Cyclic 2-amino-3-cyanothiophenes and derivatives thereof for the treatment of cancer

Abstract

This invention relates to cyclic 2-amino-3-cyanothiophene and its derivatives for the treatment of cancer. The invention covers compounds of formula (I) – wherein R… 1a R 1b R 2a R 2b Z, R 3 R 5 A, U, V, W, L, and E have the meanings given in the claims and specification, the use of the compounds as inhibitors of mutant Ras family proteins, pharmaceutical compositions and formulations containing such compounds, and their use as medicines / medical uses, particularly as agents for the treatment and / or prevention of oncological diseases.

Description

[0001] This application is a divisional application of Chinese patent application No. 202180059643.1 (filed on June 1, 2021, entitled "Cyclic 2-amino-3-cyanothiophene and its derivatives for the treatment of cancer"). Technical Field

[0002] This invention relates to cyclic 2-amino-3-cyanothiophene of formula (I) and its derivatives.

[0003]

[0004] Where R 1a R 1b R 2a R 2b Z, R 3 R 5 A, U, V, W, L, and E have the meanings given in the claims and specification, the use of the compounds as inhibitors of mutant Ras family proteins, pharmaceutical compositions and formulations containing such compounds, and their use as medicines / medical uses, particularly as agents for the treatment and / or prevention of oncological diseases (e.g., cancer). Background Technology

[0005] Ras family proteins, including KRAS (V-Ki-ras2 Kirsten rat sarcoma virus oncogene homologue), NRAS (neuroblastoma RAS virus oncogene homologue), and HRAS (Harvey rat sarcoma virus oncogene), and any mutants thereof, are small GTPases present in cells in either GTP-bound or GDP-bound states (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Nimnual et al. Sci. STKE., 2002, 2002(145):pe36). Ras family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rates (Hunter et al., Mol. CancerRes., 2015, 13(9):1325-35). Binding to GTPase-activating proteins (GAPs) such as NF1 increases the GTPase activity of Ras family proteins. Guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) promote the release of GDP from Ras family proteins, thereby allowing GTP binding (Chardin et al., Science, 1993, 260(5112):1338-43). When in the GTP-bound state, Ras family proteins are active and bind to effector proteins, including C-RAF and phosphoinositol 3-kinase (PI3K), to promote the RAF / mitogen or extracellular signal-regulated kinase (MEK / ERK) pathway, the PI3K / AKT / mammalian target of rapamycin (mTOR) pathway, and the RalGDS (Ral guanine nucleotide dissociation stimulator) pathway (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6). These pathways affect a variety of cellular processes, such as proliferation, survival, metabolism, movement, angiogenesis, immunity, and growth (Young et al., Adv. Cancer Res., 2009, 102:1-17; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6).

[0006] Cancer-associated mutations in Ras family proteins suppress their intrinsic and GAP-induced GTPase activity, leading to an increase in the population of GTP-binding / active mutant Ras family proteins (McCormick et al., Expert Opin. Ther. Targets., 2015, 19(4):451-4; Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-35). This, in turn, leads to the sustained activation of downstream effector pathways of mutant Ras family proteins (e.g., RAF / MEK / ERK, PI3K / AKT / mTOR, RalGDS pathways). KRAS mutations (e.g., amino acids G12, G13, Q61, A146) have been found in various human cancers, including lung, colorectal, and pancreatic cancer (Cox et al., Nat. Rev. Drug Discov., 2014, 13(11):828-51). Mutations in HRAS (e.g., amino acids G12, G13, Q61) and NRAS (e.g., amino acids G12, G13, Q61, A146) have also been found in a variety of human cancer types, but are generally less frequent than KRAS mutations (Cox et al., Nat. Rev. DrugDiscov., 2014, 13(11):828-51). Alterations in Ras family proteins / Ras genes (e.g., mutations, overexpression, gene amplification) have also been described as mechanisms of resistance to cancer drugs such as EGFR antibodies cetuximab and panitumumab (Leto et al., J. Mol. Med. (Berl. 2014 July; 92(7):709-22) and EGFR tyrosine kinase inhibitors osimertinib / AZD9291 (Ortiz-Cuaran et al., Clin. Cancer Res., 2016, 22(19):4837-47; Eberlein et al., Cancer Res., 2015, 7 5(12):2489-500).

[0007] Mutations at residue 12 of Ras family proteins, specifically glycine-to-cysteine ​​transitions (G12C mutations, such as KRASG12C, NRAS G12C, and HRAS G12C), are caused by a GC-to-TA base transversion at codon 12. These mutations are common in RAS genes, accounting for 14% of all KRAS mutations, 2% of all NRAS mutations, and 2% of all HRAS mutations across cancer types. G12C mutations are particularly prevalent in KRAS-mutant non-small cell lung cancer, affecting approximately half of all cases, and are associated with DNA adducts formed from tobacco smoke. G12C mutations are not only associated with lung cancer but have also been found in other RAS-mutant cancer types, such as accounting for 3-5% of all KRAS-mutant colorectal cancers.

[0008] Inhibitors of G12C-mutant Ras family proteins, such as covalent binders of KRAS G12C, NRAS G12C, and HRAS G12C, capable of covalently binding to G12C-mutant Ras family proteins, are expected to inhibit downstream signaling of Ras family proteins in cells (e.g., ERK phosphorylation). In cancer cells associated with dependence on mutant Ras family proteins (e.g., KRAS-mutant cancer cell lines), such binders / inhibitors are expected to produce anticancer effects (e.g., inhibition of proliferation, survival, metastasis, etc.).

[0009] To date, no G12C-mutant Ras family protein inhibitors have been approved for therapeutic use. Recently, the first batch of selective drugs targeting KRAS G12C have entered clinical development, with sotorasirb and adagraxib already in late-stage trials for the treatment of KRAS G12C-induced lung cancer (see corresponding patent applications WO 2018 / 217651, WO 2017 / 201161, WO 2019 / 099524, WO 2020 / 102730). There is a need for new or even improved G12C-mutant Ras family protein inhibitors suitable for clinical use. Detailed Implementation

[0010] compound

[0011] It has now been discovered, surprisingly, that compounds of formula (I) (where R) 1a R 1b R 2a R 2b Z, R 3 R 5The compounds (A, p, U, V, W, L, and E, with the meanings given below) act as inhibitors of G12C mutant Ras family proteins involved in controlling cell proliferation, possessing antitumor activity and suitable for inhibiting uncontrolled cell proliferation caused by malignant diseases. This antitumor activity is believed to derive from the inhibition of G12C mutant Ras family proteins, particularly KRAS G12C, which are key mediators of proliferation and survival in certain tumor cells. Further, it is believed that the compounds according to the invention interact with and then covalently bind to G12C mutant Ras family proteins, particularly KRAS G12C, via an electrophilic portion (e.g., a Michael receptor) present in the compounds of formula (I) (confirmed by crystallography of KRAS G12C). Upon covalent binding to G12C mutant Ras family proteins, particularly KRAS G12C (most likely located at position 12 of the Ras family protein), the compounds weaken or substantially eliminate the ability of G12C Ras family proteins to acquire their active pro-proliferative / pro-survival conformation.

[0012] In fact, the binding of compounds of formula (I) according to the invention results in selective and very strong anti-proliferative cell activity in G12C mutant KRAS cell lines compared to wild-type KRAS cells, as well as a larger selective window. This superior potency can potentially lead to lower systemic exposure and / or the dose required to achieve full efficacy in humans, thus with good / better tolerability (e.g., lower risk of idiosyncratic toxicity), enabling more potent targeting of pathways when necessary and with beneficial results, and increasing flexibility in combination therapy. The compounds exhibit strong biomarker modulation activity, such as pERK in G12C mutant KRAS cell lines. Selected compounds were tested in a selective kit, and these compounds showed good selectivity for other targets (e.g., kinases). Last but not least, the selected compounds disclosed herein were tested to show good permeability, excellent solubility, and just the right amount of PK properties.

[0013] Therefore, in a first aspect, the present invention relates to a compound of formula (I).

[0014] ,

[0015] in

[0016] [A0]

[0017] R 1a and R 1b All are independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-5 cycloalkyl and 3-5 membered heterocyclic groups;

[0018] R 2a and R 2b All are independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-5 cycloalkyl and 3-5 membered heterocyclic groups;

[0019] And / or, optionally, R 1a Or R 1b One of them and R 2a Or R 2b One of them, together with the carbon atoms to which they are attached, forms a cyclopropane ring;

[0020] [B0]

[0021] Z is -(CR) 6a R 6b ) n -;

[0022] Each R 6a and R 6b Independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-5 cycloalkyl and 3-5 membered heterocyclic groups;

[0023] n is selected from 0, 1, and 2;

[0024] [C0]

[0025] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4Alkyl)2, -CN, C 3-5 cycloalkyl and 3-5 membered heterocyclic groups;

[0026] [D0]

[0027] Ring A is Diazole or thiadiazole;

[0028] [E0]

[0029] U is selected from nitrogen (=N-) and R. A Substituted carbon (=C(R) A )-);

[0030] V is selected from nitrogen (=N-) and R. B Substituted carbon (=C(R) B )-);

[0031] W is selected from nitrogen (=N-) and R. C Substituted carbon (=C(R) C )-);

[0032] R A R B and R C Each is independently selected from hydrogen and C. 1-6 Halogenated alkyl, optionally C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2;

[0033] [F0]

[0034] R 5 Selected from Ra1 and R b1 ;

[0035] R a1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups. b1 and / or R c1 replace;

[0036] 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 Alkyl)C(=O)R c1 -NHS(=O)2R c1 -N(C 1-4 alkyl)S(=O)2R c1 -NHC(=O)OR c1 -N(C 1-4 Alkyl)C(=O)OR c1 and divalent substituents = O;

[0037] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups. d1 and / or R e1 replace;

[0038] Each R d1 Independently selected from -OR e1 -NR e1 R e1 Halogen, -CN, -C(=O)R e1 -C(=O)OR e1 -C(=O)NR e1 R e1 -S(=O)2R e1 -S(=O)2NR e1 R e1 -NHC(=O)R e1 -N(C 1-4 Alkyl)C(=O)R e1 -NHS(=O)2R c1 -N(C 1-4 alkyl)S(=O)2R c1 -NHC(=O)OR e1 -N(C 1-4 Alkyl)C(=O)OR e1 and divalent substituents = O;

[0039] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10The aryl and 5-10 heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl groups, 3-11 membered heterocyclic groups—which may optionally be substituted by one or more of the same or different of the following groups: C 1-4 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group (2) and divalent substituent = O;

[0040] [G0]

[0041] L is -L 1 -L 2 -L 3 -, where L 1 Connect to E;

