available in an analogous manner starting from different A-5 pyrimidines. Crude product A-6 is purified by chromatography if necessary. Table 5: # tret structure [min] [M + H] + HPLC method F F F
[0257] [0257] A-5a (200.0 mg, 0.470 mmol, 1.0 equiv.) Is dissolved in DMSO (2 ml) and ACN (1 ml). An aqueous solution of sodium hydroxide (20%, 313 µL, 1.881 mmol, 4 equiv.) Is added and the resulting mixture stirred for 30 min until complete conversion of the starting material is observed. Triethylamine (130 µL, 0.933 mmol, 2.0 equiv.), 1-methyl-cyclopropylamine hydrochloride (62.8 mg, 0.583 mmol, 1.3 equiv.) And HATU (266.3 mg, 0.700 mmol, 1, 5 equiv.) Are added and the resulting mixture stirred for 20 min until complete conversion is observed. Water is added and the mixture diluted with DCM. The aqueous layer is extracted with DCM, the organic layers are combined and dried over magnesium sulfate. The resulting crude product A-7a can be used without further purification in the next step.
[0258] [0258] The following intermediates A-7 (Table 6) are available in a similar way starting from different pyrimidines A-5 and coupling with various C-1 amines or their corresponding salts. Crude product A-7 is purified by chromatography if necessary.
[0259] [0259] A-6a (16.0 mg, 0.032 mmol, 1.0 equiv.) Is dissolved in DMSO (1.5 ml). An aqueous solution of sodium hydroxide (20%, 16 µL, 0.096 mmol, 3.0 equiv.) Is added and the resulting mixture stirred for 30 min until complete conversion of the starting material is observed. Triethylamine (8.5 µL, 0.061 mmol, 2.0 equiv.), 1-fluoromethyl-cyclopropylamine hydrochloride (4.8 mg, 0.038 mmol, 1.3 equiv.) And HATU (17.3 mg, 0.045 mmol, 1.5 equiv.) are added and the resulting mixture is stirred for 20 min until complete conversion is observed. Water is added and the mixture diluted with DCM. The aqueous layer is extracted with DCM, the organic layers are combined and dried over magnesium sulfate. The resulting crude product A-7dp can be used without further purification in the next step.
[0260] [0260] The following intermediates A-7 (Table 7) are available in an analogous manner starting from different pyrimidines A-6 and coupling with various C-1 amines or their corresponding salts. Crude product A-7 is purified by chromatography if necessary. Table 7: # tret structure [min] [M + H] + HPLC method F F F
[0261] [0261] To a stirred solution of D-1a (20.00 g, 172.24 mmoles, 1.0 equiv.) In DCM (200 ml), EDCI (49.35 g, 258.37 mmoles, 1 is added) , 5 equiv.), Triethylamine (26.14 g, 258.37 mmoles, 1.5 equiv.), DMAP (0.21 g, 1.72 mmol, 0.01 equiv.) And N, O- dimethylhydroxylamine (25.20 g, 258.37 mmol, 1.5 equiv.) at 0 ° C. The reaction mixture is warmed to room temperature and stirred for 16 h. After complete conversion of the starting material, 1N HCl is added to the reaction mixture. The aqueous layer is extracted with EtOAc, the combined organic layers are washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by flash column chromatography (5% ethyl acetate in hexane) generating the desired product D-2a.
[0262] [0262] The following D-2 intermediates (Table 8) are available in an analogous manner starting from different D-1 acids. The crude product D-2 is purified by chromatography if necessary.
[0263] [0263] To a stirred solution of D-2a (150 mg, 0.942 mmol, 1.0 equiv.) In THF (5 ml), 3-bromophenylmagnesium bromide (0.5 N, 2.26 ml, 1.130 mmol, 1.2 equiv) at -15 ° C. The reaction mixture is warmed to room temperature and stirred for 3 h. After complete conversion of the starting material, water is added. The aqueous layer is extracted with EtOAc, the organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by flash column chromatography (eluent: 10% ethyl acetate in hexane) generating the desired product D-3a. Experimental procedure for the synthesis of D-3b O O N O O
[0264] [0264] A stirred solution of 1,3-dibromo-2-fluoro-benzene (15.95 g, 62.82 mmol, 1.0 equiv.) In anhydrous THF (100 ml) is cooled to -78 ° C. n-Butyl lithium (1.6 N, 47.1 ml, 75.36 mmoles, 1.2 equiv.) is added in drops and the resulting mixture is stirred for 30 min at -78 ° C. D-2b (10.00 g, 62.82 mmoles, 1.0 equiv.) Dissolved in THF (40 ml) is added slowly. After complete conversion, saturated aqueous ammonium chloride is added. The aqueous layer is extracted with EtOAc, the organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (gradient elution: 10% to 20% ethyl acetate in petroleum ether) generating the desired product D-3b.
[0265] [0265] The following D-3 intermediates (Table 9) are available in an analogous manner starting from different D-2 amides. The crude product D-3 is purified by chromatography if necessary. Table 9: # tret structure [min] [M + H] + HPLC method
[0266] [0266] To a stirred solution of D-3d (150 g, 738.89 mmoles, 1.0 equiv.) In DCM (1.5 L), diethylamine sulfur trifluoride (178.64 g, 1108 g) is slowly added , 33 mmoles, 1.5 equiv) at 0 ° C. The reaction mixture is warmed to room temperature and stirred for 16 h. After complete conversion of the starting material, ice water is added. The aqueous layer is extracted with EtOAc, the organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product B-1a is used without further purification in the next step.
[0267] [0267] The following B-1 intermediates (Table 10) are available in an analogous manner starting from different D-3 bromobenzenes. The crude product B-1 is purified by chromatography if necessary. Table 10: # tret structure [min] [M + H] + HPLC method F
[0268] [0268] To a stirred solution of ethyl bromodifluoroacetate (126.50 g, 623 mmoles, 2.5 equiv.) In DMSO (225 ml), copper powder (39.26 g, 623 mmoles, 2.5 equiv) is added ) at room temperature. After 1 h, B-1f (75.00 g, 249.26 mmoles, 1.0 equiv) is added and the resulting mixture heated to 70 ° C and stirred for another 3 h. After complete conversion of the starting material, ice water and EtOAc are added. Insolubles are removed by filtration and the aqueous layer is extracted with EtOAc. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by column chromatography (gradient elution: 0% to 10% ethyl acetate in petroleum ether) generating the desired product D-4a. Experimental procedure for the synthesis of B-1g F F F F HO O The F
[0269] [0269] To a stirred solution of D-4a (100.00 g, 336.62 mmoles, 1.0 equiv.) In anhydrous toluene (1 L), methylmagnesium bromide (1 N, 1.34 L) is slowly added , 1340 mmoles, 4.0 equiv) at 0 ° C. The resulting mixture is stirred for 1 h at room temperature. After complete conversion of the starting material, saturated aqueous ammonium chloride is added and the aqueous layer is extracted with EtOAc. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by chromatography (25% ethyl acetate in hexane) generating the desired product B-1g. Experimental procedure for the synthesis of D-5a The S
[0270] [0270] B-1h (480.00 g, 2274 mmoles, 1.0 equiv.) And ethane-1,2-dithiol (213.78 g, 2274 mmoles, 1.0 equiv.) Are dissolved in toluene (5 L), TsOH (78.24 g, 454.9 mmoles, 0.2 equiv.) Is added at room temperature and the resulting mixture heated to reflux for 24 h. After complete conversion of the starting material, a 10% aqueous NaOH solution is added and the aqueous layer is extracted with EtOAc. The organic layers are combined, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by chromatography (gradient elution: 0% to 10% ethyl acetate in petroleum ether) generating the desired product D-5a. Experimental procedure for the synthesis of B-1i S F F
[0271] [0271] To a stirred solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (793.8 g, 2785 mmoles, 4.0 equiv.) In DCM (1.5 L) , HF-pyridine (70%, 800 ml, 30800 mmoles, 44 equiv.) is added at -70 ° C. To this mixture, D-5a (200.00 g, 696.28 mmoles, 1.0 equiv.) Dissolved in DCM (0.5 L) is added in drops. The temperature is kept below -60ºC for 4 h and then the resulting mixture is stirred for another 16 h at room temperature. After complete conversion of the starting material, a 2N aqueous NaOH solution and a 30% aqueous NaHSO3 solution are added. The organic layer is washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel (gradient elution: 0% to 3% ethyl acetate in petroleum ether) generating the desired product B-1i. Experimental procedure for the synthesis of B-1j F F
[0272] [0272] B-1i (140.00 g, 448.79 mmoles, 1.0 equiv.) Is dissolved in DCM (1.5 L) and DBU (102.32 g, 673.19 mmoles, 1.5 equiv. .) is added at 0ºC. The resulting mixture is stirred for 6 h at room temperature. After complete conversion of the starting material, the mixture is diluted with DCM, washed with 0.5 N aqueous HCL, water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by chromatography (gradient elution: 0% to 10% ethyl acetate in petroleum ether) generating the desired product B-1j. Experimental procedure for the synthesis of B-1k F F
[0273] [0273] To a stirred solution of B-1j (130.00 g, 562.68 mmol, 1.0 equiv.) And 2-nitrobenzenesulfonyl chloride (124.35 g, 562.68 mm, 1.0 equiv.) in acetonitrile (1.3 L) K3PO4 (23.86 g, 112.54 mmoles, 0.2 equiv) and hydrazine hydrate (56.27 g, 1125.36 mmoles, 2.0 equiv are slowly added ) at 0ºC. The resulting mixture is stirred for 24 h at room temperature. After complete conversion of the starting material, water is added and the aqueous layer is extracted with EtOAc. The organic layers are combined, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel (gradient elution: 0% to 5% ethyl acetate in petroleum ether) generating the desired product B-1k. Synthesis of B-2 intermediates Experimental procedure for the synthesis of B-2a F F F F
[0274] [0274] B-1a (125.0 g, 555.54 mmol, 1.0 equiv.) Is dissolved in anhydrous 1,4-dioxane (1.2 L). Triethylamine (140.27 ml, 1388.85 mmoles, 2.5 equiv.) And tributyl (1-ethoxyvinyl) tin (240.66 g, 666.65 mmoles, 1.2 equiv.) Are added and the resulting solution is purged with argon for 15 min. Bis (triphenylphosphine) palladium (II) chloride (3.90 g, 5.6 mmoles, 0.01 equiv.) Is added and the reaction mixture heated to 100ºC in an autoclave for 16 h. After complete conversion of the starting material, the reaction mixture is cooled to room temperature and treated with 1 N HCl and stirred for another 16 h. The aqueous layer is extracted with EtOAc, the combined organic layers are dried over Na2SO4, filtered and the solvent is removed under reduced pressure. The crude product B-2a is used without further purification in the next step.
