Chimeric compounds with KRAS-SOS1 inhibitory or degradation activity and uses thereof

Abstract

The present invention provides a series of SOS1 target inhibition / degradation chimeric compounds, their preparation methods and pharmaceutical uses. The compounds can be used to treat or prevent KRAS-SOS1-mediated diseases and related diseases.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to KRAS-SOS1 inhibition / degradation chimeric compounds and preparation methods, as well as use of the compounds in preparing medicaments for treating or preventing KRAS-SOS1-mediated diseases and related diseases. Background Art

[0002] RAS family proteins include four subtypes: KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey rat sarcoma viral oncogene), and any mutants thereof. Small GTPases are located on the cell membrane in a GTP- or GDP-bound state. RAS family proteins have weak intrinsic GTP hydrolase activity and slow nucleotide exchange rates. GTPase-activating proteins (GAPs), such as NF1, can increase the GTPase activity of RAS family proteins. Binding of guanine nucleotide exchange factors (GEFs), such as SOS1 (Seven of Sevenless 1), can promote the release of GDP from RAS family proteins, thereby achieving GTP binding conversion. When in the GTP-bound state, RAS family proteins are activated and bind to downstream effector proteins, including C-RAF and phosphoinositide 3-kinase (PI3K), thereby activating the RAF / mitogen- or extracellular signal-regulated kinase (MEK ERK) pathway, the PI3K AKT / mammalian target of rapamycin (mTOR) pathway, and the RalGDS (guanine nucleotide dissociation stimulator) pathway. These pathways are associated with various cellular processes, such as proliferation, survival, metabolism, migration, etc. (Young et al., Adv. Cancer Res., 2009, 102: 1-17; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3): 205-6).

[0003] SOS1 (Seven of Sevenless 1) is the human homolog of the originally identified Drosophila SOS protein. The SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multidomain protein with two tandem N-terminal histone domains (HDs), followed by a Dbl homology domain (DH), a pleckstrin homology domain (PH), a helical linker (HL), a RAS exchanger motif (REM), a CDC25 homology domain, and a C-terminal proline-rich domain (PR). SOS1 has two binding sites for RAS family proteins; a catalytic site that binds to GDP-bound RAS family proteins to promote guanine nucleotide exchange; and an allosteric site that can bind to GTP-bound RAS family proteins, resulting in further enhancement of the catalytic GEF function of SOS1 (Reedman et al., Proc. Natl. Acad. Sci. USA., 2006, 103(45): 16692-7; Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56).

[0004] Published data indicate that SOS1 is crucial for the activation of cancer-associated KRAS mutant proteins and cancer-driving signaling (Jeng et al., Nat. Commun., 2012, 3:1168). SOS1 is the product of the gene SOS1, which encodes a guanosine-releasing protein. Its role in the KRAS signaling pathway is to promote GDP release from RAS, which in turn binds to GTP, converting KRAS from an inactive state to an active state. Therefore, SOS1 is a RAS activator. By binding activated KRAS to an allosteric site on SOS1, SOS1 itself is activated by KRAS. Thus, a positive feedback loop exists between SOS1 and KRAS that increases KRAS signaling. SOS1 activation of KRAS is processive; that is, once a single SOS1 molecule is activated, it can sequentially activate multiple RAS molecules to amplify KRAS signaling. Therefore, we believe that targeting SOS1 may be a feasible approach for targeting KRAS-driven tumors.

[0005] In addition, Drs. Craig Crews and Raymond Deshaies designed a series of bifunctional chimeric molecules based on peptide compounds to induce the degradation of methionyl aminopeptidase 2 (MetAP-2). They formally proposed the PROTAC concept and applied for related patent WO2002020740A3. However, because these large and bulky peptide-based connecting compounds had difficulty entering cells, the first generation of PROTACs failed.

[0006] In 2008, Crews' team designed the second-generation PROTACs based on the E3 ubiquitin protein ligase MDM2 to degrade the androgen receptor (AR).

[0007] In 2015, Crews' team designed a new generation of PROTACs based on the novel E3 ubiquitin ligase VHL and its CRBN ligand. WO2013106643A3 discloses compounds and methods for enhancing the degradation of target proteins and other peptides via E3 ubiquitin ligases. WO2015160845A2 discloses imide-based proteolysis regulators and related methods of use. Summary of the Invention

[0008] The present invention describes novel SOS1 inhibition / degradation chimeric compounds and provides a series of compounds as shown in Formula I, ALB (I), or a pharmaceutically acceptable salt thereof, wherein:

[0009] B is an E3 ligase binding group covalently bound to L;

[0010] L is a linking group covalently bound to B and A;

[0011] A is a protein binding group covalently bonded to L.

[0012] Furthermore, the B is a group that binds to an E3 ligase, wherein the E3 ligase is selected from von Hippel-Lindau (VHL), Cereblon, XIAP, E3A, MDM2, anaphase-promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HE RC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4 , RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Park in, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO1 5. FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH 8. MindBomb1 / MIB1, MindBomb2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RN F43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5, or ZNRF3.

[0013] Furthermore, the B is a group that binds to an E3 ligase selected from VHL, Cereblon, MDM2 or cIAP.

[0014] Furthermore, the B is a group that binds to an E3 ligase selected from VHL or Cereblon.

[0015] Furthermore, the B is selected from compounds that bind to VHL, hydroxyproline compounds that bind to VHL, compounds that bind to Cereblon, tetrahydro-benzodiazepines, amide compounds, phthalimide compounds, thalidomide or its derivatives, lenalidomide or its derivatives, and pomalidomide or its derivatives.

[0016] Furthermore, B is selected from the following general formula: in:

[0017] G is selected from CH2, C=O, S(=O)2, NH or N(C 1-6 alkyl);

[0018] Each R 8 Independently selected from oxo, thio, H, OH, C 1-6 Alkyl or -CH2(3-10 membered heterocyclyl);

[0019] R 8a independently selected from oxo and thio;

[0020] W1, W2, W3, W4 are independently selected from nitrogen, carbon or carbon, and the hydrogen on it is replaced by any one of halogen, methyl, halomethyl, hydroxyl, and deuterated methyl;

[0021] n0 is an integer selected from 0, 1, 2, 3, 4, 5 or 6. In addition, oxo and thioxo refer to ═O and ═S substitution.

[0022] Furthermore, B is selected from the following general formula: in:

[0023] Each R 8b Independently selected from oxo, thio, H, OH, C 1-6 Alkyl or CH2(3-10 membered heterocyclyl);

[0024] R 8c independently selected from oxo and thio;

[0025] R 8d Independently selected from oxo, thio, C 1-6 Alkyl, -C 3-10 cycloalkyl, halogen or hydrogen;

[0026] Y is selected from N, NH, N(C 1-6 alkyl), N(C 6-10 aryl), N(3-10 membered heterocyclyl), N(5-10 membered heteroaryl), N(C 3-10 cycloalkyl), O or S;

[0027] W1, W2, W3, W4 are independently selected from nitrogen, carbon or carbon, and the hydrogen on it is replaced by any one of halogen, methyl, halomethyl, hydroxyl, and deuterated methyl;

[0028] n0 is an integer selected from 0, 1, 2, 3, 4, 5 or 6;

[0029] The dotted line indicates the presence or absence of a bond, and oxo and thioxo refer to =O and =S substitution.

[0030] Furthermore, B is selected from the following general formula: in:

[0031] G is selected from CH2, C=O, S(=O)2, NH or N(C 1-6 alkyl);

[0032] R 8e independently selected from oxo and thio;

[0033] R 8f independently selected from oxo and thio;

[0034] R 8g Selected from hydrogen, C 1-6 Alkyl, hydroxy or -CH2(3-10 membered heterocyclyl);

[0035] R 8h independently selected from oxo and thio;

[0036] W1, W2, W3, and W4 are independently selected from nitrogen, carbon, or carbon wherein the hydrogen on the carbon is replaced by any of halogen, methyl, halomethyl, hydroxyl, and deuterated methyl.

[0037] Furthermore, wherein B is as follows: Preferably:

[0038] Further, where B is as follows: in:

[0039] R 9 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 One of the alkyl groups;

[0040] R 10 Selected from hydrogen, C 1-6 alkyl;

[0041] R 11 Selected from hydrogen, C 1-6 alkyl;

[0042] R 12 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 One of the alkyl groups;

[0043] R 13 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 One of the alkyl groups.

[0044] Furthermore, wherein B is as follows: in:

[0045] R 9 Selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, C 1-4 One of the alkyl groups, preferably a hydroxyl group;

[0046] R 10 Selected from hydrogen, C 1-4 Alkyl, preferably C 3-4 alkyl;

[0047] R 11 Selected from hydrogen, C 1-3 alkyl;

[0048] R 12 Selected from hydrogen, deuterium, C 1-3 Alkyl, deuterated C 1-3 Alkyl or halogenated C 1-3 One of the alkyl groups;

[0049] R 13 Selected from C 1-3 alkyl.