[0042] L 1 Selected from the bond, -NH-, -N(C 1-4 Alkyl group, -O group, -C(=O) group, -NH-C(=O) group, -N(C) group 1-4 Alkyl)-C(=O)-, -C(=O)-NH-, -C(=O)-N(C 1-4 Alkyl)-, -C(=O)-, C 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4-12 membered heterocyclic alkylene and 5-10 membered heteroarylalkylene;

[0043] L 2 Selected from C 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4-12 membered heterocyclic alkylene and 5-10 membered heteroarylalkylene;

[0044] L 3 Selected from the bond, -NH-, -N(C 1-4 Alkyl group, -O group, -C(=O) group, -NH-C(=O) group, -N(C) group 1-4 Alkyl)-C(=O)-, -C(=O)-NH-, -C(=O)-N(C 1-4 Alkyl)-, -C(=O)-, C 1-6 Alkylene, C 3-7Cycloalkylene, phenylene, 4-12 membered heterocyclic alkylene and 5-10 membered heteroarylalkylene;

[0045] Where L 1 L 2 and L 3 Each C in 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4-12-membered heterocyclic and 5-10-membered heteroaryl groups are optionally and independently substituted by one or more identical or different substituents selected from the following: C 2-6 Alkyne group, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 5-6 heteroaryl, halogen, -OH, -CN, C 1-6 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)-OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl group 2, divalent substituent =O, and C group optionally substituted with one or more identical or different substituents selected from the following. 1-6 Alkyl groups: halogens, -OH, -CN, C 1-4 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)-OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2;

[0046] [H0]

[0047] E is

[0048]

[0049] Indicates a double or triple bond;

[0050] Q 1 Selected from bonds, -CH2-, -CH(OH)-, -C(=O)-, -C(=O)N(R) G1 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G1 - and -C(=NR) H1 )-;

[0051] Each RG1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, cyano-C 1-6 Alkyl, (C 1-4 Alkyl)HN-C 1-6 Alkyl, (C 1-4 Alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 Cycloalkyl and 3-11 membered heterocyclic groups;

[0052] Each R H1 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl;

[0053] if To represent a double bond, then

[0054] R D Selected from hydrogen, C 3-7 Cycloalkyl, phenyl, halogen, -CN, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -NHC(=O)-C 1-6 Alkyl groups and C groups optionally substituted with one or more identical or different substituents selected from the following 1-6 Alkyl groups: phenyl, 3-11 membered heterocyclic groups, C 1-6 Alkoxy, halogen, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)NH(C) 1-6 Alkyl), -NHC(=O)-C 1-6 Alkyl, -OC(=O)-C 1-6 Alkyl and phenyl-C 1-6 Alkoxy;

[0055] R E and R F Each independently selected from R a2 and R b2 ;

[0056] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups. b2 and / or R c2 replace;

[0057] 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 -S(=O)2R c2 -S(=O)2NR c2 R c2 -NHC(=O)R c2 -N(C 1-4 Alkyl)C(=O)R c2 -NHC(=O)OR c2 -N(C 1-4 Alkyl)C(=O)OR c2 and divalent substituents = O;

[0058] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, -OH, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6Alkyl, -C(=O)-NH2, -C(=O)-NH-(C 1-6 -alkyl), -C(=O)-N(C 1-6 -alkyl)2 and divalent substituents =O;

[0059] or

[0060] R D and R E Together with the carbon atoms attached to them, they form 4-7 membered unsaturated alicyclic rings or 4-7 membered unsaturated heterocyclic rings, wherein the 4-7 membered unsaturated alicyclic rings or 4-7 membered unsaturated heterocyclic rings and R F Optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -NH2, -CN, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2, halogen, -C(=O)OC 1-6 Alkyl group and divalent substituent = O;

[0061] or

[0062] If Q 1 It is -C(=O)N(R) G1 )-, then -C(=O)N(R G1 )- of R G1 and R F Together they form a connector selected from the following: -C(=O)-, -CH2-, -CH2-C(=O)-, -C(=O)-CH2- and -C2H4-;

[0063] if To represent a triple bond, then

[0064] R D and R E None of them exist;

[0065] R F It is R a2 ;

[0066] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups. b2 and / or R c2 replace;

[0067] 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 -S(=O)2R c2 -S(=O)2NR c2 R c2 -NHC(=O)R c2 -N(C 1-4 Alkyl)C(=O)R c2 -NHC(=O)OR c2 -N(C 1-4 Alkyl)C(=O)OR c2 and divalent substituents = O;

[0068] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups;

[0069] or

[0070] E is

[0071]

[0072] Q 2 Selected from bonds, -CH2-, -CH(OH)-, -C(=O)-, -C(=O)N(R) G2 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G2 - and -C(=NR) H2 )-;

[0073] Each R G2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, cyano-C 1-6Alkyl, (C 1-4 Alkyl)HN-C 1-6 Alkyl, (C 1-4 Alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 Cycloalkyl and 3-11 membered heterocyclic groups;

[0074] Each R H2 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl;

[0075] R I Selected from hydrogen and halogens;

[0076] R J It is hydrogen; or

[0077] R I and R J Together with the carbon atoms attached to them, they form cyclopropane or ethylene oxide rings;

[0078] R K Selected from hydrogen, C 1-6 Alkyl groups, -CN groups, and halogens;

[0079] R L Selected from hydrogen, C 1-6 Alkyl groups, -CN, halogens, and -C(=O)-C 1-6 alkyl;

[0080] or

[0081] E is

[0082]

[0083] Q 3 Selected from -C(=O)- and -C(=O)N(R) G3 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G3 - and -C(=NR) H3 )-;

[0084] Each R G3 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, cyano-C 1-6 Alkyl, (C 1-4 Alkyl)HN-C 1-6 Alkyl, (C 1-4Alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 Cycloalkyl and 3-11 membered heterocyclic groups;

[0085] Each R H3 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl;

[0086] R M Selected from halogens, -CN and -OC(=O)-C 1-6 alkyl;

[0087] or

[0088] E is

[0089]

[0090] Q 4 Selected from bonds, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(C 1-4 Alkyl group, -S(=O)2- and -S(=O)2NH-;

[0091] Ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and 5-membered heteroaryl;

[0092] q is selected from 1, 2, 3, and 4;

[0093] Each R N Selected independently from C 1-4 Alkyl, C 1-4 Halogenated alkyl, vinyl, ethynyl, halogen, -CN, nitro and C 1-4 Alkoxy;

[0094] Or its salt.

[0095] In a second aspect, the present invention relates to a compound of formula (I*) or a salt thereof.

[0096] ,in

[0097] R 1a R 1b R 2a R 2b Z, R 3 Ring A, U, V, W, R 5 L and E are defined as in equation (I) in the first aspect.

[0098] In a third aspect, the present invention relates to a compound of formula (Ia) or a salt thereof.

[0099] ,in

[0100] R 1a R 1b R 2a R 2b Z, R 3 U, V, W, R 5 L and E are defined as in equation (I) in the first aspect.

[0101] In a fourth aspect, the present invention relates to a compound of formula (Ia*) or a salt thereof.

[0102] ,in

[0103] R 1a R 1b R 2a R 2b Z, R 3 U, V, W, R 5 L and E are defined as in equation (I) in the first aspect.

[0104] It should be understood that compounds (I*), (Ia) and (Ia*) are each subsets of compound (I), and whenever compound (I) is mentioned, it is also intended to mention and include compounds (I*), (Ia) and (Ia*), unless otherwise stated.

[0105] It should be understood that compound (Ia*) is a subset of the corresponding compound (Ia), and whenever compound (Ia) is mentioned, it is also intended to mention and include compound (Ia*) unless otherwise stated.

[0106] The following structural aspects represent preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], [D0], [E0], [F0], [G0], and [H0], namely [A1] to [A3], [B1] to [B5], [C1] to [C5], [D1] to [D2], [E1] to [E9], [F1] to [F8], [G1] to [G3], and [H1] to [H8].

[0107] In one aspect [A1], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0108] R 1a and R 1b Both are independently selected from hydrogen and C 1-4alkyl;

[0109] R 2a and R 2b They are all independently selected from hydrogen and halogens.

[0110] In another aspect [A2], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0111] R 1a and R 1b Each is independently selected from hydrogen and methyl;

[0112] R 2a and R 2b They are all independently selected from hydrogen and fluorine.

[0113] On the other hand [A3], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0114] R 1a R 1b R 2a and R 2b It is hydrogen.

[0115] In another aspect [B1], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0116] Z is -(CR) 6a R 6b ) n -;

[0117] n is 0.

[0118] In another aspect [B2], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0119] Z is -(CR) 6a R 6b ) n -;

[0120] n is 1;

[0121] R 6a and R 6b All are independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C3-5 Cycloalkyl and 3-5 membered heterocyclic groups.

[0122] On the other hand [B3], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0123] Z stands for -CH2-.

[0124] On the other hand [B4], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0125] Z is -(CR) 6a R 6b ) n -;

[0126] n is 2;

[0127] Each R 6a and R 6b Independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-5 Cycloalkyl and 3-5 membered heterocyclic groups.

[0128] On the other hand [B5], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0129] Z stands for -CH2-CH2-.

[0130] In another aspect [C1], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0131] R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, cyano-C 1-4 Alkyl, halogen, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2 and -CN.

[0132] In another aspect [C2], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0133] R 3 Selected from hydrogen, methyl, ethyl, -CF3, -CHF2, methoxy, trifluoroethoxy, cyanomethyl, -OH and -CN.

[0134] In another aspect [C3], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0135] R 3 It is hydrogen.

[0136] In another aspect [C4], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0137] R 3 It is C 1-4 alkyl.

[0138] In another aspect [C5], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0139] R 3 It is a methyl group.

[0140] On the other hand [D1], the present invention relates to a compound of formula (I) or (I*) or a salt thereof, wherein

[0141] Ring A is selected from

[0142] 、 、 、 、 and 。

[0143] On the other hand [D2], the present invention relates to a compound of formula (I) or (I*) or a salt thereof, wherein

[0144] Ring A is .

[0145] On the other hand [E1], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0146] U is R A Substituted carbon (=C(R) A )-);

[0147] V is R B Substituted carbon (=C(R) B )-);

[0148] W stands for nitrogen (=N-);

[0149] R A and RB Each is independently selected from hydrogen and C. 1-6 Halogenated alkyl, optionally C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2.

[0150] On the other hand [E2], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0151] U is =CH-;

[0152] V is =CH-;

[0153] W stands for nitrogen (=N-).