[0275] [0275] The following B-2 intermediates (Table 11) are available in an analogous manner starting from different B-1 bromobenzenes. The crude product B-2 is purified by chromatography if necessary. Table 11: 3 tret structure [min] [M + H] + HPLC method F
[0276] [0276] To a stirred solution of B-2i (80.00 g, 368.60 mmoles, 1.0 equiv.) In THF (800 ml), TMS-acetylene (54.31 g, 552.94 mmoles) is added , 1.5 equiv.), Triethylamine (111.69 g, 1105.84 mmol, 3.0 equiv.), CuI (4.034 g, 36.86 mmol, 0.1 equiv.) And Pd (PPh3) 2Cl2 ( 25.88 g, 36.87 mmoles, 0.1 equiv.) At room temperature. The resulting mixture is heated to reflux for 16 h. After complete conversion of the starting material, ice water and EtOAc are added and the aqueous layer is extracted with EtOAc. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by flash column chromatography (gradient elution: 0% to 10% ethyl acetate in hexane) generating the desired product D-6a. Experimental procedure for the synthesis of B-2j Si F F
[0277] [0277] To a stirred solution of D-6a (60.00 g, 256.04 mmoles, 1.0 equiv.) In DCM (1.2 L) and methanol (1.2 L), potassium carbonate is added (353.87 g, 2560.38 mmoles, 10.0 equiv.) At room temperature. The resulting mixture is stirred for 2 h. After complete conversion of the starting material, ice water is added and the aqueous layer is extracted with DCM. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by flash column chromatography (gradient elution: 20% ethyl acetate in hexane) generating the desired product B-2j. Experimental procedure for the synthesis of B-2k F F F F
[0278] [0278] B-2j (98.00 g, 604.34 mmoles, 1.0 equiv.) Is dissolved in 1,1,1,3,3,3-hexafluoro propanol (500 ml) in a teflon flask. HF-pyridine (70%, 250 ml, 9625 mmoles, 16 equiv.) Is added and the vial is sealed. The resulting mixture is stirred for 3 d at room temperature. After complete conversion of the starting material, ice water and EtOAc are added and the aqueous layer is extracted with EtOAc. The organic layers are combined, washed with a solution of
[0279] [0279] To a stirred solution of D-7a (120.00 g, 479.98 mmoles, 1.0 equiv.) In THF (1.2 L), is added methylmagnesium bromide (1 N, 720 ml, 720 .00 mmoles, 1.5 equiv) in drops at -78ºC. The resulting mixture is stirred for 3 h at the same temperature. After complete conversion of the starting material, a saturated aqueous ammonium chloride solution is added and the aqueous layer is extracted with EtOAc. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (gradient elution: 0% to 10% ethyl acetate in petroleum ether) generating the desired product D-8a. Experimental procedure for the synthesis of B-2l I I F F
[0280] [0280] To a stirred solution of D-8a (24.00 g, 90.21 mmoles, 1.0 equiv.) In acetonitrile (240 ml), tetrapropylammonium perrutenate (3.166 g, 9.01 mmoles) is added , 0.1 equiv.) And 4-methylmorpholine N-oxide (15.83 g, 135.30 mmol, 1.5 equiv.) At room temperature. The resulting mixture is stirred for 4 h at the same temperature. After complete conversion of the starting material, the insolubles are removed by filtration and the filtrate concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (gradient elution: 0% at
[0281] [0281] To a stirred solution of B-2l (22.00 g, 83.32 mmoles, 1.0 equiv) in DMSO (220 ml), ethyl bromodifluoroacetate (50.74 g, 249.95 mmoles, 3 , 0 equiv.) And copper powder (15.75 g, 250.00 mmoles, 3.0 equiv) at room temperature. The resulting mixture is heated to 80 ° C and stirred for 16 h. After complete conversion of the starting material, ice water and diethyl ether are added. Insolubles are removed by filtration and the aqueous layer is extracted with diethyl ether. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by chromatography (gradient elution: 0% to 3% ethyl acetate in petroleum ether) generating the desired product D-9a. Experimental procedure for the synthesis of B-2m F F F OH B HO
[0282] [0282] D-10a (20.00 g, 121.98 mmol, 1.0 equiv.) And 2,2,2-trifluoroethyl iodide (51.23 g, 243.95 mmol, 2.0 equiv.) are added to a stirred suspension of tris (dibenzylidene acetone) -dipaladium (7.819 g, 8.54 mmoles, 0.1 equiv.), xantphos (7.05 g, 12.20 mmoles, 0.1 equiv.) and carbonate cesium (118.93 g, 365.94 mmoles, 3.0 equiv.) in THF (200 ml) under an argon atmosphere. The resulting mixture is stirred for one minute and then heated to 80ºC for 12 h in a sealed tube. After complete conversion of the starting material, ice water and EtOAc are added and the aqueous layer is extracted with EtOAc. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by flash column chromatography generating the desired product B-2m. Synthesis of B-3 intermediates Experimental procedure for the synthesis of B-3a F F F F F F The N
[0283] [0283] B-2a (170.00 g, 903.53 mmoles; 1.0 equiv.) Is dissolved in THF (1.7 L). (R) - (+) - 2-methyl-2-propanesulfinamide (164.13 g; 1355.33 mmoles; 1.5 equiv.) And titanium tetraethoxide (618.03 g, 2710.66 mmoles; 3.0 equiv.) are added at room temperature and the resulting reaction mixture is heated to 80ºC for 16 h. After complete conversion of the starting material, ice water and EtOAc are added and the aqueous layer is extracted with EtOAc. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product B-3a is used without further purification in the next step.
[0284] [0284] The following intermediates B-3 and D-10 (Table 12) are available in an analogous manner starting from different acetophenones B-2 and D-9. The crude product is purified by chromatography if necessary. Table 12: # tret structure [min] [M + H] + HPLC method F F
[0285] [0285] A solution of B-3a (170.00 g, 583.53 mmoles; 1.0 equiv.) Is dissolved in THF (1.7 L) and cooled to 0 ° C. Sodium borohydride (21.59 g; 583.51 mmoles; 1.0 equiv.) Is added and the resulting reaction mixture stirred at room temperature for 6 h. After complete conversion of the starting material, ice water and EtOAc are added and the aqueous layer is extracted with EtOAc. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by chromatography (gradient elution: 33% ethyl acetate in petroleum ether) generating the desired product B-4a.
[0286] [0286] The following intermediates B-4 (Table 13) are available in an analogous way starting from different sulfinamides B-
[0287] [0287] A solution of D-11a (26.00 g, 71.55 mmoles; 1.0 equiv.) Is dissolved in THF (260 ml) and water (5 ml) cooled to -78 ° C. Sodium borohydride (8.156 g; 214.63 mmoles; 3.0 equiv.) Is added and the resulting reaction mixture is warmed to room temperature and stirred for 4 h. After complete conversion of the starting material, ice water and EtOAc are added and the aqueous layer is extracted with EtOAc. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography generating the desired product B-4n. Experimental procedure for the synthesis of B-4o F F F F HO F O NH NH S S
[0288] [0288] To a stirred solution of B-4n (5.00 g, 15.46 mmoles, 1.0 equiv.) In THF (50 ml), cesium carbonate (15.12 g, 46.38 mmoles) is added , 3.0 equiv.) And 18-crown-6 (2.04 g, 7.73 mmoles, 0.5 equiv.) At room temperature. The resulting mixture is heated to 80ºC for 16 h. After complete conversion of the starting material, water and EtOAc are added and the aqueous layer is extracted with EtOAc. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by flash column chromatography (80% EtOAc in hexane) and reverse phase chromatography to generate the desired product B-4o. Experimental procedure for the synthesis of B-4p F F F HO F O NH NH S S
[0289] [0289] To a stirred solution of B-4n (1.00 g, 3.09 mmoles, 1.0 equiv.) In THF (10 ml), potassium tert-butoxide (0.52 g, 4, 64 mmoles, 1.5 equiv.) And 18-crown-6 (2.04 g, 7.73 mmoles, 0.5 equiv.)
[0290] [0290] Acetophenone B-2n (5.00 g, 24.3 mmoles, 1.0 equiv.) Is dissolved in toluene (15 ml) and 2-methyltetrahydrofuran (5.0 ml). Sodium tert-amylate (281 µL, 50% in toluene, 1.21 mmol, 5% in mol) is added and the reaction mixture is purged with Ar atmosphere. (R) -RUCY-Xyl- BINAP (58, 0 mg, 49.0 µmoles, 0.2 mol%) is added to the reaction mixture. The reaction mixture is charged with a hydrogen atmosphere (3 bar) and stirred at room temperature for 19 h until complete conversion of B-2n is achieved. The reaction is diluted with EtOAc (50 ml) and washed with water (1 × 50 ml), aqueous HCL (1 × 10 ml, 1.0 M) and water (1 × 50 ml). The organic layer is dried over Na2SO4, filtered and concentrated in vacuo to provide the desired product.