[0050] Furthermore, the B is selected from:

[0051] The A is a group that binds to the following: KRAS, SOS, including all variants, mutants, splice variants, insertions and deletions or fusions thereof.

[0052] Furthermore, the A is selected from KRAS inhibitors and SOS inhibitors.

[0053] Furthermore, the A is selected from SOS1 inhibitors.

[0054] Furthermore, the A is a small molecule targeting SOS1.

[0055] Furthermore, the A is shown in the following formula: in:

[0056] R 1 Yes-OR A ;

[0057] R A Selected from C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein C 3-10 Cycloalkyl or 3-10 membered heterocyclic group are optionally substituted by one or more, same or different R a1 and / or R b1 replace;

[0058] Each R a1 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted by one or more, identical or different R b1 and / or R c1 replace;

[0059] Each R b1 Independently selected from -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 ,-C(O)OR c1 , -C(O)NR c1 R c1 , -S(O)2R c1 , -S(O)2NR c1 R c1 ,-NHC(O)R c1 ,-N(C 1-4 alkylene)C(O)R c1 , or a divalent substituent =O, and =O may be the only substituent in a non-aromatic ring system;

[0060] Each R c1 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl;

[0061] or,

[0062] R 1 Selected from C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, wherein C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted by one or more, identical or different R a2 and / or R b2 replace;

[0063] per R a2 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted by one or more, identical or different R b2 and / or R c2 replace;

[0064] Each R b2 Independently selected from -OR c2 , -NR c2 R c2 , halogen, -CN, -C(O)R c2 ,-C(O)OR c2 , -C(O)NR c2 R c2 ,-OC(O)R c2 , -S(O)2R c2 , -S(O)2NR c2 R c2 ,-NHC(O)R c2 ,-N(C 1-4 alkylene)C(O)R c2 ,-NHC(O)OR c2 or a divalent substituent =O, =NH, where =O or =NH may be a substituent only in a non-aromatic ring system;

[0065] Each R c2 are independently selected from hydrogen, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C6-10 aryl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted by one or more, identical or different R d2 and / or R e2 replace;

[0066] Each R d2 Independently selected from -OR e2 , -NR e2 R e2 , halogen, -CN, -C(O)R e2 ,-C(O)OR e2 , -C(O)NR e2 R e2 , -S(O)2R e2 , -S(O)2NR e2 R e2 ,-NHC(O)R e2 ,-N(C 1-4 alkylene)C(O)R e2 or a divalent substituent =O, which may be a substituent only in a non-aromatic ring system;

[0067] Each R e2 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 3-10 5-membered heterocyclic group or 5-10-membered heteroaryl group, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl are optionally substituted by one or more, identical or different R f2 and / or R g2 replace;

[0068] Each R f2 Independently selected from -OR g2 , -NR g2 R g2 , halogen, -CN, -C(O)R g2,-C(O)OR g2 , -C(O)NR g2 R g2 , -S(O)2R g2 , -S(O)2NR g2 R g2 ,-NHC(O)R g2 ,-N(C 1-4 alkylene)C(O)R g2 and the divalent substituent is ═O, and ═O may be the only substituent in a non-aromatic ring system;

[0069] Each R g2 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl;

[0070] or,

[0071] R 1 Selected from C 2-4 Alkyl or C 2-4 Alkenyl, where C 2-4 Alkyl or C 2-4 The alkenyl groups are all R b3 replace;

[0072] R b3 Selected from -C(O)R c3 ,-C(O)OR c3 , -C(O)NR c3 R c3 ,-C(O)NHOR c3 or -C(O)N(C 1-4 alkylene)OR C3 ;

[0073] Each R c3 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted by one or more, identical or different R d3 and / or Re3 replace;

[0074] Each R d3 Independently selected from -OR e3 , -NR e3 R e3 , halogen, -CN, -C(O)R e3 ,-C(O)OR e3 , -C(O)NR e3 R e3 , -S(O)2R e3 , -S(O)2NR e3 R e3 ,-NHC(O)R e3 ,-N(C 1-4 alkylene)C(O)R e3 or a divalent substituent =O, which may be a substituent only in a non-aromatic ring system;

[0075] Each R e3 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl;

[0076] R 2 Selected from hydrogen, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2 or halogen;

[0077] R 3 Selected from hydrogen, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2 or halogen;

[0078] R 4 Selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, hydroxy-C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered hydroxy-heterocyclyl, halogen or -SO2-C 1-4 alkyl;

[0079] R 5Selected from hydrogen or -NH2;

[0080] R 6 Selected from hydrogen, C 1-4 Alkyl or halogen;

[0081] R 7 Selected from C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0082] Furthermore, the A is shown in the following formula: in:

[0083] R 2 Selected from hydrogen, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2 or halogen;

[0084] R 3 Selected from hydrogen, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2 or halogen;

[0085] R 4 Selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, hydroxy-C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered hydroxy-heterocyclyl, halogen or -SO2-C 1-4 alkyl;

[0086] R 5 Selected from hydrogen or -NH2;

[0087] R 6 Selected from hydrogen, C 1-4 Alkyl or halogen;

[0088] R 7 Selected from C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0089] Furthermore, the A is shown in the following formula: in:

[0090] R 2 Selected from hydrogen, C 1-4 Alkyl, -OC 1-4Alkyl; preferably -OC 1-4 alkyl;

[0091] R 3 Selected from hydrogen, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH2, or halogen; preferably hydrogen, C 1-4 alkyl;

[0092] R 4 Selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, hydroxy-C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen; preferably halogenated C 1-4 alkyl;

[0093] R 5 Selected from hydrogen or -NH2;

[0094] R 6 Selected from hydrogen, C 1-4 Alkyl or halogen;

[0095] R 7 Selected from C 1-3 Alkyl or halogenated C 1-3 Alkyl; preferably C 1-3 alkyl.

[0096] Furthermore, the A is shown in the following formula:

[0097] Indicates the linking site between A and L, or the linking site between B and L.

[0098] The L is selected from the following general formula:

[0099] -[(CH2) m1 -O(CH2) m2 ] p -(X) q -[(CH2) m3 -O(CH2) m4 ] r -(X) s -(CH2) m5 -Z-,

[0100] -(CH2) m7 -(X) t -(CH2) m8 -(X) u -Z-;

[0101] Each X can be independently selected from single bonds, S(=O)2, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl; preferably:

[0102]

[0103] Each Z can be independently selected from a single bond, NH(CH2) m9 , C(O)-(CH2) m10 , C(O)NH(CH2) m11 ,NHC(O)-(CH2) m12 -O-(CH2) m13 -;

[0104] When X is a single bond, it means that the X group does not exist; when Z is a single bond, it means that the Z group does not exist;

[0105] m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13, p, q, r, s, t, and u are independently selected from integers of 0-20, preferably integers of 0-15, and preferably integers of 0-12.

[0106] Furthermore, the L is selected from the following general formula:

[0107]

[0108] n, n1 are independently selected from integers of 0-20, preferably integers of 0-15, integers of 1-15, preferably integers of 0-12, integers of 1-12, It indicates the connection point between L and A or B, wherein the L group can be connected to A at its left end and to B at its right end, or vice versa, unless it is not actually possible to connect.

[0109] Furthermore, the L is selected from the following structures:

[0110]

[0111] Furthermore, the L is selected from the following general formula: n is selected from an integer of 0-12,

[0112] Furthermore, the compound or its pharmaceutically acceptable salt structure is selected from the following general formula:

[0113]

[0114] Furthermore, the compound or a pharmaceutically acceptable salt thereof is one of the following compounds:

[0115]

[0116]

[0117] It is expected that the selective SOS1 inhibition / degradation chimeric compounds described herein will provide pharmacological benefits to patients with cancers associated with reliance on RAS family protein signaling. Such cancers expected to be targeted by SOS1 inhibition / degradation chimeric compounds include those in which components (proteins, genes) in the RAS family protein pathways exhibit alterations (mutations, gene amplifications, overexpression), such as KRAS, NRAS, HRAS, tyrosine kinases (e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A / B, FGFR1 / 2 / 3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2 / 3, AXL), GAPs (e.g., NF1), and SOS1.

[0118] Furthermore, given the role of SOS1 in RAC1 activation, cancers that display a dependence on RAC1 also offer promising targets for SOS1 inhibition / degradation chimeric compounds.