[0154] On the other hand [E3], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0155] U is R A Substituted carbon (=C(R) A )-);

[0156] V is R B Substituted carbon (=C(R) B )-);

[0157] W was R C Substituted carbon (=C(R) C )-);

[0158] R A R B and R C Each is independently selected from hydrogen and C. 1-6Halogenated alkyl, optionally C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2.

[0159] On the other hand [E4], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0160] U is =CH-;

[0161] V is =CH-;

[0162] W is = CH-.

[0163] On the other hand [E5], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0164] U is nitrogen (=N-);

[0165] V is R B Substituted carbon (=C(R) B )-);

[0166] W stands for nitrogen (=N-);

[0167] R B Selected from hydrogen, C 1-6 Halogenated alkyl, optionally C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2.

[0168] On the other hand [E6], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0169] U is nitrogen (=N-);

[0170] V is =CH-;

[0171] W stands for nitrogen (=N-).

[0172] On the other hand [E7], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0173] U is R A Substituted carbon (=C(R) A )-);

[0174] V is nitrogen (=N-);

[0175] W stands for nitrogen (=N-);

[0176] R A Selected from hydrogen, C 1-6 Halogenated alkyl, optionally C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocycles, and C-membered rings optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2.

[0177] On the other hand [E8], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0178] U is R A Substituted carbon (=C(R) A )-);

[0179] V is nitrogen (=N-);

[0180] W stands for nitrogen (=N-);

[0181] R A Selected from hydrogen and halogens.

[0182] On the other hand [E9], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0183] U is nitrogen (=N-);

[0184] V is nitrogen (=N-);

[0185] W stands for nitrogen (=N-).

[0186] In another aspect [F1], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0187] R 5 Selected from R a1 and R b1 ;

[0188] R a1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups.b1 and / or R c1 replace;

[0189] 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 Alkyl)C(=O)R c1 and divalent substituents = O;

[0190] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups. d1 and / or R e1 replace;

[0191] Each R d1 Independently selected from -OR e1 -NR e1 R e1 Halogen, -CN, -C(=O)R e1 -C(=O)NR e1 R e1 and divalent substituents = O;

[0192] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C6-10 The aryl and 5-10 heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl groups, 3-11 membered heterocyclic groups—which are optionally bounded by one or more identical or different C groups. 1-4 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2 and divalent substituents =O substitution.

[0193] On the other hand [F2], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0194] R 5 It is R a1 ;

[0195] R a1 Selected from 3-11-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 3-11-membered heterocyclic group and the 5-10-membered heteroaryl group are optionally separated by one or more identical or different R groups. b1 and / or R c1 replace;

[0196] Each R b1 Independently selected from -OR c1 -NR c1 R c1 Halogen, -C(=O)OR c1 and divalent substituents = O;

[0197] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl groups and 3-11 membered heterocyclic groups are optionally separated by one or more identical or different R groups. d1 and / or R e1 replace;

[0198] Each R d1Independently selected from -OR e1 -NR e1 R e1 and halogens;

[0199] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 The cycloalkyl and 3-11 membered heterocyclic groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl groups and 3-11 membered heterocyclic groups—which are optionally separated by one or more identical or different C groups. 1-4 Alkyl substitution.

[0200] On the other hand [F3], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0201] R 5 It is selected from the following R a1 :

[0202]

[0203] Each R a1 Optionally by one or more identical or different R b1 and / or R c1 replace;

[0204] Each R b1 Independently selected from -OR c1 -NR c1 R c1 Halogen, -C(=O)OR c1 and divalent substituents = O;

[0205] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl groups and 3-11 membered heterocyclic groups are optionally separated by one or more identical or different R groups. d1 and / or R e1 replace;

[0206] Each R d1 Independently selected from -OR e1 -NR e1 R e1and halogens;

[0207] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 The cycloalkyl and 3-11 membered heterocyclic groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl groups and 3-11 membered heterocyclic groups—which are optionally separated by one or more identical or different C groups. 1-4 Alkyl substitution.

[0208] On the other hand [F4], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0209] R 5 It is selected from the following R a1 :

[0210]

[0211] Each R a1 Optionally substituted with one or more of the same or different of the following groups:

[0212] ·C 1-6 Alkyl group, optionally substituted with one or more identical or different substituents selected from the following: C 3-6 Cycloalkyl, hydroxyl, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkoxy groups and optionally C 1-4 Alkyl-substituted 3-7 membered heterocyclic groups;

[0213] ·C 3-6 cycloalkyl groups, which are optionally substituted with one or more of the same or different halogens;

[0214] • 3-11 membered heterocyclic groups, optionally substituted by one or more identical or different substituents selected from the following; C 1-4 Alkyl, C 3-6 cycloalkyl and halogen; and

[0215] • Selected from the following substituents: halogen, -C(=O)-OC 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group)2 and divalent substituent =O.

[0216] On the other hand [F5], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0217] R 5 Selected from

[0218]

[0219]

[0220]

[0221] On the other hand [F6], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0222] R 5 It is R b1 ;

[0223] R b1 Independently selected from -OR c1 and -NR c1 R c1 ;

[0224] Each R c1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups. d1 and / or R e1 replace;

[0225] Each R d1 Independently selected from -OR e1 -NR e1 R e1 Halogen, -C(=O)R e1 and -C(=O)NR e1 R e1 ;

[0226] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C6-10 The aryl and 5-10 heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3-11 membered heterocyclic groups—which are optionally separated by one or more identical or different C groups. 1-4 Alkyl, C 1-6 Alkoxy groups, halogens, and divalent substituents = O substitution.

[0227] On the other hand [F7], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0228] R 5 It is R b1 ;

[0229] R b1 Yes - OR c1 ;

[0230] Each R c1 Selected independently from C 1-6 Alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3-11 membered heterocyclic groups are optionally separated by one or more identical or different R groups. d1 and / or R e1 replace;

[0231] Each R d1 Independently selected from -NR e1 R e1 and halogens;

[0232] Each R e1 Independently selected from hydrogen and C 1-6 Alkyl groups and 3-11 membered heterocyclic groups, wherein the C 1-6 The alkyl group and the 3-11 membered heterocyclic group are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl groups and 3-11 membered heterocyclic groups—which are optionally separated by one or more identical or different C groups. 1-4 Alkyl substitution.

[0233] On the other hand [F8], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0234] R 5 Selected from

[0235]

[0236] In another aspect [G1], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0237] L is -L 1 -L 2 -L 3 -, where L 1 Connect to E;

[0238] L 1 Selected from key, C 1-6 Alkyl groups and 4-12 membered heterocyclic groups;

[0239] L 2 Selected from C 1-6 Alkylenes, phenylenes, and 4-12 membered heterocyclic groups;

[0240] L 3 Selected from the bond, -NH-, -N(C 1-4 Alkyl)- and -O-;

[0241] Where L 1 and L 2 Each C in 1-6 The alkylene, phenylene, and 4-12 membered heterocyclic groups are optionally and independently substituted by one or more identical or different substituents selected from the following: C 2-6 Alkyne group, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 5-6 heteroaryl, halogen, -OH, -CN, C 1-6 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)-OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl group 2, divalent substituent =O, and C group optionally substituted with one or more identical or different substituents selected from the following. 1-6 Alkyl groups: halogen, -OH, -CN, -NH2, C 1-4 Alkoxy, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)-OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2.

[0242] In another aspect [G2], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0243] L is -L 1 -L 2 -L 3 -, where L 1 Connect to E;

[0244] L 1 Selected from key, C 1-6 Alkyl groups and 4-12 membered heterocyclic groups;

[0245] L 2 Selected from C 1-6 Alkylenes, phenylenes, and 4-12 membered heterocyclic groups;

[0246] L 3 Selected from the bond, -NH-, -N(C 1-4 Alkyl)- and -O-;

[0247] Where L 1 and L 2 Each C in 1-6 Alkylene, phenylene, and 4-12 membered heterocyclic groups are optionally and independently bound by one or more identical or different C16 groups. 1-6 Alkyl substitution.

[0248] On the other hand [G3], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0249] L is selected from

[0250]

[0251]

[0252]

[0253] In another aspect [H1], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0254] E is

[0255] ;

[0256] Q 1 Selected from -CH2-, -C(=O)-, -C(=O)N(R) G1 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G1 - and -C(=NR)H1 )-;

[0257] Each R G1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl;

[0258] Each R H1 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl;

[0259] R D Selected from hydrogen, C 3-7 Cycloalkyl, phenyl, halogen, -CN, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl groups and C groups optionally substituted with one or more identical or different substituents selected from the following 1-6 Alkyl groups: phenyl, 3-11 membered heterocyclic groups, C 1-6 Alkoxy, halogen, -OH, -N(C) 1-6 Alkyl group 2, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)NH(C) 1-6 Alkyl), -NHC(=O)-C 1-6 Alkyl, -OC(=O)-C 1-6 Alkyl and phenyl-C 1-6 Alkoxy;

[0260] R E and R F Each independently selected from R a2 and R b2 ;

[0261] R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups. b2 and / or R c2 replace;

[0262] Each R b2 Independently selected from -OR c2 -NRc2 R c2 Halogen, -CN, -C(=O)OR c2 -C(=O)NR c2 R c2 -NHC(=O)R c2 -N(C 1-4 Alkyl)C(=O)R c2 -NHC(=O)OR c2 and -N(C 1-4 Alkyl)C(=O)OR c2 ;

[0263] Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, 3-11 membered heterocyclic, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, 3-11 membered heterocyclic, C 6-10 The aryl and 5-10 heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, -OH, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl group)2 and divalent substituent =O.

[0264] On the other hand [H2], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0265] E is

[0266] ;

[0267] Q 1 Selected from -CH2-, -C(=O)-, -C(=O)NH- and -C(=O)N(C 1-4 alkyl)-;

[0268] R D Selected from hydrogen, halogens and C 1-6 alkyl;

[0269] R E and R F Each independently selected from R a2 and Rb2 ;

[0270] R a2 Selected from hydrogen and C 1-6 Alkyl, wherein the C 1-6 Alkyl groups are optionally surrounded by one or more identical or different R groups. b2 and / or R c2 replace;

[0271] Each R b2 Independently selected from -OR c2 and -C(=O)NR c2 R c2 ;

[0272] Each R c2 Selected independently from C 1-6 Alkyl groups and 3-11 membered heterocyclic groups.

[0273] On the other hand [H3], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0274] E is selected from

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] In another aspect [H4], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0282] E is selected from

[0283]

[0284] On the other hand [H5], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0285] E is

[0286]

[0287] Q 1Selected from -CH2-, -C(=O)-, -C(=O)N(R) G1 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G1 - and -C(=NR) H1 )-;

[0288] Each R G1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl;

[0289] Each R H1 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl;

[0290] R F C selected from hydrogen and optionally substituted with substituents selected from the following 1-6 Alkyl groups: -OH, C 1-6 Alkoxy, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 Alkyl)2.