[0291] [0291] The following B-6 intermediates (Table 14) are available in an analogous way starting from different acetophenones B-2. The crude product is purified by chromatography if necessary. Table 14: # tret structure [min] m / z HPLC method [M + H] +: B-6a 1.283 D_LC_SSTD 191.1
[0292] [0292] A solution of B-4a (13.20 g, 45.00 mmoles; 1.0 equiv.) In 1,4-dioxane (100 ml) is cooled to 0ºC and treated with 4 N HCl in 1.4 -dioxane (50.00 ml, 200.00 mmol, 4.4 equiv.). The reaction mixture is stirred for 3 h. After complete conversion of the starting material, the reaction mixture is concentrated under reduced pressure, the precipitate is filtered and washed with diethyl ether to obtain the desired product B-5a as HCl salt.
[0293] [0293] The following benzyl amines B-5 (Table 15) are available in an analogous manner starting from different sulfinamides B-
[0294] [0294] Alcohol B-6a (2.00 g, 9.61 mmoles, 1.0 equiv.) Is dissolved in anhydrous toluene (20 ml). Diazabicycloundecene (1.73 ml, 11.5 mmoles, 1.2 equiv.) And diphenylphosphonic azide (2.28 ml, 10.6 mmoles, 1.1 equiv.) Are added subsequently. The reaction mixture is stirred at 40 ° C for 18 h until complete conversion of B-6a is achieved. The reaction mixture is cooled to room temperature and the organic layer is washed with aqueous Na2CO3 solution (2 × 10 ml). Azide B-7a thus obtained is not isolated, but directly converted in the next step.
[0295] [0295] Pd / C (200 mg, 10% w / w, 10% Pd) is added to the organic layer. The reaction mixture is charged with an atmosphere of H2 (10 bar) and is stirred for 24 h until complete conversion of B-7a is achieved. The reaction is filtered and the volatiles are removed in vacuo. The residue is dissolved in methyl tert-butyl ether (30 ml) and treated with HCl in dioxane (4.8 ml, 4 M). The white precipitate is filtered, washed with methyl tert-butyl ether (20 ml) and further dried in vacuo to provide the desired product B-5k. The crude product is purified by chromatography if necessary.
[0296] [0296] The following B-5 intermediates (Table 16) are available in an analogous way starting from different B-6 alcohols through B-7 azides. Table 16: # tret structure [min] [M + H] + HPLC method B-7a n.a. at. at.
[0297] [0297] To a stirred solution of D-12a (6.50 g, 35.093 mmoles, 1.0 equiv.) In DCM (100 ml), diethylaminosulfur trifluoride (8.48 g, 52.67 mmoles, 1 is added) , 5 equiv) in drops at 0ºC. The reaction mixture is slowly warmed to room temperature and stirred for 16 h. After complete conversion of the starting material, a solution of
[0298] [0298] To a stirred solution of D-13a (2.40 g, 11.582 mmoles, 1.0 equiv.) In 1,4-dioxane (5.0 ml), 4 N HCl in 1,4-dioxane is added (10 ml, 40.00 mmoles, 3.5 equiv) at 0 ° C. The reaction mixture is warmed to room temperature and stirred for 16 h. After complete conversion of the starting material, the reaction mixture is concentrated under reduced pressure. N-Pentane is added to the crude product. The solid material is filtered and washed with n-pentane to generate the desired product C-1a as the HCl salt. Experimental procedure for the synthesis of D-15a:
[0299] [0299] Amino acid D-14a (2.00 g, 19.7 mmoles, 1.0 equiv.) And phthalic anhydride (2.92 g, 19.7 mmoles, 1.0 equiv.) Are suspended in acid acetic acid (20 ml). The reaction mixture is adjusted to reflux and the solution obtained is stirred at that temperature for 3 h. The reaction mixture is cooled to 0 ° C while the product D-15a crystallizes. Water (20 ml) is added and the reaction mixture is stirred at that temperature for 1 h. The precipitate is filtered, washed with water and further dried in vacuo to provide the desired product. The crude product is further purified by chromatography if necessary (tret = 1.03 min; [M-H] + = 230.0; HPLC method
[0300] [0300] D-15a acid (2.00 g, 8.6 mmoles, 1.0 equiv.) Is suspended in toluene (10 ml) and N, N-dimethylformamide (0.1 ml). Thionyl chloride (1.08 g, 9.1 mmoles, 1.05 equiv.) Is added at room temperature, then the reaction mixture is adjusted to reflux and the solution obtained is stirred at that temperature for 3 h until conversion complete D-15a to be achieved (sudden cooling with benzylamine). The reaction mixture is cooled to room temperature while the D-16a product crystallizes. Heptane (10 ml) is added and the reaction mixture is further cooled to 5ºC and stirred at that temperature for 1 h. The precipitate is filtered, washed with water and further dried in vacuo to provide the desired product. The crude product is further purified by chromatography if necessary (tret = 1.27 min; [M + H] + = 246/247/248; HPLC method D_LC_SSTD as benzylamide after abrupt cooling with benzylamine; 1H NMR (400 MHz, CDCl3) δ ppm 1.70-1.85 (m, 2 H), 2.10-2.31 (m, 2 H), 7.64-8.11 (m, 4 H). synthesis of D-17a:
[0301] [0301] Acyl chloride D-16a (2.00 g, 8.0 mmol, 1.0 equiv.) And 10% Pd / C (dry, 100 mg, 5% w / w) are suspended in tetrahydrofuran ( 12 ml) and 2,6-lutidine (1.03 g, 9.6 mmoles, 1.2 equiv.). The reaction mixture is hydrogenated at 3 bar and 30ºC. After 20 h, an additional catalyst is added (25 mg) and hydrogenation continues for another 24 h. After that time, the reaction mixture is filtered and the filtrate is evaporated. The residual is divided between toluene and an aqueous solution of NaHCO3. The organic phase is separated and washed again with the NaHCO3 solution and finally with a citric acid solution. The organic layer is dried (Na2SO4) and concentrated under reduced pressure. The crude product is further purified by chromatography if necessary (tret = 1.26 min; [M + H] + = 216; HPLC method D_LC_BSTD). Experimental procedure for the synthesis of D-18a:
[0302] [0302] Aldehyde D-17a (2.00 g, 9.3 mmoles, 1.0 equiv.) Is dissolved in dichloromethane (12 ml) and a 50% toluene solution of bis (2-methoxyethyl) amino sulfur trifluoride (9.90 g, 22.3 mmoles, 2.4 equiv.) Is added slowly at room temperature. After two days of stirring, the reaction mixture is carefully treated with an aqueous solution of NaHCO3 and more dichloromethane (15 ml). The organic layer is dried (Na2SO4) and concentrated under reduced pressure. The crude product D-18a is further purified by chromatography or crystallization if necessary (tret = 1.24 min; [M + H] + = 238; HPLC method D_LC_SSTD).
[0303] [0303] (Potential alternative fluorination agents to be used for the conversion of D-17a are, for example, difluorosulfonium (diethylamino) tetrafluoroborate and sulfur tetrafluoride) Experimental procedure for the synthesis of C-1a:
[0304] [0304] Imide D-18a (15.0 g, 63.2 mmoles, 1.0 equiv.) Is suspended in N- (2-hydroxyethyl) ethylenediamine (45 ml) and the mixture heated to
[0305] [0305] To a stirred solution of D-19a (5.00 g, 58.08 mmoles, 1.0 equiv.) In DCM (50 ml), (S) - (-) - 1-phenylethylamine (6 , 21 g, 58.08 mmoles, 1.0 equiv) and magnesium sulfate (13.94 g, 116.16 mmoles, 2.0 equiv.). The reaction mixture is stirred at room temperature for 16 h. After complete conversion of the starting material, insolubles are removed by filtration and the filtrate is concentrated under pressure. The crude product D-20a is used without further purification in the next step. Experimental procedure for the synthesis of D-21a and D-21b O O F O F F F F F
[0306] [0306] To a stirred solution of D-20a (8.00 g, 42.27 mmoles, 1.0 equiv.) In acetonitrile (80 ml) and DMF (8 ml), potassium fluoride and hydrogen (2 , 64 g, 33.85 mmoles, 0.8 equiv) and trifluoroacetic acid (5.30 g, 46.49 mmoles, 1.1 equiv) at 0 ° C. The reaction mixture is stirred for 10 min, then trimethyl-trifluoromethyl-silane (9.02 g, 63.43 mmoles, 1.5 equiv.) Is added and the resulting mixture warmed to room temperature and stirred for another 16 H. After complete conversion of the starting material, water and ethyl acetate are added, the aqueous layer extracted with ethyl acetate and the combined organic layers washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by SFC generating the desired products D-21a and D-21b. Experimental procedure for the synthesis of C-1b The F F F O NH F F
[0307] [0307] D-21a (2.00 g, 7.714 mmoles, 1.0 equiv.) Is dissolved in 3 N HCl in methanol (6.00 ml, 18.00 mmoles, 2.3 equiv.) And stirred for 5 min at room temperature. The solvent is removed under reduced pressure and the resulting solid material is dissolved in methanol (20 ml). Alumina palladium (10% by weight, 200.00 mg, 0.188 mmol, 0.025 equiv.) Is added and the resulting mixture is stirred for 16 h at room temperature. After complete conversion, insolubles are removed by filtration and the filtrate is concentrated under reduced pressure. Diethyl ether is added to the crude product. The solid material is filtered and washed with diethyl ether to generate the desired product C-1b as the HCl salt.
[0308] [0308] The following C-1 amines (Table 17) are available in an analogous manner starting from different D-21 intermediates. The crude product C-1 is purified by chromatography if necessary and isolated as HCl salt.