[0119] Furthermore, SOS1 inhibition / degradation chimeric compounds are expected to provide pharmacological benefits in diseases associated with dysregulation of RAS family protein pathways, such as neurofibromatosis, Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial cutaneous syndrome (CFC), Legius syndrome, and hereditary gingival fibromatosis.

[0120] For therapeutic purposes, the chimeric compounds disclosed in the present invention can effectively prevent the disease, alleviate the symptoms, or prolong the survival of the treated patients.

[0121] RAS family proteins include KRAS (V-Ki-ras2 Kirsten murine sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog) and HRAS (Harvey murine sarcoma viral oncogene) and any mutants thereof. The SOS1 inhibitory / degradation chimeric compound disclosed in the present invention binds to SOS1 to inhibit or degrade it, thereby preventing SOS1-mediated nucleotide exchange and subsequently reducing the level of RAS in the GTP-bound form. More specifically, the SOS1 inhibitory / degradation chimeric compound exhibits a pharmacological inhibitory effect on the binding of the SOS1 catalytic site to the RAS family protein. Therefore, this chimeric compound interacts with SOS1, such as the catalytic site on SOS1, and reduces the level of binding to the RAS family protein without adding the SOS1 inhibitory / degradation chimeric compound. Thus, it is envisioned that the SOS1 inhibition / degradation chimeric compound will reduce the level of binding to the RAS family protein by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100% compared to binding without the addition of the chimeric compound.

[0122] The chimeric compounds provided herein and their pharmaceutically acceptable salts can be used alone or in combination with at least one other therapeutic agent in therapy.

[0123] The present invention discloses a pharmaceutical composition comprising a chimeric compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other therapeutically active ingredients. The other therapeutically active ingredients may be another biologically active ingredient or at least one of another chimeric compound of the present invention. The other biologically active agent described in the present invention is an anticancer agent, such as an epidermal growth factor receptor inhibitor.

[0124] The present invention discloses a pharmaceutical composition comprising the chimeric compound disclosed in the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutical carriers; the pharmaceutical preparation is any clinically acceptable dosage form.

[0125] The chimeric compounds and pharmaceutically acceptable salts thereof provided by the present invention can be formulated into solid dosage forms, such as capsules, tablets, pills, lozenges, sugar-coated tablets, granules, powders, ointments, creams, drops, and the like; the compounds and pharmaceutically acceptable salts thereof provided by the present invention can be formulated into liquid dosage forms, such as elixirs, syrups, emulsions, dispersants, suspensions, solutions, sprays, and the like.

[0126] The pharmaceutically acceptable carriers and / or pharmaceutically acceptable diluents that can be used in the pharmaceutical composition or pharmaceutical preparation of the present invention can be any conventional carriers and / or diluents in the field of pharmaceutical preparations.

[0127] The pharmaceutically acceptable salts of the present invention include acid addition salts and base salts.

[0128] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0129] The "pharmaceutically acceptable salts" of the present invention refer to derivatives of the disclosed compounds, wherein the parent compound is modified by preparing its acid or base salts. The pharmaceutically acceptable salts of the present invention include acid salts and base salts.

[0130] Furthermore, the acids used to prepare the pharmaceutically acceptable acid addition salts of the above-mentioned base compounds useful in this aspect are acids that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, sucrose, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, gentisate, malate, malonate, mandelate, salicylate, succinate, trifluoroacetate, and the like.

[0131] Furthermore, pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives of the present invention, including but not limited to salts derived from such pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucamine-(meglumine), as well as lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines, and the like.

[0132] The compounds described herein include stereoisomers of the compounds. Stereoisomers described herein refer to enantiomers produced when asymmetric carbon atoms are present in the compound as shown in Formula I; cis-trans isomers produced when a carbon-carbon double bond or cyclic structure is present in the compound; and tautomers produced when a ketone or oxime is present in the compound. As a specific embodiment, the stereoisomers described herein include, but are not limited to, enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof.

[0133] The pharmaceutically acceptable salts of the present invention may exist in unsolvated and solvated forms.

[0134] The present invention discloses a use of the above compound or a pharmaceutically acceptable salt thereof in preparing a drug for treating and / or preventing diseases and / or conditions related to signal transduction dependent on RAS family proteins by inhibiting / degrading SOS1.

[0135] The present invention discloses the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing tumor-related diseases that can inhibit / degrade SOS1 by targeting. The tumor-related diseases include, but are not limited to, cancers in which components (proteins, genes) in the RAS family protein pathway exhibit alterations (mutations, gene amplifications, overexpression), such as KRAS, NRAS, HRAS, tyrosine kinases (such as EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A / B, FGFR1 / 2 / 3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2 / 3, AXL), GAPs (such as NF1), and SOS1.

[0136] The present invention also provides the use of the above-mentioned chimeric compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing tumor-related diseases, wherein the tumor-related diseases include but are not limited to carcinoma, lymphoma, blastoma, sarcoma, leukemia, lymphoid malignancy, squamous cell carcinoma, esophageal cancer, thyroid cancer, melanoma, pancreatic cancer, lung cancer including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, bile duct cancer, gastric cancer or gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, multiple myeloma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, urothelial carcinoma and head and neck cancer.

[0137] The present invention provides the use of the chimeric compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing diseases and / or conditions that can have therapeutic benefits by inhibiting / degrading the interaction between SOS1 and RAS family proteins and / or RAC1.

[0138] The present invention also provides the use of the above-mentioned chimeric compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing RAS pathology, wherein the RAS pathology is preferably selected from neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple pigmentation (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial cutaneous syndrome (CFC), Legius syndrome or hereditary gingival fibromatosis.

[0139] The present invention discloses a method for treating and / or preventing cancer, which comprises administering to a subject an effective therapeutic amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned composition, wherein the cancer includes, but is not limited to, carcinoma, lymphoma, blastoma, sarcoma, leukemia, lymphoid malignancy, squamous cell carcinoma, esophageal cancer, thyroid cancer, melanoma, pancreatic cancer, lung cancer including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, bile duct cancer, gastric cancer or gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, multiple myeloma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, urothelial cancer and head and neck cancer.

[0140] The present invention also provides the use of the above-mentioned chimeric compound or a pharmaceutically acceptable salt thereof for treating and / or preventing tumor-related diseases, including but not limited to carcinoma, lymphoma, blastoma, sarcoma, leukemia, lymphoid malignancy, squamous cell carcinoma, esophageal cancer, thyroid cancer, melanoma, pancreatic cancer, lung cancer including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, bile duct cancer, gastric cancer or gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, multiple myeloma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, urothelial cancer and head and neck cancer.

[0141] The present invention also provides the use of the above-mentioned chimeric compound or a pharmaceutically acceptable salt thereof in the treatment and / or prophylaxis of RAS pathology, wherein the RAS pathology is preferably selected from neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple pigmentation (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial cutaneous syndrome (CFC), Legius syndrome or hereditary gingival fibromatosis.

[0142] Definitions and Explanations

[0143] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indefinite or unclear without a specific definition, but should be understood in its ordinary meaning. When a trade name appears in this text, it is intended to refer to the corresponding product or its active ingredient.

[0144] The compounds described in the present invention are named according to their chemical structural formulas. If the naming of a compound does not conform to its chemical structural formula when representing the same compound, the chemical structural formula shall prevail.

[0145] In the present invention, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, definitions of some terms are provided below. When the definitions and explanations of the terms provided in the present invention are different from those commonly understood by those skilled in the art, the definitions and explanations provided in the present invention shall prevail.

[0146] Indicates the connection site between groups.

[0147] C x-y (where x and y respectively represent a positive integer (x < y)) indicates that a chain, ring structure or chain-ring structure can be composed of a maximum of y and a minimum of x carbon atoms.

[0148] The number of atoms in a group containing one or more heteroatoms (such as heteroaryl, heteroarylalkyl, heterocyclic group, heterocyclic alkyl) refers to the total number of atoms in the ring or the number of atoms in the ring and the carbon chain.

[0149] The indication of the number of carbon atoms in a group composed of a combination of a carbon chain and a carbon ring structure (such as cycloalkylalkyl, arylalkyl) refers to the total number of carbon atoms of all carbon ring and carbon chain members. Obviously, the ring structure has at least three members.