[0291] In another aspect [H6], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0292] E is

[0293]

[0294] Q 1 Selected from -C(=O)- and -C(=O)N(R) G1 -, -S(=O)2- and -S(=O)2N(R) G1 )-;

[0295] Each R G1 Independently selected from hydrogen and C 1-6 alkyl;

[0296] R F C selected from hydrogen and optionally substituted with substituents selected from the following 1-6 Alkyl groups: -OH, C 1-6 Alkoxy, -NH2, -NH(C) 1-4 alkyl) and -N(C) 1-4 Alkyl)2.

[0297] On the other hand [H7], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0298] E is selected from

[0299]

[0300] On the other hand [H8], the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

[0301] E is selected from

[0302]

[0303] All of the above structural aspects [A1] to [A3], [B1] to [B5], [C1] to [C5], [D1] and [D2], [E1] to [E9], [F1] to [F8], [G1] to [G3], and [H1] to [H8] are preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], [D0], [E0], [F0], [G0], and [H0]. The structural aspects of different molecular portions of compounds of formulas (I), (I*), (Ia), and (Ia*) according to the invention [A0] to [A3], [B0] to [B5], [C0] to [C5], [D0] to [D3], [E0] to [E9], [F0] to [F8], [G0] to [G3], and [H0] to [H8] can be combined with each other as needed in combinations [A][B][C][D][E][F][G][H] (for compounds of formulas (I) and (I*)) and combinations [A][B][C][E][F][G][H] (for compounds of formulas (Ia) and (Ia*)) to obtain preferred compounds (I), (I*), (Ia), and (Ia*). Each such combination [A][B][C][D][E][F][G][H] represents and defines a separate embodiment or a general subset of compounds (I) and (I*) according to the invention. Each such combination [A][B][C][E][F][G][H] represents and defines a separate embodiment or a general subset of compounds (Ia) and (Ia*) according to the invention.

[0304] Preferred embodiments of the invention having formula (Ia) are the example compounds Ia-1 to Ia-170 and any subset thereof.

[0305] The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of compounds of formulas (I), (I*), (Ia) and (Ia*), including all embodiments thereof.

[0306] The present invention further relates to hydrates of compounds of formula (I), (I*), (Ia) and (Ia*), including all embodiments thereof.

[0307] The present invention further relates to solvates of compounds of formula (I), (I*), (Ia) and (Ia*) (including all embodiments thereof).

[0308] For example, compounds of formulas (I), (I*), (Ia), and (Ia*) with ester groups (including all embodiments thereof) are potential prodrugs (esters are cleaved under physiological conditions) and are also part of this invention.

[0309] The present invention further relates to pharmaceutically acceptable salts of compounds of formulas (I), (I*), (Ia) and (Ia*), including all embodiments thereof.

[0310] The present invention further relates to compounds of formula (I), (I*), (Ia) and (Ia*) (including all embodiments thereof) with pharmaceutically acceptable salts formed from inorganic or organic acids or bases.

[0311] intermediate

[0312] In a fifth aspect, the present invention relates to a compound of formula (II) or a salt thereof.

[0313] ,in

[0314] R 1a R 1b R 2a R 2b Z, R 3 Ring A, U, V, W, R 5 And L is defined as in equation (I) of the first aspect.

[0315] The compound of formula (II) is an intermediate in the synthesis of the compound of formula (I) (the hydrogen in the residue HL- is replaced by the group E in the final synthetic step).

[0316] In a sixth aspect, the present invention relates to a compound of formula (II*) or a salt thereof.

[0317] ,in

[0318] R 1a R 1b R 2a R 2b Z, R 3 Ring A, U, V, W, R 5And L is defined as in equation (I) of the first aspect.

[0319] In a seventh aspect, the present invention relates to a compound of formula (B-5) or a salt thereof.

[0320] ,in

[0321] R 1a R 1b R 2a R 2b Z, R 3 U, V, W, R 5 And L is defined as in equation (I) of the first aspect.

[0322] In an eighth aspect, the present invention relates to a compound of formula (B-5*) or a salt thereof.

[0323] ,in

[0324] R 1a R 1b R 2a R 2b Z, R 3 U, V, W, R 5 And L is defined as in equation (I) of the first aspect.

[0325] It should be understood that compounds (II*), (B-5) and (B-5*) are each subsets of compound (II), and whenever compound (II) is mentioned, it is also intended to mention and include compounds (II*), (B-5) and (B-5*), unless otherwise stated.

[0326] It should be understood that compound (B-5*) is a subset of the corresponding compound (B-5), and whenever compound (B-5) is mentioned, this is also intended to refer to and include compound (B-5*), unless otherwise stated.

[0327] All the above-described structural aspects [A1] to [A3], [B1] to [B5], [C1] to [C5], [D1] and [D2], [E1] to [E9], [F1] to [F8] and [G1] to [G3] of the compounds disclosed as formulas (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), and (Ie*) are also preferred embodiments of the corresponding structural aspects [A0], [B0], [C0], [D0], [E0], [F0] and [G3] of the compounds disclosed as formulas (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie), and (Ie*).

[0328] Therefore, the structural aspects [A0] to [A3], [B0] to [B5], [C0] to [C5], [D0] to [D2], [E0] to [E9], [F0] to [F8], and [G0] to [G3] of the different molecular portions of the compounds involving formulas (II), (II*), (B-5), and (B-5*) can be combined with each other as needed in combinations [A][B][C][D][E][F][G] (for compounds of formulas (II) and (II*)) and combinations [A][B][C][E][F][G] (for compounds of formulas (B-5) and (B-5*)) to obtain preferred compounds of formulas (II), (II*), (B-5), and (B-5*). Each such combination [A][B][C][D][E][F][G] represents and defines a separate embodiment or a general subset of the compounds of formulas (II) and (II*). Each such combination [A][B][C][E][F][G] represents and defines a separate implementation or general subset of the compounds of formula (B-5) and (B-5*).

[0329] Pharmaceutical Composition

[0330] Suitable pharmaceutical compositions for administering compounds of formula (I), (I*), (Ia), or (Ia*) according to the invention will be apparent to those skilled in the art, and include, for example, tablets, pills, capsules, suppositories, lozenges, sugar lozenges, solutions—particularly for injection (subcutaneous, intravenous, intramuscular) and infusion (injection)—elixirs, syrups, capsules, emulsions, inhalants, or dispersible powders. The content of compound (I), (I*), (Ia), or (Ia*) should range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-%, as a whole composition, i.e., an amount sufficient to achieve the dosage range specified below. If necessary, the specified dosage may be administered several times daily.

[0331] Suitable tablets can be obtained, for example, by mixing compound (I), (I*), (Ia), or (Ia*) with a known pharmaceutically acceptable excipient, such as an inert diluent, carrier, disintegrant, adjuvant, surfactant, binder, and / or lubricant. Tablets may also comprise several layers.

[0332] Coated tablets can be prepared by coating a tablet core, similarly produced to a tablet core, with excipients commonly used for tablet coating (e.g., collidone, shellac, gum arabic, talc, titanium dioxide, or sugar). To achieve delayed release or prevent incompatibility, the tablet core may also consist of multiple layers. Similarly, tablet coatings can consist of multiple layers to achieve delayed release, possibly using the aforementioned excipients for tablets.

[0333] Syrups or elixirs containing one or more compounds (I), (I*), (Ia), or (Ia*) or in combination with one or more other pharmaceutically active substances may additionally contain excipients such as sweeteners (e.g., saccharin), cyclamate, glycerin, or sugar and flavor enhancers (e.g., flavorings such as vanillin or orange extract). They may also contain excipients such as suspending adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as condensation products of fatty alcohols and ethylene oxide, or preservatives such as parabens.

[0334] Solutions for injection and infusion are prepared in a conventional manner, for example by adding excipients such as isotonic agents, preservatives such as parabens, or alkali metal salts of stabilizers such as ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants (and if water is used as, for example, a diluent, an organic solvent may optionally be used as a solubilizer or dissolving agent), and are transferred to injection vials or ampoules or infusion bottles.

[0335] Capsules containing one or more compounds (I), (I*), (Ia), or (Ia*) or in combination with one or more other pharmaceutically active substances can be prepared, for example, by mixing the compound / one or more active substances with an inert excipient (such as lactose or sorbitol) and filling them into gelatin capsules.

[0336] Suitable suppositories can be manufactured, for example, by mixing with excipients provided for this purpose, such as neutral fats or polyethylene glycol or their derivatives.

[0337] Excipients that may be used include, for example, water; pharmaceutically acceptable organic solvents such as paraffin (e.g., petroleum grade), vegetable oils (e.g., peanut or sesame oil); monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol); carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk); synthetic mineral powders (e.g., highly dispersed silicates and silicates); sugars (e.g., sucrose, lactose, and glucose); emulsifiers (e.g., lignin, waste sulfite liquid, methylcellulose, starch, and polyvinylpyrrolidone); and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium dodecyl sulfate).

[0338] The pharmaceutical composition is administered via conventional methods, preferably orally or transdermally, with oral administration being the most preferred route. For oral administration, in addition to the excipients mentioned above, tablets may contain other excipients such as sodium citrate, calcium carbonate, and dicalcium phosphate, along with various excipients such as starch, preferably potato starch, and gelatin. Furthermore, lubricants (such as magnesium stearate, sodium dodecyl sulfate, and talc) may be used simultaneously during the tableting process. In the case of an aqueous suspension, in addition to the excipients mentioned above, the active substance may also be combined with various flavor enhancers or colorants.

[0339] For parenteral use, a solution of the active substance with a suitable liquid excipient can be used.

[0340] The daily dose range of compounds of formula (I), (I*), (Ia) or (Ia*) is typically from 1 mg to 2000 mg, preferably from 250 to 1250 mg.

[0341] However, it may sometimes be necessary to deviate from the prescribed dosage, depending on weight, age, route of administration, severity of the disease, individual response to the drug, the nature of the formulation, and the duration or interval of drug administration (continuous or intermittent treatment with once or more daily doses). Therefore, in some cases, using a dose less than the minimum given above may be sufficient, while in others, it may be necessary to exceed the upper limit. When administering a large dose, dividing it into multiple smaller doses throughout the day may be preferable.

[0342] Therefore, in another aspect, the present invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0343] Compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising such compounds and salts, may also be administered in combination with other pharmacologically active substances, such as with other antitumor compounds (e.g., chemotherapy), i.e., in combination therapy (see further description of combination therapy below).