[0309] [0309] To a stirred solution of D-22a (330 mg, 1.293 mmol, 1.0 equiv.) In THF (1.0 ml), triethylamine (99%, 544 µL, 3.875 mmol, 3.0 equiv) ) and TBTU (518.8 g, 1.616 mmol, 1.3 equiv.). The reaction mixture is stirred at room temperature for 15 min, then dimethylamine hydrochloride (110.7 mg, 1.358 mmol, 1.1 equiv.) Is added. The resulting mixture is stirred for an additional 2 h. After complete conversion of the starting material, water and DCM are added and the aqueous layer is extracted with DCM. The organic layers are combined, dried over MgSO4 and concentrated under reduced pressure. The crude product D-23a is used without further purification in the next step.
[0310] [0310] The following D-23 amides (Table 18) are available in an analogous manner starting from different D-22 acids. The crude product D-23 is purified by chromatography if necessary. Table 18: # tret structure [min] [M + H] + HPLC method O
[0311] [0311] D-23a (360 mg, 1.275 mmol, 1.0 equiv.) Is dissolved in DCM (5.0 ml) and treated with 4 N HCl in 1,4-dioxane (2.55 ml, 10,200 mmoles, 8.0 equiv.). The reaction mixture is stirred for 18 h. After complete conversion of the starting material, the solvents are partially removed under reduced pressure. The solid material is filtered and dried to generate the desired product C-1d as an HCl salt.
[0312] [0312] The following C-1 amides (Table 19) are available in an analogous manner starting from different D-23 intermediates. The crude product C-1 is purified by chromatography if necessary and isolated as HCl salt. Table 19: # tret structure [min] [M + H] + HPLC method
[0313] [0313] At 0ºC, dimethyl 3-oxopentanedioate E-1a (10.0 g, 57.4 mmoles, 1.0 equiv.) Is combined with N, N-dimethylformamide dimethyl acetal (7.60 ml, 57.4 mmoles, 1.0 equiv.) in 2-methyltetrahydrofuran (75 ml). After stirring 3 h at 0-4ºC, the reaction mixture is warmed to room temperature and aqueous hydrochloric acid (4 N, 26 ml) is slowly added (intermediate E-2a is not isolated). After stirring 3 h at room temperature, the organic layer is separated, washed with water and then brine and concentrated under reduced pressure. The crude product E-3a is further purified by distillation or chromatography if necessary (tret = 0.99 / 1.04 min; [M + H] + = 203; HPLC method D_LC_SSTD). Synthesis of E-4 intermediates Experimental procedure for the synthesis of E-4a:
[0314] [0314] Dimethyl 2-formyl-3-oxopentanedioate E-3a (4.34 g, 21.5 mmoles, 1.15 equiv.) And a methanol solution of C-1a amine (2.00 g 18.7 mmoles, 1.0 equiv in 14.5 ml of methanol) are combined in methanol (5.5 ml) at room temperature. After stirring overnight at that temperature, NaOMe (3.8 ml, 21.5 mmoles, 1.15 equiv. 30% w / w in methanol) is added, rinsing with additional methanol (2 ml). After stirring 2 h at room temperature, water (24 ml) is slowly added followed by the addition of concentrated hydrochloric acid (4.7 ml). The precipitate is filtered, washed with water and further dried in vacuo to provide the desired product. The crude product is purified by chromatography if necessary (tret = 1.06 min; [M-H] + = 258; HPLC method D_LC_SSTD). Synthesis of E-5 intermediates Experimental procedure for the synthesis of E-5a:
[0315] [0315] 4-Hydroxypyridinone E-4a (2.00 g, 7.7 mmoles, 1.0 equiv.) Is suspended in acetonitrile (16 ml). Triethylamine (1.61 ml, 11.6 mmoles, 1.5 equiv.) Is added at room temperature followed by p-toluenesulfonyl chloride (1.47 g, 7.7 mmoles, 1.0 equiv.) In portions, rinsing with acetonitrile (4 ml). The reaction mixture is stirred at room temperature for 2 h until complete conversion is achieved, then it is concentrated on the rotary evaporator and treated with water (20 ml). After stirring 1 h at room temperature, the precipitate is filtered, washed with water and further dried in vacuo to provide the desired product. The crude product is purified by chromatography if necessary (tret = 1.34 min; [M-H] + = 414; HPLC method D_LC_SSTD). Synthesis of E-6 intermediates Experimental procedure for the synthesis of E-6a:
[0316] [0316] Tosylate E-5a (4.00 g, 9.78 mmoles, 1.0 equiv.), Acetamide (686 mg, 11.6 mmoles, 1.0 equiv.), K3PO4 (2.26 g, 10 , 6 mmoles, 1.1 equiv.), Palladium chloride dimer (π-cinamyl) (75.2 mg, 145 µmoles, 1.5 mol%) and Xantphos (168 mg, 290 µmoles, 3.0% in mol) are suspended in dioxane (20 ml). The reaction mixture is purged with Ar atmosphere and stirred at reflux for 2 h until complete conversion is achieved. At 50 ° C, conc. (36%, 83 µL, 968 mmoles, 0.1 equiv.) And water (40 ml) are added. The reaction is further cooled and stirred at room temperature for 2 h. The precipitate is filtered, washed with water and further dried in vacuo to provide the desired product. The crude product E-6a is purified by chromatography if necessary (tret = 1.123 min; [M + H] + = 301.0; HPLC method D_LC_SSTD). Synthesis of E-7 intermediates Experimental procedure for the synthesis of E-7a:
[0317] [0317] Acetamide E-6a (2.50 g, 8.33 mmoles, 1.0 equiv.) Is suspended in methanolic NH3 (7 M, 20 ml) and stirred at room temperature for 5 days until conversion complete E-6a to be achieved. The solvent is removed in vacuo and the solid residue is dissolved in methanol (10 ml). Aqueous NaOH solution (1 M, 10 ml) is added to the reaction mixture and the reaction is stirred at 50 ° C for 20 min. The reaction mixture is filtered, the residual solids are washed with methanol (5 ml) and the filtrate is neutralized using aqueous HCL (1 M, ca. 10 ml). The precipitate is filtered, washed with water and acetonitrile and further dried in vacuo to provide the desired product. The crude product E-7a is purified by chromatography if necessary (tret = 0.885 min; [M + H] + = 268.0; HPLC method D_LC_SSTD). Synthesis of compounds (I) according to the invention Experimental procedure for the synthesis of I-1 F F F F F NH O F N O NH N N N
[0318] [0318] A-7a (272.0 mg, 0.586 mmol, 1.0 equiv.) Is dissolved in 2-propanol (0.5 ml). A 5N aqueous HCl solution (586 µL, 2.928 mm, 5.0 equiv.) Is added and the resulting mixture stirred for 1 hour at 50 ° C until complete conversion of the starting material is observed. The reaction mixture is basified with aqueous ammonia, filtered and the filtrate purified by basic reverse phase chromatography (gradient elution: 20% to 60% acetonitrile in water) to provide the desired product. Experimental procedure for the synthesis of I-97
[0319] [0319] E-7a (1.00 g, 3.74 mmoles, 1.0 equiv.) Is suspended in MeCN (20 ml). K3PO4 (2.00 g, 9.42 mmoles, 2.5 equiv.) And hexachlorocyclotriphosphaene (1.30 g, 3.74 mmoles, 1.0 equiv.) Are added and the reaction mixture is stirred at temperature room for 1 h. Phenylamine B-5k hydrochloride (930 mg, 4.12 mmol, 1.1 equiv.) Is added and the reaction mixture is stirred for an additional 1 h. Aqueous NH3 solution (25%, 2.0 ml) and, after 1 h, a saturated K2CO3 solution (20 ml) are added. The biphasic reaction mixture is stirred at room temperature for 16 h and the organic layer is concentrated in vacuo. The I-97 crude product is purified by chromatography if necessary.
[0320] [0320] The following compounds I (Table 20) are available in an analogous way starting from different acetals A-7 or starting from different building blocks E-7 and B-5. The crude products are purified by chromatography if necessary.
[0321] [0321] A-7ct (90 mg, 0.196 mmol, 1.0 equiv.) Is dissolved in 2-propan (0.5 ml). A 2 N aqueous HCl solution (500 µL, 1,000 mmol, 5.1 equiv.) Is added and the resulting mixture stirred for 3 h at 50 ° C until complete conversion of the starting material is observed. The reaction mixture is basified with aqueous ammonia, filtered and the filtrate purified by basic reverse phase chromatography (gradient elution: 15% to 85% acetonitrile in water) to provide the desired product.
[0322] [0322] The following compounds I (Table 21) are available in an analogous manner starting from different A-7 pyrimidines. The raw products are purified by chromatography if necessary. Table 21: tret [min] Method IC50 # structure [M + H] + HPLC [nM]
[0323] [0323] A-7ak (56.0 mg, 0.120 mmol, 1.0 equiv.) Is dissolved in 2-propanol (0.5 ml). A 2 N HCl aqueous solution (500 µL, 1,000 mmol, 8.3 equiv.) Is added and the resulting mixture stirred for 1 h at 50 ° C until complete conversion of the starting material is observed. 2 M aqueous NaOH (500 µL, 1,000 mmol, 8.3 equiv.) Is added and the resulting mixture stirred for an additional hour at room temperature until complete conversion of the intermediate is observed. The reaction mixture is filtered and the filtrate purified by basic reverse phase chromatography (gradient elution: 30% to 70% acetonitrile in water) to provide the desired product.
[0324] [0324] The following compounds I (Table 22) are available in an analogous manner starting from different A-7 pyrimidines. For the preparation of some compounds, also other bases, such as aqueous ammonia, were used instead of aqueous NaOH. The crude products are purified by chromatography if necessary. Table 22: tret [min] IC50 method # structure [M + H] + HPLC [nM] F F
[0325] [0325] I-1 (179.0 mg, 0.445 mmol, 1.0 equiv.) Is dissolved in acetonitrile (1.5 ml). A solution of NBS (80.8 mg, 0.454 mmol, 1.0 equiv.) In acetonitrile (0.5 ml) is added in drops and the resulting mixture stirred for 1 h at room temperature until complete conversion of the material. departure is observed. The reaction mixture is diluted with DCM and washed with water. The organic layers are combined, dried (MgSO4) and concentrated under reduced pressure to provide the desired product I-131.