[0150] Generally, for a group containing two or more subunits (such as heteroarylalkyl, heterocyclic alkyl, cycloalkylalkyl, arylalkyl), the last named subunit is the group connection point. For example, the substituent aryl C 1-6 Alkyl refers to an aryl bonded to C<​​​​​​Term C 1-6 Alkyl, including, for example, H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3CC(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-, H3CC(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)-, H3C-CH2-CH(CH2CH3)-, H3C-CH2-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH2-CH(CH3)-, CH(H3C-CH2-CH2)(H3C-CH3)-, C(H3C)2(H3C-CH2-CH3)-, H3C-CH2-CH(CH3)-CH(CH3)-, H3C-CH(CH3)-CH2-CH(CH3)-, (H3C-CH2)2-C(CH3)-, (H3C)2-CH-CH(CH2CH3)-, (H3C)2-CH-C(CH3)2-, (H3C)3-C-CH(CH3)-, H3C-CH(CH3)-CH(CH3)-CH2-, H3C-CH2-C(CH3)2-CH2-, (H3C)3-C-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-CH2-, H3C-CH2-CH(CH3)-CH2-CH2-.

[0153] Other examples of alkyl groups are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (-Pr; isopropyl; -CH(CH3)2), 1-butyl (n-butyl, n-Bu; -CH2CH2CH2CH3), 2-methyl-1-propyl (isobutyl; -Bu; -CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl; i-Bu; -C(CH3)3), 1-pentyl (n-pentyl; 2), 2-methyl-1-butyl (-CH(CH3)CH(CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethyl-1-propyl (neopentyl; -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)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 2,3- Dimethyl-1-butyl (-CH2CH(CH3)CH(CH3)CH3), 2,2-dimethyl-1-butyl (-CH2C(CH3)2CH2CH3), 3,3-dimethyl-1-butyl (-CH2CH2C(CH3)3), 2-methyl-1-pentyl (-CH2CH(CH3)CH2CH2CH3), 3-methyl-1-pentyl (-CH2CH2CH(CH3) 3) CH2CH3), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl), 1-decyl (n-decyl), etc.;

[0154] The terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., without further definition, refer to saturated hydrocarbon radicals having the corresponding number of carbon atoms, including all isomeric forms. 1-3 Alkyl, C 1-4 Alkyl groups are as defined above, i.e. saturated hydrocarbon groups having the corresponding number of carbon atoms, including all isomeric forms.

[0155] If the alkyl group is part of another group, such as C x-y Alkoxy, halogenated C x-y Alkyl, deuterated C x-y Alkyl, etc., the above-mentioned definition of alkyl also applies.

[0156] The term alkylene can also be derived from alkyl. Unlike alkyl, alkylene is divalent, requiring two bonding groups. Formally, the second valency is created by removing a hydrogen atom from the alkyl group. Examples of corresponding groups are -CH3 and -CH2-, -CH2CH3 and -CH2CH2-, or =CHCH3.

[0157] The term "C 1-4 "Alkylene" 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)-.

[0158] Other examples of alkylene groups are methylene, ethylene, propylene, 1-methylethylene, butene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexene, etc.

[0159] The generic terms propene, butene, pentene, hexene etc. without any further definition refer to all possible isomeric forms having the corresponding number of carbon atoms, i.e. propene includes 1-methylethylene, butene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

[0160] If the alkylene group is part of another (bonded) group, e.g. in HO-C x-y Alkyleneamino or H2N-C x-y In the alkyleneoxy group, the above definition of alkylene also applies.

[0161] Unlike an alkyl group, an alkenyl group consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C double bond, and a carbon atom can only be part of a C-C double bond. If, in an alkyl group having at least two carbon atoms as defined above, two hydrogen atoms on adjacent carbon atoms are removed and the free valencies are saturated to form a second bond, the corresponding alkenyl group is formed.

[0162] Examples of alkenyl groups are ethenyl (vinyl), prop-1-enyl, allyl (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-methylenepropyl, 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-methylene-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.

[0163] The generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl and the like without any further definition refer to all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propenyl includes prop-1-ene and prop-2-ene, butene includes but-1-ene, but-2-ene, but-3-ene, 1-methyl-prop-1-ene, 1-methyl-prop-2-ene and the like.

[0164] The alkenyl group may optionally be present in the cis or trans or Z orientation of the double bond.

[0165] When the alkenyl group is part of another (bonded) group, e.g. in C x-y Alkenylamino or C x-y In the alkenyloxy group, the above definition of alkenyl also applies.

[0166] Unlike an alkylene group, an alkenylene group consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C double bond, and a carbon atom can only be part of one C-C double bond. If, in an alkylene group having at least two carbon atoms as defined above, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding alkenylene group is formed.

[0167] Examples of alkenylene are vinylene, propenylene, 1-methylvinylene, butenyl, 1-methylpropylene, 1,1-dimethylvinylene, 1,2-dimethylethylene, pentene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexene and the like.

[0168] The generic terms propene, butene, pentene, hexene etc. without any further definition refer to all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propene includes 1-methylvinylene and butene includes 1-methylpropene, 2-methylpropene, 1,1-dimethylvinylene and 1,2-dimethylvinylene.

[0169] The alkenylene group may optionally be present with the double bond in the cis or trans or Z orientation.

[0170] The above definition of alkenylene also applies when alkenylene is part of another (bonded) group, e.g. in HO-C x-y Alkenyleneamino or H2N-C x-y In alkenyleneoxy.

[0171] Unlike alkyl groups, alkynyl groups consist of at least two carbon atoms, of which at least two adjacent carbon atoms are linked together by a C-C triple bond. If, in an alkyl group having at least two carbon atoms as defined above, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl group is formed.

[0172] Examples of alkynyl groups are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, and the like.

[0173] The general terms propynyl, butynyl, pentynyl, hexynyl, heptyl, octyl, nonyl, decyl, etc., without further definition, refer to all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl, butenyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc. If a hydrocarbon chain carries at least one double bond and at least one triple bond, it belongs to the subclass alkynyl by definition.

[0174] If the alkynyl group is part of another (composite) group, e.g. in C x-y Alkynamine or C x-y For alkynyloxy, the above-mentioned definition of alkynyl also applies.

[0175] Unlike alkylene, alkynylene consists of at least two carbon atoms, at least two adjacent carbon atoms being linked together via a C-C triple bond. If, in an alkylene group as defined above, there are at least two carbon atoms, in each case two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynylene is formed. Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene, butynyl, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynyl, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynyl etc. The general terms propynylene, butynylene, pentynylene, hexynylene etc. without any further definition refer to all conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynyl includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.

[0176] If alkynylene is part of another (bonded) group, the above definition of alkynylene also applies, e.g. in HO-C x-y Alkynylideneamino or H2N-C x-y Alkynylideneoxy.

[0177] Heteroatoms refer to oxygen, nitrogen and sulfur atoms.

[0178] Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previously defined alkyl (alkenyl, alkynyl) groups by replacing one or more hydrogen atoms of the hydrocarbon chain with identical or different halogen atoms, independently of one another. If a haloalkyl (haloalkenyl, haloalkynyl) group is to be further substituted, the substitutions may occur independently of one another in the form of mono- or poly-substitutions on all hydrogen-carrying carbon atoms.

[0179] Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCI=CH2, -CBr=CH2, -C≡C-CF3, -CHFCH2CH3, -CHFCH2CF3, etc.

[0180] The term haloalkylene (haloalkenylene, haloalkynyl) is also derived from the previously defined haloalkyl (haloalkenyl, haloalkynyl) group. Unlike haloalkyl (haloalkenyl, haloalkynyl) groups, haloalkylene (haloalkenylene, haloalkynyl) groups are divalent and require two binding partners. Formally, the second valence is formed by removing a hydrogen atom from a haloalkyl (haloalkenyl, haloalkynyl) group.

[0181] Corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or =CFCH2F and the like.

[0182] The above definitions also apply if the corresponding halogen-containing group is part of another (bonded) group.

[0183] Halogen refers to fluorine, chlorine, bromine and / or iodine atoms.

[0184] Cycloalkyl groups are composed of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings, and spirocyclic hydrocarbon rings and are saturated. In bicyclic hydrocarbon rings, the two rings are linked together so that they share at least two carbon atoms. In spiro hydrocarbon rings, one carbon atom (the spiro atom) belongs to both rings.

[0185] If cycloalkyl is to be substituted, the substitutions may occur independently of one another and in each case as mono- or polysubstitutions on all hydrogen-carrying carbon atoms.Cycloalkyl itself can be attached as a substituent to the molecule via any suitable position of the ring system.

[0186] Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norformyl), bicyclo[3.1.1]heptyl (pinenyl), spiro[2.5]octyl, spiro[3.3]heptyl and the like.

[0187] If the cycloalkyl group is part of another (composite) group, the above definition of cycloalkyl also applies, for example, to C x-y Cycloalkylamino, C x-y Cycloalkoxy or C x-y Cycloalkylalkyl.

[0188] If the free valencies of the cycloalkyl group are saturated, a cycloaliphatic radical is obtained.