[0344] The elements of such combinations can be administered by methods customary to the technician, as well as by methods used in monotherapy (whether dependent or independent), such as by oral, enteral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection or implantation), nasal, vaginal, rectal or local administration routes, and can be formulated alone or together in appropriate dosage units containing conventional, non-toxic, pharmaceutically acceptable excipients suitable for each route of administration.

[0345] The combination can be administered at therapeutically effective single or separate daily doses. The active ingredients of the combination can be administered at such therapeutically effective doses in monotherapy, or at such doses as those used in monotherapy but which produce the desired (combined) therapeutically effective amount when combined.

[0346] However, when the combined use of two or more active substances or principal ingredients results in a synergistic effect, it is also possible to reduce the amount of one, several, or all of the substances or principal ingredients to be administered while still achieving the desired therapeutic effect. For example, this can be used to avoid, limit, or reduce any unwanted side effects associated with the use of one or more substances or principal ingredients when they are used in their usual amounts, while still obtaining the desired pharmacological or therapeutic effect.

[0347] Therefore, in another aspect, the present invention also relates to a pharmaceutical composition comprising a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof, and one or more (preferably one or two, most preferably one) other pharmacologically active substances.

[0348] In another aspect, the present invention also relates to a pharmaceutical preparation comprising a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof, and one or more (preferably one or two, most preferably one) other pharmacologically active substances.

[0349] Pharmaceutical compositions that are used together or in combination may also be provided in the form of a kit.

[0350] Therefore, in another aspect, the present invention also relates to a kit comprising...

[0351] • A first pharmaceutical composition or dosage form comprising a compound of formula (I), (I*), (Ia), or (Ia*) and optionally one or more pharmaceutically acceptable excipients, and

[0352] • A second pharmaceutical composition or dosage form comprising another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0353] In one aspect, the kit includes a third pharmaceutical composition or dosage form that still contains another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0354] Medical Uses - Treatment Methods

[0355] Indications - Patient Population

[0356] This invention is primarily aimed at RAS G12C inhibitors, particularly compounds of formulas (I), (I*), (Ia), and (Ia*) (including all embodiments thereof), which may be useful for the treatment and / or prevention of diseases and / or conditions mediated by RAS G12C mutations (e.g., and preferably KRAS G12C, NRAS G12C, and HRAS G12C).

[0357] Therefore, in another aspect, the present invention relates to compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof, for use as pharmaceuticals.

[0358] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof for use in a method of treating a human or animal body.

[0359] In another aspect, the present invention relates to compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof for the treatment and / or prevention of diseases and / or conditions mediated by RAS G12C mutations.

[0360] In another aspect, the present invention relates to the use of compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating and / or preventing diseases and / or conditions mediated by RAS G12C mutations.

[0361] In another aspect, the present invention relates to a method for treating and / or preventing diseases and / or conditions mediated by RAS G12C mutations, the method comprising administering to a person a therapeutically effective amount of a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof.

[0362] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of cancer.

[0363] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof for use in methods of treating and / or preventing cancer in a human or animal body.

[0364] In another aspect, the present invention relates to the use of compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating and / or preventing cancer.

[0365] In another aspect, the present invention relates to a method for treating and / or preventing cancer, the method comprising administering to a person a therapeutically effective amount of a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof.

[0366] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof for providing inhibition of G12C mutant RAS.

[0367] In another aspect, the present invention relates to the use of compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof in the manufacture of medicaments for providing inhibition of G12C mutant RAS.

[0368] In another aspect, the present invention relates to a method for providing inhibition of G12C mutant RAS, the method comprising administering to a human a therapeutically effective amount of a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof.

[0369] On the other hand, it is based on identifying the link between a patient's G12C mutation status and potential sensitivity to treatment with compounds of formula (I), (I*), (Ia), or (Ia*). RAS G12C inhibitors, such as compounds of formula (I), (I*), (Ia), or (Ia*), can subsequently be advantageously used to treat patients with KRAS G12C, HRAS G12C, or NRAS G12C mutations who may be resistant to other therapies. Therefore, this provides opportunities, methods, and tools for selecting patients (particularly cancer patients) for treatment with compounds of formula (I), (I*), (Ia), or (Ia*). This selection is based on whether the tumor cells to be treated have wild-type or G12C-mutated KRAS, HRAS, or NRAS genes. The G12C KRAS, HRAS, or NRAS gene status can therefore be used as a biomarker to indicate that treatment with compounds of formula (I), (I*), (Ia), or (Ia*) may be advantageous.

[0370] According to one aspect, a method is provided for selecting a patient to be treated with a compound of formula (I), (I*), (Ia), or (Ia*), the method comprising:

[0371] • Provide samples containing tumor cells from the patient;

[0372] • Determine whether the RAS gene in the patient's tumor cell sample encodes wild-type (glycine 12) or mutant (cysteine ​​12) KRAS, HRAS, or NRAS proteins; and

[0373] Based on this, patients are selected to be treated with compounds of formula (I), (I*), (Ia), or (Ia*).

[0374] The method may or may not include actual patient sample separation steps.

[0375] In one aspect, if the tumor cell DNA has a G12C-mutated KRAS gene, the patient is selected to be treated with a compound of formula (I), (I*), (Ia), or (Ia*).

[0376] On the other hand, if the tumor cell DNA has a G12C-mutated HRAS gene, the patient is selected to be treated with a compound of formula (I), (I*), (Ia), or (Ia*).

[0377] On the other hand, if the tumor cell DNA has a G12C-mutated NRAS gene, the patient is selected to be treated with a compound of formula (I), (I*), (Ia), or (Ia*).

[0378] According to another aspect, compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof are provided for the treatment of cancers with tumor cells carrying the G12C-mutant RAS gene.

[0379] According to another aspect, compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof are provided for the treatment of cancers with tumor cells carrying the G12C-mutant KRAS gene.

[0380] According to another aspect, compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof are provided for the treatment of cancers with tumor cells carrying the G12C-mutant HRAS gene.

[0381] According to another aspect, compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof are provided for the treatment of cancers with tumor cells carrying the G12C-mutated NRAS gene.

[0382] According to another aspect, a method for treating cancer with tumor cells carrying a G12C-mutated RAS gene is provided, the method comprising administering to a human an effective amount of a compound of formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof.

[0383] According to another aspect, a method for treating cancer with tumor cells carrying G12C-mutated KRAS, HRAS, or NRAS genes is provided, the method comprising administering an effective amount of a compound of formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof.

[0384] Determining whether a tumor or cancer contains G12C KRAS, HRAS, or NRAS mutations can be done by evaluating the nucleotide sequence encoding the KRAS, HRAS, or NRAS protein, by evaluating the amino acid sequence of the KRAS, HRAS, or NRAS protein, or by evaluating the characteristics of a putative KRAS, HRAS, or NRAS mutant protein. Wild-type human KRAS, HRAS, or NRAS sequences are known in the art. Methods for detecting mutations in the KRAS, HRAS, or NRAS nucleotide sequences are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting assay, and microarray analysis. In some embodiments, G12C KRAS, HRAS, or NRAS mutations in a sample are evaluated by real-time PCR. In real-time PCR, fluorescent probes specific to KRAS, HRAS, or NRASG12C mutations are used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRAS, HRAS, or NRAS G12C mutations are identified using direct sequencing of specific regions (e.g., exon 2 and / or exon 3) in the KRAS, HRAS, or NRAS genes. This technique will identify all possible mutations in the sequencing region. Methods for detecting mutations in KRAS, HRAS, or NRAS proteins are known to those skilled in the art. These methods include, but are not limited to, using binding agents specific to mutant proteins (e.g., antibodies), protein electrophoresis, Western blotting, and direct peptide sequencing to detect KRAS, HRAS, or NRAS mutants.

[0385] Methods for determining whether a tumor or cancer contains G12C KRAS, HRAS, or NRAS mutations can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed into cell lysate. In some embodiments, the sample is processed into DNA or RNA. In some embodiments, the sample is a liquid biopsy, and the test is performed on a blood sample to look for circulating tumor cancer cells in the blood or DNA fragments from tumor cells in the blood.

[0386] Based on the methods and uses defined and disclosed herein (above and below), a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof is used to treat / prevent diseases / conditions / cancers / tumors / cancer cells selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, appendiceal cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

[0387] On the other hand, according to the methods and uses defined and disclosed herein (above and below), a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof is used to treat / prevent diseases / conditions / cancers / tumors / cancer cells selected from pancreatic cancer, lung cancer (preferably non-small cell lung cancer (NSCLC)), cholangiocarcinoma and colorectal cancer.

[0388] Particularly preferred, the cancer to be treated / prevented by a compound of formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, according to the methods and uses defined and disclosed herein (above and below), is selected from:

[0389] • Lung adenocarcinoma carrying the KRAS G12C mutation (preferably non-small cell lung cancer (NSCLC));

[0390] • Colorectal adenocarcinoma carrying the KRAS G12C mutation;

[0391] • Pancreatic cancer carrying the KRAS G12C mutation (preferably pancreatic ductal adenocarcinoma (PDAC)).

[0392] Additionally, the following cancers, tumors, and other proliferative diseases can be treated with compounds of formula (I), (I*), (Ia), or (Ia*) or their pharmaceutically acceptable salts – but are not limited thereto. Preferably, the treatment methods, approaches, uses, compounds for said uses, and pharmaceutical compositions for said uses as disclosed herein (above and below) are applied to treat diseases / conditions / cancers / tumors (i.e., the corresponding cells) carrying RAS G12C mutations (preferably KRAS G12C mutations) or identified as carrying RAS G12C mutations (preferably KRAS G12C mutations) as described and / or mentioned herein:

[0393] Cancers / tumors / cancers of the head and neck: for example, tumors / cancers / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, retromolar triangle, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including floor of tongue, tonsils, tonsillar column, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including superior larynx, glottis, subglottis, vocal cords), hypopharynx, and salivary glands (including minor salivary glands);

[0394] Lung cancers / tumors / carcinomas: for example, non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioloalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma);

[0395] Mediastinal vegetations include, for example, neurogenic tumors (including neurofibroma, schwannoma, malignant schwannoma, neurosarcoma, ganglioneuroma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminomatous tumor), thymic tumors (including thymoma, thymic lipoma, thymic carcinoma, thymic carcinoid), and mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymal tumor, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, and lymphangiomyoma).