[0326] [0326] The following compounds I (Table 23) are available in an analogous manner starting from different compounds I. The crude products are purified by chromatography if necessary. Table 23: tret [min] Method # structure [M + H] + HPLC F F
[0327] [0327] I-131 (23.0 mg, 0.048 mmol, 1.0 equiv.) Is dissolved in dioxane (0.75 ml) and water (0.25 ml). Cesium carbonate (90%, 26.0 mg, 0.072 mmol, 1.5 equiv.), Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (DCM complex) (3.9 mg, 0.005 mmol, 0.1 equiv. .) and trimethylboroxine (99%, 7.5 µL, 0.054 mmol, 1.1 equiv.) are added. The flask is washed with argon and the reaction mixture is stirred for 16 h at 100ºC until total conversion of the starting material is observed. The reaction mixture is diluted with DCM and washed with aqueous NaHCO3. The organic layers are combined, dried (MgSO4) and concentrated under reduced pressure. Purification by basic reverse phase chromatography (gradient elution: 25% to 85% acetonitrile in water) provides the desired product.
[0328] [0328] The following compounds I (Table 24) are available in an analogous manner starting from different compounds I. The crude products are purified by chromatography if necessary. Table 24: tret [min] Method IC50 # structure [M + H] + HPLC [nM] F F
[0329] [0329] I-137 (50.0 mg, 0.107 mmol, 1.0 equiv.) Is dissolved in dioxane (0.8 ml) and water (0.2 ml). Potassium carbonate (90%, 33.0 mg, 0.214 mmol, 2.0 equiv.), Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (DCM complex) (9.0 mg, 0.011 mmol, 0.1 equiv. .) and cyclopropylboronic acid (14.0 mg, 0.161 mmol, 1.5 equiv.) are added. The flask is washed with argon and the reaction mixture is stirred for 4 h at 100ºC until complete conversion of the starting material is observed. The reaction mixture is diluted with DCM and washed with aqueous NaHCO3. The organic layers are combined, dried (MgSO4) and concentrated under reduced pressure. Purification by basic reverse phase chromatography (gradient elution: 25% to 85% acetonitrile in water) provides the desired product (HPLC method: LCMSBAS1, tret. = 1.27 min; [M + H] + = 429; IC50 = 11 nM).
[0330] [0330] The following Examples describe the biological activity of the compounds according to the invention, without restricting the invention to those Examples.
[0331] [0331] Compounds of formula (I) are characterized by their many possible applications in the therapeutic field. KRAS AlphaScreen Binding Assay :: SOS1
[0332] [0332] This assay can be used to examine the potency with which compounds inhibit protein-protein interaction between SOS1 and KRAS G12D. This demonstrates the molecular mode of action of compounds. The low IC50 values are indicative of the high potency of the SOS1 inhibiting compound in this test configuration:
[0333] [0333] Reagents:  SST1 marked with GST (564_1049_GST_TEV_ECO) produced internally  GST-TEV-SOS1 (564-1049) is purchased from Viva Biotech Ltd.  6xHis-Tev-K-RasG12D (1-169) Avi é purchased from Xtal BioStructures, Inc. (lot # X129-110)  GDP (Sigma code no G7127)  AlphaLISA Glutathione Accepting Spheres (PerkinElmer, Cat No. AL109)  Streptavidin AlphaScreen Donating Spheres (PerkinElmer Cat No. 6760002)
[0334] [0334] Assay buffer:  1 x PBS  0.1% BSA  100 µM EDTA or without EDTA (IC50s in the tables are measured without EDTA, unless marked with an asterisk)  Tween 20 0.05% Mixture KRAS :: SOS1 GDP:
[0335] [0335] 10 nM (final test concentration) of KRAS G12D, 10 µM (final test concentration) of GDP and 5 nM (final test concentration) of GST-SOS1 are mixed in test buffer before use and kept at room temperature. Mixture of spheres:
[0336] [0336] AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads are mixed in assay buffer at a concentration of 10 µg / mL (final assay concentration) each before use and kept at room temperature. Test protocol:
[0337] [0337] The compounds are diluted to an initial final concentration of 100 µM and are tested in duplicate. Ready-to-test plates (ARPs) are generated using an Access Lab workstation with a Labcyte Echo 550 or 555 acoustic dispenser. For an initial compound concentration of 100 µM, 150 nL of compound solution are transferred per well in 11 concentrations in duplicate with 1: 5 series dilutions.
[0338] [0338] The test is performed using a fully automated robotic system in a dark room below 100 Lux. 10 µL of KRAS :: SOS1 GDP mixture is added in columns 1-24 to 150 nL of compound solution (final dilution in assay 1: 100, final concentration of 1% DMSO).
[0339] [0339] After an incubation time of 30 minutes, 5 µL of ball mixture is added in columns 1-23. The plates are kept at room temperature in a dark incubator. After an additional 60-minute incubation, the signal is measured using the PerkinElmer Envision HTS Multilabel Reader using PerkinElmer's AlphaScreen specifications. Each plate contains the following controls:  diluted DMSO + KRAS mixture :: SOS1 GDP + ball mixture  diluted DMSO + KRAS mixture :: SOS1 GDP Calculation of Result:
[0340] [0340] IC50 values are calculated and analyzed using a 4-parameter logistic model.
[0341] [0341] The exemplary compound tables disclosed herein contain IC 50 values determined using the above assay. Cell Proliferation Assays
[0342] [0342] Cell proliferation assays are used to examine the potency with which the compounds inhibit SOS1-mediated proliferation, growth and apoptosis of cancer cell lines in vitro. This demonstrates the molecular mode of action of compounds. Low IC50 values are indicative of high potency of SOS1-inhibiting compounds in this assay configuration. In particular, it is observed that SOS1 inhibitory compounds demonstrate a potent inhibitory effect on the proliferation of KRAS mutant human cancer cell lines and not on BRAF V600E mutant cancer cell lines or KRAS wild type human cancer cell lines. not dependent. This confirms the molecular mode of action of SOS1 inhibitor compounds, selectively targeting cancer cells dependent on the protein function of the RAS family.
[0343] [0343] Cell proliferation assays are performed under conditions of soft agar independent of three-dimensional (3D) anchorage, with the following human cell lines:
[0344] [0344] NCI-H358: human non-small cell lung cancer (NSCLC) with a KRAS G12C mutation;
[0345] [0345] PC-9: human non-small cell lung cancer (NSCLC) with wild-type KRAS and an EGFR del 19 mutation;
[0346] [0346] NCI-H1792: human non-small cell lung cancer (NSCLC) with a KRAS G12C mutation;
[0347] [0347] SW900: human non-small cell lung cancer (NSCLC) with a KRAS G12V mutation;
[0348] [0348] A-549: human non-small cell lung cancer (NSCLC) with a KRAS G12S mutation;
[0349] [0349] NCI-H2122: human non-small cell lung cancer (NSCLC) with a KRAS G12C mutation;
[0350] [0350] NCI-H520: non-small human cell lung cancer (NSCLC) with wild-type KRAS; MIA PaCa-2: human pancreatic cancer (PAC) cell with a KRAS G12C mutation;
[0351] [0351] DLD-1: human colon cancer with KRAS G13D mutation;
[0352] [0352] A-375: human melanoma cancer with wild-type KRAS, but a BRAFV600E mutation, which is used as a non-responsive cell line after treatment with an SOS1 inhibiting compound;
[0353] [0353] All cell lines, except PC-9, can be purchased from the American Type Culture Collection (ATCC). PC-9 can be purchased from the European Collection of Authenticated Cell Cultures (ECACC). Materials used:  Corning 96-well ultra-low connection plates (CLS2474-24EA);
[0354] [0354] NCI-H358 cells (ATCC HTB-182), DLD-1 cells (ATCC CCL-221), NCI-H520 cells (ATCC HTB-182), PC-9 cells (ECACC 90071810), NCI-H1792 cells ( ATCC CRL-5895 cells) and NCI-H2122 cells (ATCC CRL-5985) are grown in cell culture flasks (175 cm2) using RPMI medium. SW900 cells (ATCC HTB-59) are grown in Leibovitz L-15 medium, A-549 cells (ATCC CCL-185) are grown in F12K medium, MIA PaCa-2 cells (ATCC CRL-1420) and A -375 (ATCC -CRL-1619) are grown in DMEM medium. The cell culture medium for all listed cell lines is supplemented with 10% FBS. Cultures are incubated at 37ºC and 5% CO2 in a humidified atmosphere, with alteration or subculture of medium carried out 2-3 times a week. SW900 cells are grown without adding CO2. Test Conditions:
[0355] [0355] The assay configuration consists of the following:  A lower layer consisting of 90 µL of medium, including 1.2% agarose  A cell layer consisting of 60 µL of medium including agarose a 0.3%  An upper layer consisting of 30 µL of medium, including test compounds (without agarose)
[0356] [0356] To prepare the bottom layer, 4% agarose (heated by microwave) is mixed with culture medium (including 2% FBS for all cell lines except SW900, for SW900, 10% FCS was used to obtain cell growth) at a final dilution of 1.2% agarose in medium. Each well is filled with 90 µL of the lower layer suspension and cooled to room temperature for 1 h. For the cell layer, cells are trypsinized, counted and plated in 60 µL of culture medium (2% SFB), including 0.3% agarose (1500 cells per well). After cooling to room temperature for 1 h, the plates are incubated overnight at 37ºC and 5% CO2 in a humidified atmosphere. The next day, the compounds (30 µL of serial dilutions) are used in triplicate. The concentration of the test compounds covers a range between at least 10 micro-molars and 0.13 nanomolar. The compounds (Stock: 10 mM in 100% DMSO) are diluted in medium. The cells are incubated at 37ºC and 5% CO2 in a humidified atmosphere for 14 days. Detection:
[0357] [0357] 20 µL / well of AlamarBlue suspension is added per well and incubated 4-24 hours in the incubator. The fluorescence intensity is determined using a fluorescence reader (2030 VICTOR X5, Perkin Elmer). The excitation wavelength is 544/15 nm, emission 590 nm. In monotherapy, data are adjusted by iterative calculation using a sigmoidal curve analysis program (GraphPAD Prism) with variable slope to determine IC 50 values. ERK phosphorylation test