[0189] The term cycloalkylene can be derived from the previously defined cycloalkyl group. Unlike cycloalkyl, cycloalkylene is divalent and requires two binding groups. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl group. Examples of corresponding groups include cyclohexyl and cyclohexylene.

[0190] If the cycloalkylene group is part of another (bonded) group (e.g. in HO-C x-y Cycloalkyleneamino or H2N-C x-y cycloalkyleneoxy), the above definition of cycloalkylene also applies.

[0191] Cycloalkenyl groups also consist of the subgroups monocyclic, bicyclic, and spirocyclic hydrocarbon rings. However, these systems are unsaturated, i.e., they contain at least one C-C double bond but no aromatic system. If, in a cycloalkyl group as defined above, two hydrogen atoms on adjacent cyclic carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding cycloalkenyl group is obtained.

[0192] If the cycloalkenyl group is to be substituted, the substitutions may occur independently of one another, in each case as mono- or polysubstitutions on all hydrogen-carrying carbon atoms. The cycloalkenyl group itself can be attached as a substituent to the molecule via every suitable position of the ring system.

[0193] Examples of cycloalkenyl groups are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexyl-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-enyl, cyclopenta-2,4-enyl, cyclopenta-3-enyl, cyclohex-1,3-enyl, cyclohepta-2,4-enyl, cyclohepta-3-enyl, cyclohepta-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-enyl, cyclopenta-2,4-enyl, cyclopenta-3-enyl, cyclohepta-1,3-enyl, cyclohepta-2,4-enyl, cyclohepta-3-enyl, cyclohepta-4-enyl, cyclohepta-1,3-enyl, cyclopenta-1,3-enyl, cyclopenta-1,3-enyl, cyclopenta-2,4-enyl, cyclopenta-3-enyl, cyclohepta-3-enyl, cyclohepta-4-enyl, cyclohepta-1,3-enyl, cyclohepta-2,4-enyl, cyclohepta-3-enyl, cyclohepta-4-enyl, cyclohepta-1,3-enyl, cyclohepta-2,4-en -dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl, cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl, bicyclo[2.2.1]hept-2,5-dienyl (norbornen-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec-2-enyl, etc.

[0194] When cycloalkenyl is part of another (bound) group, the above definition of cycloalkenyl also applies, for example, to C x-y Cycloalkenylamino, C x-y Cycloalkenyloxy or C x-y Cycloalkenylalkyl.

[0195] If the free valencies of the cycloalkenyl radical are saturated, an unsaturated alicyclic radical is obtained.

[0196] The term cycloalkenylene can thus be derived from the previously defined cycloalkenyl. Unlike cycloalkenyl, cycloalkenylene is divalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from the cycloalkenyl. Corresponding groups are, for example, cyclopentenyl and cyclopentenylene. If cycloalkenylene is part of another (bound) group, the above definition of cycloalkenylene also applies, for example, in the case of HO-C x-y Cycloalkenyleneamino or H2N-C x-y Cycloalkenyleneoxy.

[0197] Aryl represents a monocyclic, bicyclic or tricyclic carbocyclic ring having at least one aromatic carbocyclic ring. Preferably, it represents a monocyclic group having six carbon atoms (phenyl) or a bicyclic group having nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or may also be partially saturated.

[0198] If the aryl group is to be substituted, the substitutions may occur independently of one another and in each case occur as mono- or polysubstituted groups on all hydrogen-carrying carbon atoms. The aryl group itself may be attached to the molecule as a substituent at any suitable position of the ring system. Examples of aryl groups are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetrahydronaphthyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorenyl, etc. Phenyl is most preferred.

[0199] If aryl is part of another (bonded) group (for example in arylamino, aryloxy or arylalkyl), the above definition of aryl also applies.

[0200] If the free valencies of the aryl group are saturated, an aromatic radical is obtained.

[0201] The term arylene can also be derived from the previously defined aryl group. Unlike aryl, arylene is divalent, requiring two bonding groups. Formally, the second valence is formed by removing a hydrogen atom from the aryl group. Examples of corresponding groups include naphthalene.

[0202] If arylene is part of another (bonded) group (for example in HO-aryleneamino or H2N-aryleneoxy), the above definition of arylene also applies.

[0203] Heterocyclyl represents a ring system derived from the previously defined cycloalkyl, cycloalkenyl and aryl groups by replacing one or more -CH2 groups in the hydrocarbon ring independently of one another by -O-, -S- or -NH- groups or by replacing one or more =CH- groups by =N- groups, wherein a total of not more than five heteroatoms may be present, at least one carbon atom must be present between two oxygen atoms, between two sulfur atoms or between an oxygen and a sulfur atom, and the ring as a whole must be chemically stable. Heteroatoms may optionally be present in all possible oxidation stages (S→sulfoxide -SO-, sulfone -SO2-, N→N-oxide). In heterocyclyl, there are no heteroaromatic rings, i.e., no heteroatoms are part of the aromatic system.

[0204] Derived directly from cycloalkyl, cycloalkenyl and aryl, heterocyclyl consists of the sub-groups monocyclic heterocycles, bicyclic heterocycles, tricyclic heterocycles and spiroheterocycles, which can exist in saturated or unsaturated form.

[0205] Unsaturated means that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In a bicyclic heterocycle, the two rings are linked together so that they have at least two (hetero)atoms in common. In a spiro heterocycle, one carbon atom (spiro atom) belongs to both rings.

[0206] If the heterocyclyl group is substituted, the substitutions may occur independently of one another in the form of mono- or poly-substitutions on all hydrogen-bearing carbon and / or nitrogen atoms. The heterocyclyl group itself can be attached as a substituent to the molecule at every suitable position of the ring system. The substituents on the heterocyclyl group are not counted as members of the heterocyclyl group.

[0207] Examples of heterocyclic groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, azacyclidinyl, azetidinyl, 1,4-dioxanthenyl, azaphenanthrenyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S, S-dioxide, 1,3-dioxolanyl , tetrahydropyranyl, tetrahydrothioinyl, [1,4]-oxaphanyl, tetrahydrothiophenyl, homothiomorpholinyl-S, S-dioxide, oxazolidinyl, dihydropyrazolinyl, dihydropyrrolinyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuranyl, tetrahydrothiophenyl-S-oxide, tetrahydrothiophenyl-S, S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazacyclic ring, 2-hydropyrrolyl, 4-hydropyranyl, 1,4-dihydro Hydrogen pyridyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 3, 9-diazabicyclo[4.2.1]nonyl, 2,6-diazabicyclo[3.2.2]nonyl, 1,4-dioxaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[4.4]nonyl, 2,6-diazaspiro[3.4]octyl, 3,9-diazaspiro[5.5]undecyl, 2.8-diazaspiro[4,5]decyl and the like.

[0208] Preferably, the heterocyclic group is a 4- to 8-membered monocyclic ring having one or two heteroatoms independently selected from oxygen, nitrogen and sulfur. Preferred heterocyclic groups are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl.

[0209] The above definition of heterocyclyl also applies if heterocyclyl is part of another (bound) group (for example in heterocyclylamino, heterocyclyloxy or heterocyclylalkyl).

[0210] If the free valencies of the heterocyclyl radical are saturated, a heterocyclyl radical is obtained.

[0211] The term heterocyclylene is also derived from the previously defined heterocyclyl. Unlike heterocyclyl, heterocyclylene is divalent and requires two binding groups. Formally, the second valency is obtained by removing a hydrogen atom from the heterocyclyl group. Examples of corresponding groups include piperidinyl and 2,3-dihydro-1H-pyrrolyl, among others.

[0212] If heterocyclylene is part of another (bound) group, for example, in HO-heterocyclyleneimino or H2N-heterocyclyleneoxy, the above definition of heterocyclylene also applies. Heteroaryl is a monocyclic heteroaromatic ring or polycyclic ring with at least one heteroaromatic ring which, in contrast to the corresponding aryl or cycloalkyl (cycloalkenyl) radicals, contains one or more independently selected, identical or different heteroatoms (nitrogen, sulfur and oxygen) instead of one or more carbon atoms, provided that the resulting radical is chemically stable. The presence of a heteroaryl radical presupposes the presence of a heteroatom and a heteroaromatic system.

[0213] If a heteroaryl group is substituted, the substitutions can be made independently of one another in the form of mono- or poly-substitutions on all hydrogen-bearing carbon and / or nitrogen atoms. The heteroaryl group itself can be attached as a substituent to the molecule via a carbon atom and a nitrogen atom at every suitable position in the ring system. The substituents on the heteroaryl group do not count towards the number of members of the heteroaryl group.