[0396] Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: such as esophageal, stomach (gastric cancer), pancreas, liver and biliary tract cancers / tumors / carcinomas (including hepatocellular carcinoma (HCC), such as childhood HCC, fibrolamellar HCC, mixed HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocarcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gallbladder, extrahepatic bile ducts, small intestine (including Tumors / cancers of the duodenum, jejunum, ileum, large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stromal tumor (GIST)), genitourinary system (including kidneys, such as renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms tumor), adrenoid tumor, Grawitz tumor; ureter; bladder, such as urachal carcinoma, urothelial carcinoma; urethra, such as distal, bulbar, prostatic; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-resistant), penis);

[0397] Testicular cancer / tumor / carcinoma: such as seminoma, non-seminomatous tumor,

[0398] Gynecological cancers / tumors / cancers: for example, tumors / cancers / cancers of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, and uterine body (including endometrium and basal layer);

[0399] Breast cancers / tumors / carcinomas: such as breast cancer (invasive ductal, colloidal, lobular, tubular, cystic, mastoid, medullary, mucinous), hormone receptor-positive breast cancer (estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer), Her2-positive breast cancer, triple-negative breast cancer, Paget's breast disease.

[0400] Cancers / tumors / cancers of the endocrine system: such as the following tumors / cancers / cancers: endocrine glands, thyroid gland (thyroid cancer / tumor; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma / tumor), adrenal cortex (adrenocortical carcinoma / tumor), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumor, paraganglionic gland, pancreatic endocrine tumors (PET; non-functional PET, pancreatic polypeptide tumor, gastrinoma, insulinoma, vasodilator intestinal peptide tumor, glucagonoma, somatostatinoma, growth hormone releasing factor tumor, adrenocorticotropic hormone tumor), carcinoid tumors;

[0401] Soft tissue sarcomas: such as fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumors of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroma, neuroepithelial tumor, extraosseous Ewing's sarcoma, paraganglioma, extraosseous chondrosarcoma, extraosseous osteosarcoma, mesenchymal tumor, alveolar soft tissue sarcoma, epithelioid sarcoma, extrarenal rhabdomyosarcoma, and desmoplastic small cell tumors;

[0402] Osteosarcoma: such as myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including periosteal, periosteal, highly malignant surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, ameloblastoma, (fibro) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma;

[0403] Mesothelioma: For example, pleural mesothelioma, peritoneal mesothelioma;

[0404] Skin cancers: such as basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial, malignant freckle-like nevus, acral freckle-like nevus, nodular, intraocular melanoma), actinic keratosis, and eyelid cancer;

[0405] Central nervous system and brain vegetations: for example, astrocytomas (cerebral, cerebellar, diffuse, fibrotic, anaplastic, pilocytic, protoplasmic, thrombocytic), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, gangliocytoma, neuroblastoma, retinoblastoma, schwannoma (e.g., auditory), spinal cord axis tumors;

[0406] Lymphomas and leukemias: For example, B-cell non-Hodgkin lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt lymphoma (BL)), T-cell non-Hodgkin lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytomas, chronic B-cell lymphoblastic leukemia (B-CLL), chronic T-cell lymphoblastic leukemia (T-CLL), B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTCL) LC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-dominant HD (NLPHD), tuberous sclerosis HD (NSHD), mixed cellular HD (MCHD), lymphocyte-rich classical HD, lymphocyte-depleted HD (LDHD)), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid / myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myeloid / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML);

[0407] Cancer of unknown origin (CUP);

[0408] The aforementioned characteristics refer to all cancers / tumors / carcinomas that originate from a specific location in the body, and are intended to include both primary tumors and metastatic tumors derived from them.

[0409] All of the above cancers / tumors / carcinomas can be further distinguished by their histopathological classification:

[0410] Epithelial cancers, such as squamous cell carcinoma (SCC) (carcinoma in situ, superficial invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signetron cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); eosinophilic carcinoma;

[0411] Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematologic malignancies, mixed and undifferentiated carcinomas;

[0412] The compounds of the present invention can be used in treatment regimens in the context of first-line, second-line, or any other line of treatment.

[0413] The compounds of the present invention can be used for the prevention, short-term or long-term treatment of the aforementioned diseases / conditions / cancer / tumors, and optionally in combination with radiotherapy and / or surgery.

[0414] The treatments, methods, uses, and compounds for said uses disclosed herein (above and below) may be performed with any compound of formula (I), (I*), (Ia), or (Ia*) as disclosed or defined herein, or with any pharmaceutical composition or kit comprising a compound of formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof (each comprising all individual embodiments or a common subset of compound (I), (I*), (Ia), or (Ia*)).

[0415] Combination therapy

[0416] Compounds of formula (I), (I*), (Ia), or (Ia*) or their pharmaceutically acceptable salts, as well as pharmaceutical compositions containing such compounds and salts, may also be used in combination with other pharmacologically active substances (e.g., with other antitumor compounds (e.g., chemotherapy)) or with other treatments (e.g., radiotherapy or surgical intervention, as adjuvant therapy before or after surgery). Preferably, one or more of the co-administered pharmacologically active substances are one or more antitumor compounds.

[0417] Therefore, in another aspect, the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof for use as defined above, wherein the compound is administered before, after or together with one or more other pharmacologically active substances.

[0418] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof for use as defined above, wherein the compound is administered in combination with one or more other pharmacologically active substances.

[0419] In another aspect, the present invention relates to the use of compounds of formula (I), (I*), (Ia) or (Ia*) as defined above, or pharmaceutically acceptable salts thereof, wherein the compounds are administered before, after or together with one or more other pharmacologically active substances.

[0420] In another aspect, the present invention relates to a method as defined above (e.g., a method of treatment and / or prevention) wherein a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof is administered before, after or together with a therapeutically effective amount of one or more other pharmacologically active substances.

[0421] In another aspect, the present invention relates to a method as defined above (e.g., a method of treatment and / or prevention) wherein a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of one or more other pharmacologically active substances.

[0422] In another aspect, the present invention relates to a method for treating and / or preventing cancer, the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof is administered simultaneously, concurrently, sequentially, successively, alternately, or alone with the one or more other pharmacologically active substances.

[0423] In another aspect, the present invention relates to a method for treating and / or preventing cancer, the method comprising administering to a patient in need a therapeutically effective amount of a RAS G12C inhibitor (preferably a KRAS G12C inhibitor) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the RAS G12C inhibitor (preferably a KRASG12C inhibitor) or a pharmaceutically acceptable salt thereof is administered in combination with the one or more other pharmacologically active substances.

[0424] In another aspect, the present invention relates to compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof for the treatment and / or prevention of cancer, wherein the compounds of formula (I), (I*), (Ia) or (Ia*) or pharmaceutically acceptable salts thereof are administered simultaneously, concurrently, sequentially, successively, alternately or alone with one or more other pharmacologically active substances.

[0425] In another aspect, the present invention relates to a RAS G12C inhibitor (preferably a KRAS G12C inhibitor) or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of cancer, wherein the RAS G12C inhibitor (preferably a KRAS G12C inhibitor) or a pharmaceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0426] In another aspect, the present invention relates to a kit comprising...

[0427] • A first pharmaceutical composition or dosage form comprising a compound of formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, and

[0428] • A second pharmaceutical composition or dosage form comprising another pharmacologically active substance, optionally one or more pharmaceutically acceptable excipients.

[0429] For the treatment and / or prevention of cancer, wherein the first pharmaceutical composition is to be administered simultaneously, concurrently, sequentially, successively, alternately, or alone with the second and / or other pharmaceutical compositions or dosage forms.

[0430] In one aspect, such a kit for the said purpose comprises a third pharmaceutical composition or dosage form, which still comprises another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0431] In another embodiment of the invention, components (i.e., combined couples) of the combination, kit, use, method and compound (including all embodiments) according to the invention are applied simultaneously.

[0432] In another embodiment of the invention, components (i.e., combined couples) of the combination, kit, use, method and compound (including all embodiments) according to the invention are applied in parallel.

[0433] In another embodiment of the invention, components (i.e., combination couples) of the combination, kit, use, method and compound (including all embodiments) according to the invention are applied sequentially.

[0434] In another embodiment of the invention, components (i.e., combination couples) of the combination, kit, use, method and compound (including all embodiments) according to the invention are applied sequentially.

[0435] In another embodiment of the invention, components (i.e., combination couples) of the combination, kit, use, method and compound (including all embodiments) according to the invention are applied alternately.

[0436] In another embodiment of the invention, components (i.e., combination couples) of the combination, kit, use, method and compound (including all embodiments) according to the invention are applied individually.

[0437] One or more pharmacologically active substances used together or in combination with a RAS G12C inhibitor (preferably a KRAS G12C inhibitor) and / or with a compound of formula (I), (I*), (Ia) or (Ia*) or a pharmaceutically acceptable salt thereof (including all individual embodiments or common subsets of compounds (I), (I*), (Ia) or (Ia*)) or in medical uses, applications, treatments and / or preventive methods as defined herein (above and below) may be selected from any one or more of the following (preferably, one or two additional pharmacologically active substances are used in all such embodiments):

[0438] 1. Inhibitors of EGFR and / or ErbB2 (HER2) and / or ErbB3 (HER3) and / or ErbB4 (HER4) or any mutant thereof.

[0439] a. Irreversible inhibitors: for example, afatinib, dacomitinib, cannatinib, neratinib, avitinib, poziotinib, AV 412, PF-6274484, HKI 357, omamotinib, osimertinib, ametinib, nazatinib, lazatinib, pelitinib;

[0440] b. Reversible inhibitors: for example, erlotinib, gefitinib, icotinib, sapitinib, lapatinib, varitinib, vandetanib, TAK-285, AEE788, BMS599626 / AC-480, GW 583340;

[0441] c. Anti-EGFR antibodies: for example, nexituzumab, panitumumab, cetuximab, ervantuzumab;

[0442] d. Anti-HER2 antibodies: for example, pertuzumab, trastuzumab, trastuzumab emtansine;

[0443] e. Inhibitors of mutated EGFR;

[0444] f. Inhibitors of HER2 with exon 20 mutations;

[0445] g. The preferred irreversible inhibitor is afatinib;

[0446] h. The preferred anti-EGFR antibody is cetuximab.

[0447] 2. Inhibitors of MEK and / or its mutants

[0448] a. For example, trametinib, cobimetinib, bimetinib, sermetinib, remmetinib, BI 3011441;

[0449] b. Trametinib and BI 3011441 are preferred;

[0450] c. The optimal choice is BI 3011441;

[0451] MEK inhibitors disclosed in d.WO 2013 / 136249;

[0452] MEK inhibitors disclosed in e.WO 2013 / 136254

[0453] 3. Inhibitors of SOS1 and / or any mutant thereof (i.e., compounds that regulate / inhibit the GEF function of SOS1, for example by binding to SOS1 and preventing protein-protein interactions between SOS1 and (mutated) Ras proteins such as KRAS)

[0454] a. For example, BAY-293, BI-3406, BI 1701963;

[0455] b. BI-3406 and BI 1701963 are preferred;

[0456] c. The optimal choice is BI 1701963;

[0457] The SOS1 inhibitor disclosed in d.WO 2018 / 115380;

[0458] SOS1 inhibitors disclosed in e.WO 2019 / 122129;

[0459] SOS1 inhibitors disclosed in f.WO 2020 / 180768, WO 2020 / 180770, WO 2018 / 172250 and WO 2019 / 201848.