[0358] [0358] ERK phosphorylation assays are used to examine the potency with which the compounds inhibit SOS1-mediated signal transduction in a mutant human cancer cell line for
[0359] [0359] ERK phosphorylation assays are performed using the following human cell lines:
[0360] [0360] DLD-1 (ATCC CCL-221): KRAS G13D mutation human colon cancer; Materials Used:  RPMI-1640 medium (ATCC® 30-2001 ™)  HyClone fetal bovine serum (FBS) (SH30071.03)  Thermo Fischer Scientific non-essential amino acids (11140035)  Thermo Fischer Scientific pyruvate (11360039)  Thermo Fischer Scientific Glutamax (35050061)  384 Greiner Bio-One plates (781182)  PerkinElmer Inc. Proxiplate ™ 384 (6008280)  AlphaLISA SureFire Ultra Assay Kit p-ERK1 / 2 (Thr202 / Tyr204) (ALSU -PERK-A500)  EGF from Sigma (E4127)  Accepting mixture: Protein A accepting spheres from Perki-nElmer (6760137M)  Donor mixture: Donating spheres coated with Streptavidine AlphaScreen from PerkinElmer (6760002)  Trametinib
[0361] [0361] DLD-1 cells (ATCC CCL-221) are seeded at 50,000 cells per well in / 60 µL of RPMI with 10% FBS, non-essential amino acids, pyruvate and glutamax on Greiner TC 384 plates. they are incubated for 1 hour at room temperature and then incubated overnight in an incubator at 37ºC and 5% CO2 in a humidified atmosphere. 60 nL of compound solution (10 mM DMSO stock solution) is then added using a Lab Echo 550 device. After 1 h incubation in the incubator mentioned above, 3 µL of epidermal growth factor (EGF, concentration end of 50 ng / mL) are added. 10 minutes later, the medium is removed and the cells are lysed by adding 20 µL of lysis buffer 1.6 times from the AlphaLISA SureFire Ultra Assay Kit pERK1 / 2 (Thr202 / Tyr204) with 100 nM protease inhibitors trametinib + 100 nM staurosporine. After 20 minutes of incubation at room temperature with shaking, 6 µL of each lysate sample is transferred to a 384-well Proxiplate and analyzed for pERK (Thr202 / Tyr204) with the AlphaLISA SureFire Ultra pERK1 / 2 Assay Kit (Thr202 / Tyr204). 3 µL of acceptor mix and 3 µL of donor mix are used in soft light and incubated for 2 hours at room temperature in the dark, before the signal is measured on a Perkin Elmer Envision plate reader using 384 AlphaScreen settings for Proxi - plates. The data are adjusted by the iterative calculation with variable slope. The slope of the sigmoidal curve is adjusted using a standard adjustment curve to determine the IC50 values.
[0362] [0362] Table 25 shows the data obtained with the published test for a selection of compounds (I) according to the invention.
[0363] [0363] The metabolic degradation of the test compound is analyzed at 37ºC with combined liver microsomes (mouse (MLM), mouse (RLM) or human (HLM)). The final incubation volume of 74 µL per time point contains TRIS buffer (pH 7.5; 0.1 M), magnesium chloride (6.5 mM), microsomal protein (0.5 mg / mL for mice) / rat, 1 mg / mL for human specimens) and the test compound at a final concentration of 1 µM. After a short pre-incubation period at 37ºC, the reactions are initiated by the addition of 8 µL of beta-nicotinamide adenine di-nucleotide phosphate, reduced form (NADPH, 10 mM) and finished by transferring an aliquot in solvent after different points in time. Additionally, the independent degradation of NADPH is monitored in incubations without NADPH, completed at the last point in time by the addition of acetonitrile. The chilled incubations are pelleted by centrifugation (1811 g, 5 min). An aliquot of the supernatant is analyzed by LC-MS / MS for the amount of parent compound.
[0364] [0364] In vitro intrinsic clearance (CLint, in vitro) is calculated over the time of the disappearance of the test drug during microsomal incubation. Each graph is adjusted to the first order elimination rate constant as C (t) = C0 * exp (-ke * t), where C (t) and C0 are the test drug concentration unchanged at the time of cubation te in pre-incubation and ke is the disappearance rate constant of the unchanged drug. Subsequently, values of CLint, in vitro (μL min − 1 · amount of protein) are converted to CLint, in vitro (mL min − 1 · kg − 1) for the entire body. CLint data, in vitro, is expanded using physiological parameters. For a better comparison between species, the predicted clearance is expressed as a percentage of hepatic blood flow [% of QH] in individual species. In general, high stability (corresponding to low% QH) of compounds between species is desired.
[0365] [0365] Table 26 shows the metabolic stability data obtained with the published test for a selection of compounds (I) according to the invention. Table 26: # MLM [% QH] RLM [% QH] HLM [% QH] I-3 51 <23 <24 I-4 46 <23 <24 I-10 41 40 <24 I-13 <24 52 <24 I-14 26 56 27 I-25 <24 <23 <24 I-27 88 <23 <24 I-47 <24 29 24 I-50 <24 <23 <24 I-51 <24 49 <24 I-54 55 <23 <24
[0366] [0366] The time-dependent inhibition for CYP3A4 is analyzed in human liver microsomes (0.02 mg / mL) with midazolam (15 µM) as a substrate. The test compounds are pre-incubated in the presence of NADPH with human liver microsomes (0.2 mg / mL) at a concentration of 25 µM for 0 min and 30 min. After pre-incubation, the incubate is diluted 1:10 and the midazolam substrate is added for the main incubation (15 min). The main incubation is quenched with acetonitrile and the formation of hydroxy-midazolam is quantified using LC / MS-MS. The formation of hydroxy-midazolam from the pre-incubation of 30 min in relation to the formation of the pre-incubation of 0 min is used as reading. Values below 100% mean that the midazolam substrate is metabolized to a lesser extent after 30 min preincubation compared to 0 min preincubation. In general, low effects after 30 min of pre-incubation are desired (corresponding to values close to 100%).
[0367] [0367] Table 27 shows the data obtained with the published test for a selection of compounds (I) according to the invention. Table 27 Determination of off-target risks
[0368] [0368] There are certain targets (44) that are considered strongly associated with adverse drug reactions in vivo, as referenced in the publication Reducing safety-related drug attrition: the use of in vitro pharmacological profiling, Nature Review Drug Discovery 11, 909 -922 (December 2012). This article was a collaborative effort between several large safety pharmacology groups in pharmaceutical companies with the aim of establishing a central panel of in vitro pharmacology trials. Eurofins Cerep (France) commercially offers measurements on its SafetyScreen44TM Panel (comprising these off-target regions) for a rational first step in preliminary safety assessments. The compounds (I) according to the invention can be analyzed against that panel to investigate off-target risks. Therapeutic Use
[0369] [0369] Due to their biological properties, the compounds of the invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and salts of all the aforementioned forms may be suitable for the treatment of diseases characterized by excessive cell proliferation or abnormal, like cancer.
[0370] [0370] For example, the following cancers, tumors and other proliferative diseases can be treated with compounds of the invention, without restriction: cancers / tumors / carcinomas of the head and neck: for example, tumors / carcinomas / cancers of the cavity nasal, paranasal sinuses, nasopharynx, oral cavity (including lip, gingiva, alveolar crest, retromolar triangle, floor of mouth, tongue, hard palate, oral mucosa), oropharynx (including base of tongue, tonsil, tonsillar pillar, soft palate, tonsillar fossa, pharynx wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands); lung cancers / tumors / carcinomas: for example, non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchialveolar) , small cell lung cancer (SCLC) (lymphocytoid cancer (oat cell), intermediate cell cancer, combined lymphocytoid cancer (oat cell));
[0371] [0371] All the cancers / tumors / carcinomas mentioned above, which are characterized by their specific location / origin in the body, must include both primary tumors and the metastatic tumors derived from them.
[0372] [0372] All the cancers / tumors / carcinomas mentioned above can be further differentiated by their histopathological classification: epithelial cancers, for example, squamous cell carcinoma
[0373] [0373] The compounds of the invention can be used in therapeutic regimens in the context of first line, second line or any other line treatments.
[0374] [0374] The compounds of the invention can be used for the prevention, short or long term treatment of the diseases mentioned above, optionally also in combination with radiotherapy and / or surgery.
[0375] [0375] Naturally, the above also includes the use of the compounds of the invention in various methods of treating the above diseases by administering a therapeutically effective dose to a patient in need of the same, as well as the use of these compounds for the manufacture of medicaments for the treatment of such diseases, as well as pharmaceutical compositions, including the compounds of the invention, as well as the preparation and / or manufacture of medicaments, including the compounds of the invention, and the like.
[0376] [0376] The compounds of the invention can be used alone or in combination with one or more other pharmacologically active substances, such as state of the art compounds or standard of care, such as, for example, cell proliferation inhibitors, subs - antiangiogenic substances, steroids or immune modulators / checkpoint inhibitors, and the like.