[0214] Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N oxide, 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, indole, isoindolyl, benzofuranyl, benzothienyl, benzothiophene, oxazolyl, benzothiazolyl, benzisoxazolyl, benzimidazolyl, indolazolyl, isoquinolyl, quinolyl, quinolyl, cinnolinyl, zinc phthalate, quinazolinyl, benzotriazinyl, indolizinyl, oxazolinyl, imidazolyl pyridinyl, naphthyridinyl, benzoxazolyl, pyridinyl, pyrimidinyl pyridinyl, purinyl, pteridinyl, benzothiazolyl, imidazolinyl, imidazolyl, quinolyl-N oxide, indolyl-N oxide, isoquinolyl-N oxide, quinazolinyl-N oxide, quinolyl-N oxide, zinc phthalate-N oxide, indolazolyl-N oxide, indolazolyl-N oxide, benzothiazolyl-N oxide, benzimidazolyl-N oxide, etc.

[0215] A further example is the structure shown below, which can be linked via each hydrogen-carrying atom (exchanged for hydrogen):

[0216] Preferably, the heteroaryl group is a 5-6 membered monocyclic ring or a 9-10 membered bicyclic ring, each having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0217] The above definition of heteroaryl also applies if heteroaryl is part of another (bound) group, such as in heteroarylamino, heteroaryloxy or heteroarylalkyl.

[0218] If the free valencies of the heteroaryl group are saturated, a heteroaromatic radical is obtained.

[0219] The term heteroarylene is also derived from the previously defined heteroaryl group. Unlike heteroaryl, heteroarylene is divalent and requires two binding groups. Formally, the second valency is obtained by removing a hydrogen atom from the heteroaryl group. An example of a corresponding group is pyrrolyl.

[0220] If heteroarylene is part of another (bound) group, for example in HO-heteroaryleneamino or H2N-heteroaryleneoxy, the above definition of heteroaryl also applies.

[0221] Substituted means that a hydrogen atom directly bonded to the atom in question is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms), an atom can be monosubstituted or polysubstituted. Substitution with a specific substituent is only possible if the number of allowed valence atoms of the substituent and the atom to be replaced corresponds to each other and the substitution results in a stable compound (i.e., a compound that does not spontaneously transform by, for example, rearrangement, cyclization, or elimination).

[0222] Divalent substituents, such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2, etc., can only be substituents on carbon atoms, while the divalent substituents =O and =NR can also be substituents on sulfur. Generally, substitution can only be made by divalent substituents on the ring system and requires the replacement of a geminal hydrogen atom, i.e., a hydrogen atom bound to the same carbon atom that was saturated before the substitution. Thus, substitution by a divalent substituent is only possible at the ring system at a group -CH2- or a sulfur atom (a =O group or a =NR group, which may have one or two =O groups, or, for example, one =O group and one =NR group, each replacing one free electron pair).

[0223] Unless otherwise indicated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0224] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0225] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0226] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0227] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0228] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0229] Unless otherwise specified, the key is a solid wedge ( ) and dotted wedge bonds ( ) represents the absolute configuration of a stereocenter, with a straight solid bond ( ) and straight dashed bond ( ) indicates the relative configuration of the stereocenter, and a wavy line ( ) represents a wedge-shaped solid bond ( ) or a dotted wedge key ( ), or with a wavy line ( ) represents a straight solid bond ( ) or a straight dashed key ( ).

[0230] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0231] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0232] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0233] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0234] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0235] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0236] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0237] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0238] When the number of a substituent is 0, it means that the substituent does not exist. For example, -A-(R)0 means that the structure is actually -A. When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0239] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0240] When a substituent's bond can cross-link to two or more atoms in a ring, the substituent can be bonded to any atom in the ring, e.g. The substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituent does not specify the atom through which it is bonded to the substituted group, the substituent can be bonded through any atom. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

[0241] When the listed linking groups do not indicate the direction of their attachment, the direction of their attachment is arbitrary.

[0242] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and the group will become a group with a corresponding valence. The chemical bond connecting the site to other groups can be represented by a straight solid bond ( ), straight dashed line key( ), or a wavy line ( )express. DETAILED DESCRIPTION

[0243] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0244] The compounds described in the present invention are named according to their chemical structural formulas. If the compound nomenclature and chemical structural formula for the same compound do not match, the chemical structural formula shall prevail.

[0245] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0246] The solvent used in the present invention is commercially available.

[0247] Compounds are named according to the conventional nomenclature in the art or using The software named the commercially available compounds using the supplier's catalog name.

[0248] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0249] Example 1

[0250]

[0251] Synthesis route:

[0252]

[0253] (1) Compound C01-1a (10 g, 94.3 mmol) and triethylamine (14.3 g, 141.5 mmol) were dissolved in dichloromethane (60 mL). TsCl (12.6 g, 66 mmol) was added in an ice-water bath and stirred at room temperature for 16 hours. Water (100 ml) was added to quench the mixture. The mixture was extracted with dichloromethane (100 ml*3). The organic phases were combined, washed with saturated sodium chloride (30 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / dichloromethane, 4:1) to obtain product C01-1b (4.3 g).

[0254] (2) C01-1b (4.5 g, 17.3 mmol) and C01-1c (3.3 g, 12.1 mmol) were added to a reaction flask, 40 ml of dimethyl sulfoxide was added, DIEA (6.7 g, 51.9 mmol) and potassium iodide (3.3 g, 19.0 mmol) were added, and the mixture was stirred at 120 degrees for 5 hours. Water (50 ml) was added, and the mixture was extracted with ethyl acetate (100 ml*3). The organic phases were combined, washed with saturated sodium chloride (30 ml), dried over anhydrous sodium sulfate, and spin-dried by column chromatography (methanol / dichloromethane, 10:1) to obtain the product C01-1d (1.2 g).

[0255] (3) C01-1d (400 mg, 1.1 mmol) was dissolved in ACN (10 mL), and IBX (616 mg, 2.2 mmol) was added. The mixture was stirred at 80°C for 2 h, and the mixture was dried by column chromatography (methanol / dichloromethane, 10:1) to obtain the product C01-1e (300 mg).

[0256] (4) C01-1e (295 mg, 0.82 mmol) and C01-1f (200 mg, 0.41 mmol) were added to a reaction flask, 2 mL of dimethyl sulfoxide and 10 mL of methanol were added, and sodium cyanoborohydride (52 mg, 0.82 mmol) was added. The mixture was stirred at room temperature for 12 hours, quenched with water (20 ml), and extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried by column chromatography (methanol / dichloromethanol, 5:1) to obtain the product C01-1g (150 mg).

[0257] (5) C01-1g (100 mg, 0.12 mmol) was added to a reaction flask, followed by 20 mL of tetrahydrofuran, 0.1 mL of acetic acid, and 30 mg of palladium on carbon. The mixture was reacted at room temperature under 2 MPa of hydrogen for 16 hours. The mixture was filtered, washed with tetrahydrofuran, and the filtrate was collected and dried. The mixture was then reversed (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) and lyophilized to obtain 36.97 mg of the target product C01. LC-MS-MC20-1018-078P2: (ES, m / z): [M+H] + =806.1

[0258] Example 2:

[0259]

[0260] Synthesis route:

[0261]

[0262] (1) C02-2a (10.0 g, 66.7 mmol) and triethylamine (10.1 g, 100.0 mmol) were dissolved in dichloromethane (60 mL), cooled to 0°C, and 4-toluenesulfonyl chloride (8.9 g, 46.7 mmol) was added. The mixture was heated to room temperature and stirred for 16 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL*3). The organic phase was washed with saturated sodium chloride aqueous solution, dried, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate / petroleum ether, 0-100%) to obtain the product C02-2b (8.0 g).

[0263] (2) C02-2b (2.0 g, 6.6 mmol), C02-2c (1.3 g, 4.6 mmol), N,N-diisopropylethylamine (2.5 g, 19.7 mmol) and potassium iodide (1.2 g, 7.2 mmol) were dissolved in dimethyl sulfoxide (15 mL) and reacted at 120°C for 5 hours. Water (60 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (60 mL*3). The organic phases were combined, washed with saturated sodium chloride, dried, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (methanol / dichloromethane, 1:19) to obtain the product C02-2d (1.0 g).

[0264] (3) C02-2d (500 mg, 1.2 mmol) and 2-iodobenzoic acid (689 mg, 2.4 mmol) were dissolved in acetonitrile (6 mL) and reacted at 80°C for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL*3). The organic phases were combined, washed with saturated sodium chloride, dried, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (methanol / dichloromethane, 1:19) to obtain the product C02-2e (410 mg).

[0265] (4) C02-2e (300 mg, 0.6 mmol) and C02-2f (296 mg, 0.7 mmol) were dissolved in methanol / dimethyl sulfoxide (2 mL / 1 mL), and sodium cyanoborohydride (77 mg, 1.2 mmol) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated, ethyl acetate (20 mL) was added, and the mixture was washed with saturated sodium chloride aqueous solution (10 mL*2). The organic phase was dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (methanol / dichloromethane, 1:9) to obtain the product C02-2g (130 mg).