[0460] 4. Oncolytic virus

[0461] 5. RAS vaccine

[0462] a. For example, TG02 (Targovax).

[0463] 6. Cell cycle inhibitors

[0464] a. For example, inhibitors of CDK4 / 6 and / or any mutants thereof

[0465] i. For example, palbocicini, ribocicini, abecili, trilasicil, PF-06873600;

[0466] ii. Palbocicini and Abecili are preferred;

[0467] iii. The preferred choice is abecili.

[0468] b. For example, periwinkle alkaloids

[0469] i. For example, Changchun Ruibin.

[0470] c. For example, inhibitors of aurora kinase and / or any mutant thereof.

[0471] i. For example, alleseltidine, bareseltidine.

[0472] 7. Inhibitors of PTK2 (= FAK) and / or any of its mutants.

[0473] a. For example, TAE226, BI 853520.

[0474] 8. Inhibitors of SHP2 and / or any of its mutants

[0475] a. For example, SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

[0476] 9. Inhibitors of PI3 kinase (= PI3K) and / or any mutant thereof

[0477] a. For example, inhibitors of PI3Kα and / or any mutant thereof.

[0478] i. For example, apelix, celeris, GDC-0077, HH-CYH33, AMG 511, bupalis, datolis, pitilis, taceleris.

[0479] 10. Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or any mutant thereof

[0480] a. For example, ponatinib, infigliatinib, nintedanib.

[0481] 11. Inhibitors of AXL and / or any of its mutants

[0482] 12. Taxane

[0483] a. For example, paclitaxel, nab-paclitaxel, docetaxel;

[0484] b. Paclitaxel is preferred.

[0485] 13. Platinum-containing compounds

[0486] a. For example, cisplatin, carboplatin, oxaliplatin

[0487] b. Oxaliplatin is preferred.

[0488] 14. Antimetabolites

[0489] a. For example, a combination of 5-fluorouracil, capecitabine, fluorouridine, cytarabine, gemcitabine, pemetrexed, trifluorouridine, and tepirapillin (= TAS102).

[0490] b. 5-Fluorouracil is preferred.

[0491] 15. Immunotherapy agents

[0492] a. For example, immune checkpoint inhibitors

[0493] i. For example, anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, and anti-TIM3 mAb;

[0494] ii. Preferably, it is PD1 mAb-resistant;

[0495] iii. For example, ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, averuzumab, duvalumab, pidocilizumab, PDR-001 (=spartazumab), AMG-404, ebbenlizumab;

[0496] iv. Preferred are nivolumab, pembrolizumab, ebbenlimumab and PDR-001 (=spartazumab);

[0497] v. The preferred options are ebbenlimumab, pembrolizumab, and nivolumab.

[0498] 16. Topoisomerase inhibitors

[0499] a. For example, irinotecan, liposomal irinotecan (nal-IRI), topotecan, etoposide;

[0500] b. Irinotecan and liposomal irinotecan (nal-IRI) are the preferred options.

[0501] 17. Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or any mutant thereof

[0502] a. For example, entarafenib, dabrafenib, verafenib, PLX-8394, RAF-709 (= Example 131 in WO 2014 / 151616), LXH254, sorafenib, LY-3009120 (= Example 1 in WO 2013 / 134243), riferafenib, TAK-632, agorafenib, CCT196969, RO5126766, RAF265.

[0503] 18. Inhibitors of mTOR

[0504] a. For example, rapamycin, tamsurolimus, everolimus, liromolimus, zoromolimus, sapaserte, Torin 1, datolis, GDC-0349, VS-5584, vetoserte, AZD8055.

[0505] 19. Epigenetic regulators

[0506] a. For example, BET inhibitors

[0507] i. For example, JQ-1, GSK 525762, OTX-015, CPI-0610, TEN-010, OTX-015, PLX51107, ABBV-075, ABBV-744, BMS986158, TGI-1601, CC-90010, AZD5153, I-BET151, BI 894999;

[0508] ii. The preferred one is BI 894999.

[0509] 20. Inhibitors of IGF1 / 2 and / or IGF1-R and / or any mutant thereof

[0510] a. For example, talutuzumab (antibody 60833 in WO 2010 / 066868), MEDI-573 (= talutuzumab), and linstatinib.

[0511] 21. Inhibitors of Src family kinases and / or any mutants thereof

[0512] a. For example, inhibitors of SrcA subfamily kinases and / or any mutants thereof, namely inhibitors of Src, Yes, Fyn, Fgr and / or any mutants thereof;

[0513] b. For example, inhibitors of SrcB subfamily kinases and / or any mutants thereof, namely inhibitors of Lck, Hck, Blk, Lyn and / or any mutants thereof;

[0514] c. For example, inhibitors of Frk subfamily kinases and / or any mutants thereof, i.e., inhibitors of Frk and / or any mutants thereof;

[0515] d. For example, dasatinib, ponatinib, bosutinib, vandetanib, KX-01, sacatinib, KX2-391, SU6656, WH-4-023.

[0516] 22. Apoptosis regulators

[0517] a. For example, an inhibitor of the interaction between MDM2 inhibitors, such as p53 (preferably functional p53, most preferably wt p53), and MDM2 and / or any mutant thereof;

[0518] i. For example, HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115, BI 907828;

[0519] ii. Preferably, HDM-201, RG-7388, AMG-232 and BI 907828 are used;

[0520] iii. The optimal choice is BI 907828;

[0521] The MDM2 inhibitor disclosed in iv.WO 2015 / 155332;

[0522] The MDM2 inhibitor disclosed in v.WO 2016 / 001376;

[0523] The MDM2 inhibitor disclosed in vi.WO 2016 / 026937;

[0524] vii.WO 2017 / 060431 disclosed the MDM2 inhibitor;

[0525] b. For example, PARP inhibitors;

[0526] c. For example, MCL-1 inhibitors;

[0527] i. For example, AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477;

[0528] 23. Inhibitors of c-MET and / or any of its mutants

[0529] a. For example, cevotinib, cabozantinib, and furitinib;

[0530] b. MET antibodies, such as imatozumab and ervantuzumab;

[0531] 24. Inhibitors of ERK and / or any of its mutants

[0532] a. For example, uroritinib, LTT462;

[0533] 25. Inhibitors of farnesyltransferase and / or any mutant thereof

[0534] a. For example, telpifab;

[0535] In further embodiments of the (combination) uses and methods described above (e.g., treatment and / or prevention methods), an additional pharmacologically active substance is administered before, after, or together with a compound of formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, wherein said additional pharmacologically active substance is

[0536] • SOS1 inhibitors; or

[0537] ·BI 1701963; or

[0538] MEK inhibitors; or

[0539] Trametinib, or

[0540] ·BI 3011441; or

[0541] • Anti-PD-1 antibody; or

[0542] • Ebenemlimab; or

[0543] • Cetuximab; or

[0544] Afatinib; or

[0545] • Standard of care (SoC) for a given indication; or

[0546] • PI3 kinase inhibitor.

[0547] In further embodiments of the (combination) uses and methods (e.g., treatment and / or prevention methods) described above, an additional pharmacologically active substance is administered in combination with a compound of formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, wherein said additional pharmacologically active substance is

[0548] • SOS1 inhibitors; or

[0549] ·BI 1701963; or

[0550] MEK inhibitors; or

[0551] Trametinib; or

[0552] ·BI 3011441; or

[0553] • Anti-PD-1 antibody; or

[0554] • Ebenemlimab; or

[0555] • Cetuximab; or

[0556] Afatinib; or

[0557] • Standard of care (SoC) for a given indication; or

[0558] • PI3 kinase inhibitor.

[0559] In another aspect of the (combination) uses and methods described above (e.g., treatment and / or prevention methods), two other pharmacologically active substances are administered before, after, or together with a compound of formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, wherein said two other pharmacologically active substances are

[0560] • MEK inhibitors (preferably BI 3011441) and SOS1 inhibitors (preferably BI 1701963); or

[0561] Trametinib and an SOS1 inhibitor (preferred BI 1701963); or

[0562] • Anti-PD-1 antibody (preferably ebendimab) and anti-LAG-3 antibody; or

[0563] • Anti-PD-1 antibody (preferably ebumab) and SOS1 inhibitor (preferably BI 1701963); or

[0564] • MEK inhibitors (preferably BI 3011441) and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0565] • SOS1 inhibitors (preferably BI 1701963) and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0566] • MEK inhibitors (preferably BI 3011441) and afatinib; or

[0567] • MEK inhibitors (preferably BI 3011441) and cetuximab; or

[0568] Trametinib and afatinib; or

[0569] Trametinib and cetuximab; or

[0570] • SOS1 inhibitors (preferably BI 1701963) and afatinib; or

[0571] • SOS1 inhibitors (preferably BI 1701963) and cetuximab.

[0572] In another aspect of the (combination) uses and methods described above (e.g., treatment and / or prevention methods), two other pharmacologically active substances are administered in combination with a compound of formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, wherein said two other pharmacologically active substances are

[0573] • MEK inhibitors (preferably BI 3011441) and SOS1 inhibitors (preferably BI 1701963); or

[0574] Trametinib and SOS1 inhibitors (preferred BI 1701963); or

[0575] • Anti-PD-1 antibody (preferably ebendimab) and anti-LAG-3 antibody; or

[0576] • Anti-PD-1 antibody (preferably ebumab) and SOS1 inhibitor (preferably BI 1701963); or

[0577] • MEK inhibitors (preferably BI 3011441) and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0578] • SOS1 inhibitors (preferably BI 1701963) and inhibitors selected from: EGFR inhibitors and / or ErbB2 (HER2) inhibitors and / or inhibitors of any mutant thereof; or

[0579] • MEK inhibitors (preferably BI 3011441) and afatinib; or

[0580] • MEK inhibitors (preferably BI 3011441) and cetuximab; or

[0581] Trametinib and afatinib; or

[0582] Trametinib and cetuximab; or

[0583] • SOS1 inhibitors (preferably BI 1701963) and afatinib; or

[0584] • SOS1 inhibitors (preferably BI 1701963) and cetuximab.