[0377] [0377] Pharmacologically active substances that can be administered in combination with the compounds according to the invention include, without restriction, hormones, hormone analogs and anti-hormones (eg tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutetimide, cyproterone acetate, finasteride, buserelin acetate, fludro-cortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (for example, anastrozol, lettuce, lettuce, lettuce, exemestane, atamestane), LHRH agonists and antagonists (eg, goserelin acetate, luprolide), inhibitors of growth factors and / or their corresponding receptors (growth factors, such as, for example, example, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), c insulin-like termination (IGF), human epidermal growth factor (HER, for example, HER2, HER3, HER4) and hepatocyte growth factor (HGF) and / or their corresponding receptors), are, for example, (anti) growth factor antibodies, (anti) growth factor receptor antibodies and tyrosine kinase inhibitors, such as, for example, cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab and trastuzumab ); antimetabolites (for example, antifolates, such as methotrexate, raltitrexed, pyrimidine analogs, such as 5-fluorouracil (5-
[0378] [0378] When two or more substances or principles are used as part of a combined treatment regimen, they can be administered through the same route of administration or through different routes of administration, essentially at the same time (ie simultaneously, concomitantly ) or at different times (for example, sequentially, successively, alternately, consecutively, or according to any other type of alternate regime).
[0379] [0379] When substances or principles are to be administered simultaneously by the same route of administration, they can be administered as different pharmaceutical formulations or compositions or as part of a combined pharmaceutical formulation or composition. In addition, when two or more substances or active ingredients are to be used as part of a combined treatment regimen, each substance or principle can be administered in the same amount and according to the same regimen used when the compound or principle it is used by itself, and that combined use may or may not lead to a synergistic effect. However, when the combined use of the two or more active substances or principles causes a synergistic effect, it may also be possible to reduce the amount of one, more or all of the substances or principles to be administered, while still achieving therapeutic action. desired. For example, this can be useful to prevent, limit or reduce any unwanted side effects that are associated with the use of one or more of the substances or principles when used in their usual amounts, while still achieving the desired pharmacological or therapeutic effect.
[0380] [0380] Obviously, the above includes the preparation and methods of preparing the compounds of the invention for combined use with the above combination partners. Also included are the preparation, and preparation methods, of the aforementioned combination partners for combined use with the compounds of the invention.
[0381] [0381] In addition, an invention also includes kits comprising at least one compound of the invention and one or more other components selected from the group consisting of other drugs used for the treatment of diseases and disorders as described above, and devices as described below. Formulations
[0382] [0382] Suitable preparations for administering the compounds of the invention will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions - particularly solutions for injection (sc, iv, im ) and infusion (injectables) - elixirs, syrups, sachets, emulsions, inhalants or dispersible powders. The content of the pharmaceutically active compound (s) must be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the composition as a whole, that is, in quantities sufficient to achieve the dosage range specified below. The specified doses can, if necessary, be administered several times a day.
[0383] [0383] Suitable tablets can be obtained, for example, by mixing the active substance (s) of the invention with known excipients, for example, inert diluents, vehicles, disintegrants, adjuvants, surfactants, binders and / or lubricants. The tablets can also comprise several layers.
[0384] [0384] The coated tablets can be prepared according to the coating cores produced in a similar way to the tablets with substances normally used for tablet coatings, for example colidone or shellac, gum arabic, talc, titanium dioxide or sugar. To obtain prolonged release or avoid incompatibilities, the core can also consist of a number of layers. Likewise, the coating of the tablet may consist of several layers to obtain a prolonged release, possibly using the excipients mentioned above for the tablets.
[0385] [0385] Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, and a flavor enhancer, for example, a flavoring , such as vanilla or orange extract. They may also contain suspension aids or thickeners, such as sodium carboxymethylcellulose, wetting agents, such as, for example, fatty alcohol condensation products with ethylene oxide, or preservatives, such as p-
[0386] [0386] Solutions for injection and infusion are prepared in the usual way, for example, with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediamine tetra acid -acetic, optionally using emulsifiers and / or dispersants, although if water is used as a diluent, for example, organic solvents can optionally be used as solvents or dissolution aids, and transferred in injection vials or ampoules or vials of infusion.
[0387] [0387] Capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substances with inert vehicles, such as lactose or sorbitol, and packaging them in gelatin capsules.
[0388] [0388] Suitable suppositories can be produced, for example, by mixing vehicles provided for this purpose, such as neutral fats or polyethylene glycol or its derivatives.
[0389] [0389] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (for example, petroleum fractions), vegetable oils (for example, peanut or sesame oil), mono alcohols or polyfunctional (for example, ethanol or glycerol), vehicles such as, for example, natural mineral powders (for example, kaolin, clays, talc, chalk), synthetic mineral powders (for example, silicic acid and highly dispersed silicates), sugars (for example, cane sugar, lactose and glucose), emulsifiers (for example, lignin, sulfur liqueurs, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (for example, magnesium stearate, talc, stearic acid and lauryl sodium sulfate).
[0390] [0390] The preparations are administered by the usual methods, preferably orally or transdermally, more preferably orally. For oral administration, the tablets can obviously contain, in addition to the vehicles mentioned above, additives, such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additives, such as starch, preferably potato starch, gelatin and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used at the same time in the tabletting process. In the case of aqueous suspensions, the active substances can be combined with various flavor enhancers or dyes, in addition to the excipients mentioned above.
[0391] [0391] For parenteral use, solutions of the active substances with suitable liquid vehicles can be used.
[0392] [0392] The dosage range of the compounds of formula (I) applicable per day is generally from 1 mg to 2000 mg, preferably from 150 to 1000 mg.
[0393] [0393] The dosage for intravenous use is 1 mg to 1000 mg with different infusion rates, preferably between 5 mg and 500 mg with different infusion rates.
[0394] [0394] However, sometimes it may be necessary to separate the specified amounts, depending on body weight, age, route of administration, severity of the disease, individual response to the drug, nature of its formulation and time or interval during which the drug is administered (continuous or intermittent treatment with one or more doses per day). Thus, in some cases, it may be sufficient to use less than the minimum dose indicated above, while in other cases the upper limit may have to be exceeded. When administering large quantities, it may be advisable to divide them into several smaller doses, spread throughout the day.
[0395] [0395] The following formulation examples illustrate the present invention without restricting its scope:
[0396] [0396] The finely ground active substance, lactose and part of the corn starch are mixed. The mixture is then sieved, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the remaining corn starch and the magnesium stearate are selected and mixed. A mixture is compressed to produce tablets of the appropriate shape and size. B) Tablets per tablet Active substance according to formula (I) 80 mg Lactose 55 mg Corn starch 190 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 15 mg Carboxymethyl sodium starch 23 mg Magnesium stearate 2 mg 400 mg
[0397] [0397] The finely ground active substance, part of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed, the mixture is sieved and worked with the remaining corn starch and water to form a granulate that is dry and sifted. Sodium carboxymethyl starch and magnesium stearate are added and mixed and the mixture is compacted to form tablets of suitable size. B) Tablets per tablet Active substance according to formula (I) 25 mg Lactose 50 mg Microcrystalline cellulose 24 mg Magnesium stearate 1 mg 100 mg
[0398] [0398] The active substance, lactose and cellulose are mixed. The mixture is then sieved, then moistened with water, kneaded, wet granulated or dried to dry granulated or directly added to the final mixture with magnesium stearate and compacted into tablets of suitable shape and size. When wet granulated, lactose or additional cellulose and magnesium stearate is added and the mixture is compacted to produce tablets of suitable shape and size. D) Ampoule solution Active substance according to formula (I) 50 mg Sodium chloride 50 mg Water for injection 5 mg
[0399] [0399] The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free of pyrogens and the filtrate is transferred under aseptic conditions in ampoules which are then sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

权利要求:
Claims (28)
[1]
1. Compound characterized by the fact that it has the formula (I) (R 4) p
THE
NH 1
R
N N 3
R N O 2
R (I), where R1 is Ra1; Ra1 is selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkenyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 heteroaryl members, where the groups C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optional - replaced by one or more identical or different Rb1 and / or Rc1; each Rb1 is independently selected from the group consisting of -ORc1, -NRc1Rc1, halogen, -CN, -C (O) Rc1, -C (O) ORc1, -C (O) NRc1Rc1, -S (O) 2Rc1 , -S (O) 2NRc1Rc1, -NHC (O) Rc1, -N (C1-4alkyl) C (O) Rc1, -NHC (O) ORc1 and -N (C1-4alkyl) C (O) ORc1; each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkylyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, where C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and heteroaryl of 5-10 members are all optionally replaced by one or more Rd1 and / or
Re1 identical or different; each Rd1 is independently selected from the group consisting of –ORe1, -NRe1Re1, halogen, -CN, -C (O) Re1, -C (O) ORe1, -C (O) NRe1Re1, -S (O) 2Re1 , - S (O) 2NRe1Re1, -NHC (O) Re1, -N (C1-4alkyl) C (O) Re1, -NHC (O) ORe1 and - N (C1-4alkyl) C (O) ORe1; each Re1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alquinyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl; R2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl and halogen; R3 is selected from the group consisting of hydrogen, C 1-4 alkyl and C1-4 haloalkyl; ring system A is selected from the group consisting of C6-10aryl, 5-10 membered heteroaryl and 9-10 membered bicyclic heterocyclyl; p denotes 1, 2 or 3; each R4 is independently selected from the group consisting of C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, hydroxy-C1-4alkyl, hydroxy-C1-4haloalkyl, C3-6cycloalkyl, 3-6 membered heterocyclyl , hydroxy-C3-6cycloalkyl, C1-4haloalkyl substituted by a 3-6 membered heterocyclyl, 3-6 membered heterocyclyl replaced by hydroxy, halogen, -NH2, -SO2-C1-4alkyl and the bivalent substituent = O, while = O can only be a substituent on a non-aromatic ring; or a salt from them.