[0266] (5) C02-2g (110 mg, 0.13 mmol) was dissolved in methanol (15 ml), and Pd / C (15 mg) and 2 drops of acetic acid were added. The mixture was stirred at room temperature under 2 MPa of hydrogen for 16 hours. The reaction mixture was filtered, dried, and reversed (A: 0.3% formic acid, B: acetonitrile; 3% to 97%), and lyophilized to obtain 26.08 mg of the target product C02. LC-MS-MC20-1021-093: (ES, m / z): [M+H] + =850.1

[0267] Example 3:

[0268]

[0269] Synthesis route:

[0270]

[0271] (1) C03-3a (10.0 g, 51.5 mmol) and triethylamine (7.8 g, 77.3 mmol) were dissolved in dichloromethane (50 mL), cooled to 0°C, and 4-toluenesulfonyl chloride (6.8 g, 36.1 mmol) was added. The mixture was heated to room temperature and stirred for 16 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL*3). The organic phase was washed with saturated sodium chloride aqueous solution, dried, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate / petroleum ether, 0-100%) to obtain the product C03-3b (6.9 g).

[0272] (2) C03-3b (2.0 g, 5.7 mmol), C03-3c (1.1 g, 4.0 mmol), N,N-diisopropylethylamine (2.2 g, 17.2 mmol) and potassium iodide (1.0 g, 6.3 mmol) were dissolved in dimethyl sulfoxide (15 mL) and reacted at 120°C for 5 hours. Water (60 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (60 mL*3). The organic phases were combined, washed with saturated sodium chloride, dried, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (methanol / dichloromethane, 1:19) to obtain the product C03-3d (1.1 g).

[0273] (3) C03-3d (450 mg, 1.0 mmol) and 2-iodobenzoic acid (560 mg, 2.0 mmol) were dissolved in acetonitrile (6 mL) and reacted at 80°C for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL*3). The organic phases were combined, washed with saturated sodium chloride, dried, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (methanol / dichloromethane, 1:19) to obtain the product C03-3e (230 mg).

[0274] (4) C03-3e (105 mg, 0.2 mmol) and C03-3f (144 mg, 0.3 mmol) were dissolved in methanol / dimethyl sulfoxide (1 mL / 1 mL), and sodium cyanoborohydride (26 mg, 0.4 mmol) was added. The mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated, ethyl acetate (15 mL) was added, and the mixture was washed with saturated sodium chloride aqueous solution (10 mL*2). The organic phase was dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (methanol / dichloromethane, 1:11) to obtain the product C03-3g (85 mg).

[0275] (5) C03-3g (85 mg, 0.09 mmol) was dissolved in methanol (15 ml), and Pd / C (10 mg) was added. The mixture was stirred at room temperature under hydrogen for 24 hours. The reaction mixture was filtered, dried, and reversely prepared (A: 0.3% formic acid, B: acetonitrile; 3% to 97%). The mixture was lyophilized to obtain 12.49 mg of the target product C03. LC-MS-MC20-1021-045-P0: (ES, m / z): [M+H] + =894.0

[0276] Embodiment 4:

[0277]

[0278] Synthesis route:

[0279]

[0280] (1) C05-5a (2 g, 6.5 mmol) was dissolved in dimethyl sulfoxide (20 mL), and C05-5 (1.2 g, 5.1 mmol), KI (1.2 g, 8.0 mmol), and DIEA (2.5 g, 21.9 mmol) were added and stirred at 120°C for 2 hours. Water (20 ml) was added and extracted with ethyl acetate (30 ml*3). The organic phases were combined and washed with saturated sodium chloride (40 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (methanol / dichloromethane, 1:10) to obtain the product C05-5c (1 g).

[0281] (2) C05-5c (500 mg, 1.0 mmol) was added to a reaction flask, and 10 mL of acetonitrile and IBX (1 g, 2.0 mmol) were added. The mixture was stirred at 80 °C for 2 hours, and water (20 ml) was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried by column chromatography (methanol / dichloromethane, 1:10) to obtain the product C05-5d (200 mg).

[0282] (3) C05-5d (300 mg, 0.74 mmol l) was added to the reaction flask, followed by methanol (5 ml), compound 5 (400 mg, 0.81 mmol), and sodium cyanoborohydride (42 mg, 0.66 mmol). The mixture was stirred at room temperature for 12 hours, 20 mL of water was added, and then the mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried by column chromatography (methanol / dichloromethane, 1:10) to obtain the product C05-5e (200 mg).

[0283] (4) C05-5e (150 mg, 0.07 mmol) was added to methanol (10 ml), and Pd / C (4 mg, 0.03 mmol) was added. The mixture was replaced with hydrogen three times and stirred under hydrogen at room temperature for 12 hours. The Pd / C was removed by filtration and the reaction mixture was prepared in the reverse direction (A: 0.3% formic acid, B: acetonitrile; 3% to 97%). The mixture was lyophilized to obtain 2.4 mg of the target product C05. LC-MS-MC20-1017-079-LCMS: (ES, m / z): [M+H] + =850.0

[0284] Example 5:

[0285]

[0286] Synthesis route:

[0287]

[0288] (1) C06-6a (250 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL), and Dess-Martin (551 mg, 1.3 mmol) and Pyridine (205 mg, 2.6 mmol) were added. The mixture was stirred at room temperature for 16 hours, and 20 mL of saturated sodium thiosulfate aqueous solution was added. The mixture was extracted with dichloromethane (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 4:1) to obtain the product C06-6b (100 mg).

[0289] (2) C06-6c (150 mg, 0.31 mmol) and C06-6b (144 mg, 0.62 mmol) were added to a reaction flask, 5 ml of methanol and 2 ml of dimethyl sulfoxide were added, and sodium cyanoborohydride (39 mg, 0.62 mmol) was added. The mixture was stirred at room temperature for 12 hours, quenched with water (20 ml), and extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (methanol / dichloromethane, 5:1) to obtain the product C06-6d (150 mg).

[0290] (3) C06-6d (150 mg, 0.21 mmol) was added to a reaction flask, followed by dichloromethane (6 mL) and trifluoroacetic acid (3 ml). The mixture was stirred at room temperature for 1 hour and then dried to give the product C06-6e (170 mg).

[0291] (4) C06-6e (160 mg, 0.25 mmol), C06-6f (163 mg, 0.38 mmol), HATU (144 mg, 0.38 mmol) and DIEA (161 mg, 1.25 mmol) were added to a reaction flask, 10 ml of DMF was added, and the mixture was stirred at room temperature for 12 hours. Water (20 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried. The product C06-6g (110 mg) was obtained by reverse phase preparation (acetonitrile / water, 3% to 100%).

[0292] (5) C06-6g (120 mg, 0.11 mmol) was added to a reaction flask, followed by 20 mL of methanol and Pd / C (30 mg). The mixture was reacted at room temperature under 2 MPa of hydrogen for four hours. The mixture was filtered, washed, and dried by reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%). The target product C06 (40.03 mg) was obtained by lyophilization. LC-MS-MC20-1018-077P2: (ES, m / z): [M+H] +=1034.1

[0293] Example 6:

[0294]

[0295] Synthesis route:

[0296]

[0297] (1) Dess-Martin periodinane (535 mg, 1.3 mmol) and pyridine (199 mg, 2.5 mmol) were dissolved in dichloromethane (4 mL). A solution of C07-7a (200 mg, 1.05 mmol) in dichloromethane (4 mL) was added dropwise. The mixture was stirred at room temperature for 16 h. 5 mL of 5% aqueous sodium thiosulfate solution and 10 mL of saturated aqueous sodium bicarbonate solution were added. The mixture was extracted with dichloromethane (20 ml * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and dried to give the crude product C07-7b (190 mg).

[0298] (2) C07-7b (160 mg, 0.3 mmol) and C07-7c (92 mg, 0.5 mmol) were dissolved in methanol / dimethyl sulfoxide (1 mL / 1 mL), and sodium cyanoborohydride (41 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, ethyl acetate (15 mL) was added, and the mixture was washed with saturated sodium chloride aqueous solution (10 mL*2), dried over anhydrous sodium sulfate, and spin-dried by column chromatography (methanol / dichloromethane, 1:9) to obtain the product C07-7d (75 mg).

[0299] (3) C07-7d (65 mg, 0.1 mmol) was dissolved in 0.5 mL of trifluoroacetic acid and 1.0 mL of dichloromethane, stirred at room temperature for 2 hours, and the reaction solution was dried to obtain the product C07-7e (65 mg of crude product).

[0300] (4) C07-7e (65 mg crude product, 0.1 mmol), C07-7f (43 mg, 0.1 mmol) and DIEA (26 mg, 0.2 mmol) were dissolved in 1 mL N,N-dimethylformamide, and HATU (49 mg, 0.13 mmol) was added. The reaction was carried out at room temperature for 2 hours. The product was prepared in reverse (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) and lyophilized to obtain the product C07-7g (80 mg).

[0301] (5) C07-7g (70 mg, 0.07 mmol) was added to methanol (15 mL), followed by palladium carbon (10 mg). After the addition, the mixture was stirred at room temperature under hydrogen atmosphere for 24 hours. The reaction mixture was filtered, dried, and reversed (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was added. The mixture was lyophilized to obtain 7.89 mg of the target product C07. LC-MS-MC20-1021-073-1: (ES, m / z): [M+H] + =990.7

[0302] Example 7:

[0303]

[0304] Synthesis route:

[0305]

[0306] (1) C08-8a (1 g, 3.6 mmol) was dissolved in dichloromethane (20 mL), and Dess-Martin periodinane (1.8 g, 4.3 mmol) and pyridine (0.7 g, 8.6 mmol) were added. The mixture was stirred at room temperature for 12 hours, and water (20 ml) was added. The mixture was extracted with dichloromethane (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and dried to obtain the product C08-8b (0.9 g).

[0307] (2) C08-8b (500 mg, 1.8 mmol) was added to a reaction flask, and 10 mL of methanol, C08-8c (200 mg, 0.4 mmol), and NaBH3CN (114 mg, 1.8 mmol) were added. The mixture was stirred at room temperature for 12 hours, 20 mL of water was added, and then extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried by column chromatography (methanol / dichloromethane, 1:10) to obtain the product C08-8d (120 mg).

[0308] (3) C08-8d (100 mg, 0.16 mmol l) was added to the reaction flask, and then dichloromethane / trifluoroacetic acid (5 mL / 5 mL) was added. The mixture was stirred at room temperature for 1 hour and dried to obtain the product C08-8e (120 mg).

[0309] (4) C08-8e (120 mg, 0.17 mmol) was added to a reaction flask, and 10 mL of dichloromethane, HATU (16 mg, 0.25 mmol), and DIEA (44 mg, 0.34 mmol) were added and stirred at room temperature for 1 hour. C08-8f (74 mg, 0.17 mmol) was added and stirred at room temperature for 1 hour. 10 mL of water was added and then extracted with dichloromethane (20 ml*3). The organic phases were combined and washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried by column chromatography (methanol / dichloromethane, 1:10) to obtain the product C08-8g (100 mg).

[0310] (5) C08-8g (100 mg, 0.09 mmol) was added to methanol (10 ml), and Pd / C (4 mg, 0.03 mmol) was added. The mixture was replaced with hydrogen three times and stirred under hydrogen at room temperature for 12 hours. The Pd / C was removed by filtration and the mixture was prepared in the reverse direction (A: 0.3% formic acid, B: acetonitrile; 3% to 97%). The mixture was lyophilized to obtain 5.4 mg of the target product C08. LC-MS-MC20-1017-081C2-LCMS: (ES, m / z): [M+H] + =1078.5

[0311] Example 8:

[0312]

[0313] Synthesis route:

[0314]

[0315] (1) C17-17a (2 g, 5.1 mmol) was dissolved in dimethyl sulfoxide (20 mL), and C17-17b (1.2 g, 5.1 mmol), KI (1.2 g, 8.0 mmol), and DIEA (2.5 g, 21.9 mmol) were added and stirred at 120°C for 2 hours. Water (200 ml) was added and extracted with ethyl acetate (50 ml*3). The organic phases were combined and washed with saturated sodium chloride (60 ml), dried over anhydrous sodium sulfate, and spin-dried by column chromatography (methanol / dichloromethane, 1:10) to obtain the product C17-17c (1 g).

[0316] (2) C17-17c (500 mg, 1.0 mmol) was added to a reaction flask, and 10 ml of acetonitrile and IBX (1 g, 2.0 mmol) were added. The mixture was stirred at 80°C for 2 hours, and water (20 ml) was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried by column chromatography (methanol / dichloromethane, 1:10) to obtain the product C17-17d (200 mg).

[0317] (3) C17-17d (150 mg, 0.30 mmol) was added to the reaction flask, followed by methanol (5 ml), C17-17e (164 mg, 0.33 mmol), and sodium cyanoborohydride (42 mg, 0.66 mmol). The mixture was stirred at room temperature for 12 hours, 20 mL of water was added, and then extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (methanol / dichloromethane, 1:10) to obtain the product C17-17f (120 mg).

[0318] (4) C17-17f (70 mg, 0.07 mmol) was added to methanol (10 ml), and Pd / C (4 mg, 0.03 mmol) was added. The mixture was replaced with hydrogen three times and stirred under hydrogen at room temperature for 12 hours. The mixture was filtered and dried by spun-drying. The reaction mixture was prepared in the reverse direction (A: 0.3% formic acid, B: acetonitrile; 3% to 97%) and lyophilized to obtain 7.8 mg of the target product C17. LC-MS-MC20-1017-078-LCMS: (ES, m / z): [M+H] + =938.1

[0319] Each embodiment 1 The H NMR and MS data are shown in the following table:

[0320] Table 1: 1 H NMR and MS data

[0321]

[0322]

[0323] Biological test data

[0324] CCK8 method to detect the inhibitory effect of compounds on tumor cell growth

[0325] Drug dilution process:

[0326] ① Take 1 vial of solution with a concentration of 25mM and dilute it with DMSO to a series of concentrations of 1000× the stock solution. The dilution process is as follows:

[0327]

[0328] ② Take 2 μL of each diluted solution and add it to different 1 mL complete culture medium to obtain 2x drug working solution.

[0329] Experimental steps for detecting the growth inhibition of tumor cells by CCK8 method

[0330] The tumor cells selected were KRAS-expressing G12C Mutated human non-small cell lung cancer cells NCI-H358①Tumor cells in the logarithmic growth phase were digested with trypsin, centrifuged at 200g for 5min, and resuspended in complete culture medium; the cells were diluted to 3×10 4 The cell suspension was placed in a separatory tank and transferred to a 96-well plate using a multi-channel pipette. 100 μL was added to each well and the plates were incubated at 37°C, 5% CO2 for 24 h. After culturing for 24 h, 100 μL of 2X drug working solution was added in sequence, gently shaken, and incubated at 37°C, 5% CO2 for 72 h. After culturing for 72 h, 20 μL of CCK-8 was added and the reaction was incubated at 37°C, 5% CO2 for 3 h. The plates were fully shaken before detection using a microplate reader and the results were measured at 450 nm.

[0331] ②Data analysis: *Cell viability: cell proliferation activity or cytotoxic activity. Cell viability* (%) = [A(drug added) - A(blank)] / [A(0 drug added) - A(blank)] × 100

[0332] A (drug added): absorbance of the wells with cells, CCK8 solution, and drug solution;

[0333] A (blank): absorbance of wells with culture medium without cells, CCK8 solution, and no drug solution;

[0334] A (0 drug addition): absorbance of a well containing cells and CCK8 solution but no drug solution.

[0335] Data were statistically analyzed using Graphpad 8.0 and IC was calculated. 50 The IC of the compound is obtained using the following nonlinear fitting formula: 50 (50% inhibitory concentration):

[0336] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hill Slope))

[0337] X: log value of compound concentration; Y: inhibition rate (% inhibition).

[0338] The results of the inhibitory effect of the compounds on H358 cell proliferation are shown in the following table:

[0339] Compound <![CDATA[IC 50 (μM)]]> C17 4.09

[0340] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0341] The above-described embodiments merely represent several implementation methods of the present invention. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make various modifications and variations without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 。 2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing diseases and / or conditions that can be treated by inhibiting or degrading SOS1.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing cancer.

5. The method of claim 4, wherein the cancer is selected from the group consisting of lymphoma, blastoma, sarcoma, leukemia, squamous cell carcinoma, esophageal cancer, thyroid cancer, melanoma, pancreatic cancer, lung cancer, peritoneal cancer, bile duct cancer, gastric cancer, glioblastoma, multiple myeloma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, anal cancer, penile cancer, urothelial cancer, and head and neck cancer. The use according to claim 4 , wherein the cancer is selected from hepatocellular carcinoma.

7. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating and / or preventing RAS pathology; wherein the RAS pathology is selected from neurofibromatosis type 1, Noonan syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-cutaneous syndrome, Legius syndrome or hereditary gingival fibromatosis.

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