[2]
2. Compound or salt, according to claim 1, characterized by the fact that R1 is Ra1;
Ra1 is selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, where C1-6alkyled, C1- 6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted by one or more, identical or different Rb1 and / or Rc1; each Rb1 is independently selected from the group consisting of -ORc1, -NRc1Rc1, halogen, -CN, -C (O) Rc1, -C (O) ORc1 and -C (O) NRc1Rc1; each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, where C1- 6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted by one or more identical or different Rd1 and / or Re1; each Rd1 is independently selected from the group consisting of –ORe1, -NRe1Re1, halogen, -CN, -C (O) Re1, -C (O) ORe1 and -C (O) NRe1Re1; each Re1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl.
[3]
3. Compound or salt, according to claim 2, characterized by the fact that R1 is Ra1; Ra1 is selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, where C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted by one or more identical or different Rb1 and / or Rc1; each Rb1 is independently selected from the group consisting of -ORc1, halogen and -C (O) NRc1Rc1; each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, where C1-6alkyl, C1-6haloalkyl, heterocyclyl 3-10 members, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted by one or more identical or different Rd1 and / or Re1; each Rd1 is independently selected from the group consisting of –ORe1 and halogen; each Re1 is independently selected from the group consisting of hydrogen and C1-6alkyl.
[4]
4. Compound or salt, according to claim 1, characterized by the fact that R1 is Ra1; Ra1 is selected from the group consisting of C3-10cycloalkyl and C4-10cycloalkenyl, where C3-10cycloalkyl and C4-10cycloalkenyl are both optionally substituted by one or more identical or different Rb1 and / or Rc1; each Rb1 is independently selected from the group consisting of -ORc1, -NRc1Rc1, halogen, -CN, -C (O) Rc1, -C (O) ORc1 and -C (O) NRc1Rc1; each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, where C1- 6alkyl, C1-6haloalkyl, C3-10cycloalkyl,
C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted by one or more identical or different Rd1 and / or Re1; each Rd1 is independently selected from the group consisting of –ORe1, -NRe1Re1, halogen, -CN, -C (O) Re1, -C (O) ORe1, -C (O) NRe1Re1; each Re1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl.
[5]
A compound or salt according to claim 4, characterized by the fact that R1 is C3-8cycloalkyl optionally substituted by one or more identical or different Rb1 and / or Rc1; each Rb1 is independently selected from the group consisting of -ORc1, halogen and -C (O) NRc1Rc1; each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, where C1-6alkyl, C1-6haloalkyl, 3- heterocyclyl 8 members, phenyl and 5-6 membered heteroaryl are all optionally substituted by one or more identical or different Rd1 and / or Re1; each Rd1 is independently selected from the group consisting of –ORe1 and halogen; each Re1 is independently selected from the group consisting of hydrogen and C1-6alkyl.
[6]
6. Compound or salt according to claim 5, characterized by the fact that R1 is C3-8cycloalkyl optionally substituted by one or more identical or different substituents selected from the group consisting of C1-4alkyl, C1-4haloalkyl, C1 -4alkoxy-C1-4alkyl, 5-6 membered heteroaryl, phenyl, halophenyl, halogen, 3-6 membered heterocyclyl, -C (O) N (C1-4alkyl) 2 and hydroxy.
[7]
7. Compound or salt, according to claim 1, characterized by the fact that R1 is selected from the group consisting of C1-6alkyl and C1-6haloalkyl.
[8]
8. Compound or salt according to claim 1, characterized by the fact that R1 is 3-10 membered heterocyclyl optionally substituted by one or more identical or different Rb1 and / or Rc1; each Rb1 is independently selected from the group consisting of -ORc1, -NRc1Rc1, halogen, -CN, -C (O) Rc1, -C (O) ORc1 and -C (O) NRc1Rc1; each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, where C1- 6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted by one or more identical or different Rd1 and / or Re1; each Rd1 is independently selected from the group consisting of –ORe1, -NRe1Re1, halogen, -CN, -C (O) Re1, -C (O) ORe1 and -C (O) NRe1Re1; each Re1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl.
[9]
9. Compound or salt, according to claim 8, characterized by the fact that
R1 is 3-10 membered heterocyclyl optionally substituted by one or more, identical or different substituents selected from the group consisting of C1-6alkyl, C1-6haloalkyl and C6-10aryl.
[10]
10. Compound or salt according to claim 9, characterized by the fact that R1 is 3-8 membered heterocyclyl optionally substituted by a substituent selected from the group consisting of C 1-6alkyl, C1-6haloalkyl and C6- 10aryl.
[11]
11. Compound or salt according to claim 1, characterized by the fact that R1 is 5-6 membered heteroaryl optionally substituted by C1-4alkyl.
[12]
12. Compound or salt according to any one of claims 1 to 11, characterized by the fact that the A ring system is selected from the group consisting of C6-10aryl, 5-10 membered heteroaryl and bicyclic heterocyclyl 9-10 members; p denotes 1 or 2; each R4 is independently selected from the group consisting of C1-4alkyl, C2-4alkynyl, C1-4haloalkyl, hydroxy-C1-4haloalkyl, C1-4haloalkyl substituted by a 3-6 membered heterocyclyl, halogen and the bivalent substituent = O , while = O can only be a substituent on a non-aromatic ring.
[13]
13. Compound or salt, according to any one of claims 1 to 11, characterized by the fact that A together with the p substituents R4 has the substructure
A B
R R
Ç
R *;
RA is selected from the group consisting of C1-4alkyl, C1-4haloalkyl, hydroxy-C1-4alkyl, hydroxy-C1-4haloalkyl, C1-4haloalkyl replaced by a 3-6 membered heterocyclyl, C3-6cycloalkyl, C3-hydroxy -6cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered hydroxyheterocyclyl, halogen and -SO2-C1-4alkyl; RB is selected from the group consisting of hydrogen and - NH2; RC is selected from the group consisting of hydrogen, C1-4alkyl and halogen; or RA and RC, together with the carbon atoms to which they are attached, form a 5-6 membered non-aromatic carbocycle, a 5-6 membered non-aromatic heterocycle or a 5-6 membered heteroaryl, in whereas the 5-6 membered non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle and 5-6 membered heteroaryl are all optionally substituted by one or more halogen or an oxo group.
[14]
14. Compound or salt, according to claim 13, characterized by the fact that A together with the substituent p R4 has the substructure
A B
R R
Ç
R *; RA is selected from the group consisting of C1-4haloalkyl, hydroxy-C1-4haloalkyl and C1-4haloalkyl substituted by a 3-6 membered heterocyclyl; RB is hydrogen; RC is selected from the group consisting of hydrogen, C1-4alkyl and fluorine;
or RA and RC, together with the carbon atoms to which they are attached, form a 5-6 membered non-aromatic carbocycle, a 5-6 membered non-aromatic heterocycle or a 5-6 membered heteroaryl, in whereas the 5-6 membered non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle and 5-6 membered heteroaryl are all optionally substituted by one or more fluorine or an oxo group.
[15]
A compound according to any one of claims 1 to 14 - or a pharmaceutically acceptable salt thereof - characterized by the fact that it is for use as a medicine.
[16]
16. A compound according to any one of claims 1 to 14 - or a pharmaceutically acceptable salt thereof - for use in the treatment and / or prevention of a disease and / or condition, characterized by the fact that the inhibition the interaction of SOS1 and a protein of the RAS and / or RAC1 family is of therapeutic benefit.
[17]
17. A compound according to any one of claims 1 to 14 - or a pharmaceutically acceptable salt thereof - characterized by the fact that it is for use in the treatment and / or prevention of cancer.
[18]
18. A compound - or a pharmaceutically acceptable salt thereof - for use according to any one of claims 15 to 17, characterized in that said compound or salt is administered before, after or together with at least one other pharmacologically active substance.
[19]
19. Compound - or a pharmaceutically acceptable salt thereof - for use according to any one of claims 15 to 17, characterized in that said compound or salt is administered in combination with at least one other pharmacologically substance active.
[20]
20. Use of a compound or a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 14, characterized in that it is for the preparation of a pharmaceutical composition, a pharmaceutical preparation or a medicine, optionally where the drug is for the treatment and / or prevention of a disease and / or condition whose inhibition of the interaction of SOS1 and a protein of the RAS or RAC1 family is of therapeutic benefit.
[21]
21. Use of a compound or a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 14, characterized in that it is for the preparation of a pharmaceutical composition, a pharmaceutical preparation or a medicine, optionally where the medication is for the treatment and / or prevention of cancer.
[22]
22. Use according to claim 20 or 21, characterized in that the compound - or a pharmaceutically acceptable salt thereof - is administered before, after or in conjunction with at least one other pharmacologically active substance.
[23]
23. Use according to claim 20 or 21, characterized in that the compound - or a pharmaceutically acceptable salt thereof - is administered in combination with a therapeutically effective amount of at least one other pharmaceutical substance. logically active.
[24]
24. A compound - or the pharmaceutically acceptable salt thereof - for use according to claim 18 or 19, or use according to claim 22 or 23, characterized in that the at least one other pharmacologically active substance is an inhibitor of MEK and / or mutants thereof.
[25]
25. Compound - or the pharmaceutically acceptable salt thereof, according to any one of claims 17 to 19, or use, according to any one of claims 21 to 23, characterized by the fact that 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 , squamous cell carcinoma of the head and neck, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma.
[26]
26. Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 14 - or a pharmaceutically acceptable salt thereof - and one or more pharmaceutically acceptable excipients.
[27]
27. Pharmaceutical preparation, characterized by the fact that it comprises a compound, as defined in any one of claims 1 to 14 - or a pharmaceutically acceptable salt thereof - and at least one (preferably one) another pharmacologically active substance.
[28]
28. Invention, characterized by any of its embodiments or any applicable categories of claim, for example, product, process or use, encompassed by the material initially disclosed, described or illustrated in the patent application.

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法律状态:
2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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EP17209865|2017-12-21|

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EP17209865.9|2017-12-21|

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PCT/EP2018/086197|WO2019122129A1|2017-12-21|2018-12-20|Novel benzylamino substituted pyridopyrimidinones and derivatives as sos1 inhibitors|

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