[0585] It can also be used with compounds of formula (I), (I*), (Ia), or (Ia*) or their pharmaceutically acceptable salts (including compounds (I), (I*), (Ia), or (Ia*). All individual implementations or common subsets of substances used together / in combination or for medical purposes, uses, treatments and / or preventive methods as defined herein (above and below) include, but are not limited to: hormones, hormone analogs and anti-hormonal drugs (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilumethoxazole, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buterlein acetate, fludrocortisone, fluorometholone, medroxyprogesterone acetate, octreotide), aromatase inhibitors (e.g., anastrozole, letrozole, liazol, voroxyzole, exemestane, atamitan), LHRH agonists and antagonists (e.g., acetoselenoline, leuprolide), growth factors and / or their corresponding receptor inhibitors (growth factors such as platelet-derived growth factor (PDGF), fibroblasts, etc.). Growth factors (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, such as HER2, HER3, HER4), and hepatocyte growth factor (HGF) and / or their corresponding receptors; inhibitors are, for example, (anti) growth factor antibodies, (anti) growth factor receptor antibodies, and tyrosine kinase inhibitors, such as cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, and trastuzumab; antimetabolites (e.g., antifolate drugs such as methotrexate, raltitrexed), pyrimidine analogs (such as 5-fluorouracil (5-FU)), ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs (such as mercaptopurine, thioguanine, cladribine, and pentostatin), cytarabine (ara C), fludarabine); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, doxil (polyethylene glycol liposomal doxorubicin hydrochloride, myocet (non-polyethylene glycol liposomal doxorubicin), donomycin, epirubicin and idarubicin, mitomycin C, bleomycin, styromycin, procainamide, streptozotocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estradiol, nitrogen mustard, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustine and lomustine, thiotepa); antimitotic agents (e.g., vinca alkaloids such as vincaine, vindesine, vinorelbine and vincristine; and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g., taquimod), microtubule inhibitors;DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g., PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK inhibitors). 1. Inhibitors, including CDK inhibitors, aurora kinase inhibitors, tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP inhibitors / SMAC mimics, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors (e.g., venetumola), Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, and rapamycin analogs (e.g., everolimus, tesimolimus, desfolimex, sirolimus). Magnetic drugs, androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors (e.g., carfilzomib), immunotherapeutic agents (such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins, such as ipilimumab, nivolumab, pembrolizumab), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T-cell conjugates (e.g., bispecific T-cell conjugates (BiTEs®, such as CD33...)). [x BCMA, CD3 x CD33, CD3 x CD19, PSMA x CD3], tumor vaccines, and various chemotherapy agents (such as amifostine, anagrelate, clodronat, filsildenafil, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesone sodium, mitotane, pamidronate disodium, and porphyrin sodium).

[0586] It should be understood that the combinations, compositions, kits, methods, uses, or compounds for said uses according to the present invention are contemplated for simultaneous, parallel, sequential, successive, alternating, or individual administration of the active ingredients or components. It should be understood that compounds of formula (I), (I*), (Ia), or (Ia*) or their pharmaceutically acceptable salts, together with one or more other pharmacologically active substances, can be formulated for administration dependently or independently; for example, compounds of formula (I), (I*), (Ia), or (Ia*) or their pharmaceutically acceptable salts, together with one or more other pharmacologically active substances, can be administered as part of the same pharmaceutical composition / dosage form, or preferably as separate pharmaceutical compositions / dosage forms.

[0587] In this context, the term "combination" or "combined" within the meaning of this invention includes, but is not limited to, products resulting from a mixture or combination of more than one active ingredient, and includes fixed and non-fixed (e.g., free) combinations (including kits) and uses, such as simultaneous, parallel, sequential, successive, alternating, or individual use of components or ingredients. The term "fixed combination" means that the active ingredient is administered to a patient as a single entity or dose. The term "non-fixed combination" means that the active ingredient is administered to a patient simultaneously, in parallel, or sequentially as a single entity without a specific time limit, wherein such administration provides a therapeutically effective level of the compound in the patient.

[0588] The application of a compound of formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, along with one or more other pharmacologically active substances, may be performed by co-application of the active ingredient or component, for example, by simultaneous or concurrent application of them in a single or two or more separate formulations or dosage forms. Alternatively, the application of a compound of formula (I), (I*), (Ia), or (Ia*) or a pharmaceutically acceptable salt thereof, along with one or more other pharmacologically active substances, may be performed by sequential or alternating application of the active ingredient or component, for example, by application of two or more separate formulations or dosage forms.

[0589] For example, simultaneous administration includes substantially simultaneous administration. This form of administration may also be referred to as “concomitant” administration. Parallel administration includes administering the active agent within the same general time period, such as on the same day or multiple days, but not necessarily at the same time. Alternating administration includes administering one agent within a time period, such as over several days or a week, followed by administering another one or more agents within a subsequent time period, such as over several days or a week, and then repeating the pattern one or more cycles. Sequential or successive administration includes administering one agent at one or more doses within a first time period (such as over several days or a week), followed by administering another one or more agents at one or more doses within a second and / or additional time period (such as over several days or a week). Overlapping schedules may also be used, which include administering the active agent on different dates during treatment, not necessarily in a regular order. Variations of these general guidelines may also be used, for example, depending on the reagents used and the condition of the subject.

[0590] definition

[0591] Terms not specifically defined herein should be given their meaning by those skilled in the art based on the published text and context. However, as used in the specification, unless otherwise specified, the following terms have indicative meanings and follow the conventions outlined below:

[0592] Where x and y each represent the prefix C of positive integers (x < y). x-y The indication of use is to directly associate the specified and mentioned chain or ring structure or combination of chain and ring structures as a whole with a maximum of y and a minimum of x carbon atoms.

[0593] The indication of the number of members in a group containing one or more heteroatoms (e.g., heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl) refers to the total number of atoms of all ring members or the sum of all ring and carbon chain members.

[0594] The indication of the number of carbon atoms in a group consisting of a combination of carbon chains and carbon ring structures (e.g., cycloalkylalkyl, arylalkyl) involves the total number of carbon atoms in all carbon ring and carbon chain members. Clearly, ring structures have at least three members.

[0595] Typically, for groups containing two or more daughter groups (e.g., heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, arylalkyl), the last named daughter group is the group attachment point, for example, aryl-C 1-6 Alkyl substituents refer to aryl groups and C 1-6 An alkyl-bonded group, which is bonded to a core or to a group to which the substituent is attached.

[0596] In groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, or similar compounds, a person skilled in the art can discern the attachment sites to one or more groups of the molecule from the free valence of the group itself.

[0597] alkyl This indicates a monovalent saturated hydrocarbon chain, which can exist in both straight (unbranched) and branched forms. If the alkyl group is substituted, the substitution can occur independently of each other on all hydrogen-carrying carbon atoms by mono- or poly-substitution in each case.

[0598] Term "C" 1-5 Alkyl groups include, for example, H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0599] Other examples of alkyl groups are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (i-Pr; isopropyl; -CH(CH3)2), 1-butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-1-propyl (isobutyl; i-Bu; -CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl; t-Bu; -C(CH3)3), 1-pentyl (n-... pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 3-methyl-1-butyl (isopentyl (-CH2CH2CH(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(CH 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.

[0600] Without further definition, the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., refer to saturated hydrocarbon groups having the corresponding number of carbon atoms, including all isomers.

[0601] If the alkyl group is another (combined) group, such as C x-y Alkylamino or C x-y If it is part of an alkyloxy group, then the above definition for alkyl also applies.

[0602] the term Alkylene It can also be derived from alkyl groups. Alkylenes are divalent, unlike alkyl groups, and require two bonding partners. Formally, the divalent form is produced by removing a hydrogen atom from the alkyl group. The corresponding groups are, for example, -CH3 and -CH2-, -CH2CH3 and -CH2CH2-, or >CHCH3, etc.

[0603] Term "C" 1-4Alkyl groups include, 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)-.

[0604] Other examples of alkylene compounds are methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene, etc.

[0605] Without further definition, the general terms propylidene, butylidene, pentylene, hexylidene, etc., refer to all conceivable isomers having the corresponding number of carbon atoms, i.e., propylidene includes 1-methylethylidene, and butylidene includes 1-methylpropylidene, 2-methylpropylidene, 1,1-dimethylethylidene, and 1,2-dimethylethylidene.

[0606] If the alkylene group is part of another (combined) group, such as in HO-C x-y alkylene amino or H2N-C x-y In the case of alkylene oxides, the above definition for alkylene oxides also applies.

[0607] Unlike alkyl groups, alkenyl It consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are connected together by a C-C double bond, and each carbon atom can 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 formally removed and their free valences are saturated to form a second bond, then the corresponding alkenyl group is formed.

[0608] Examples of alkenyl groups include vinyl, propenyl, allyl (propenyl-2-enyl), isopropenyl, butenyl, butenyl, butenyl, butenyl, 2-methyl-propenyl, 2-methyl-propenyl, 1-methyl-propenyl, 1-methyl-propenyl, 1-methylenepropyl, pentenyl, pentenyl, pentenyl, pentenyl, pentenyl, pentenyl, pentenyl, pentenyl, pentenyl, pentenyl, 3-methyl-butenyl, 3-methyl-butenyl -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, hex-1,3-dienyl, hex-1,4-dienyl, pent-1,4-dienyl, pent-1,3-dienyl, but-1,3-dienyl, 2,3-dimethylbut-1,3-diene, etc.

[0609] Without further definition, the general terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, hepadienyl, octadienyl, nonadienyl, decanadienyl, etc., refer to all conceivable isomers having the corresponding number of carbon atoms. That is, propenyl includes prop-1-enyl and prop-2-enyl, and butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, etc.

[0610] With respect to one or more double bonds, the alkenyl group may optionally be present in cis or trans or E or Z orientation.

[0611] When the alkenyl group is part of another (combined) group, such as in C x-y alkenylamino or C x-y When the alkenyloxy group is present, the above definition for alkenyl also applies.

[0612] Unlike alkylene groups, imide It consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are connected together by a C-C double bond, and each carbon atom can be part of a 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 their free valences are saturated to form a second bond, then the corresponding alkenyl group is formed.

[0613] Examples of alkenyl groups include vinylidene, propenyl, 1-methylvinylidene, butenyl, 1-methylpropenyl, 1,1-dimethylvinylidene, 1,2-dimethylvinylidene, pentenyl, 1,1-dimethylpropenyl, 2,2-dimethylpropenyl, 1,2-dimethylpropenyl, 1,3-dimethylpropenyl, hexenyl, etc.

[0614] Without further definition, the general terms propenyl, butenyl, pentenyl, hexenyl, etc., refer to all conceivable isomers having the corresponding number of carbon atoms, i.e., propenyl includes 1-methylvinylene, and butenyl includes 1-methylpropenyl, 2-methylpropenyl, 1,1-dimethylvinylene, and 1,2-dimethylvinylene.

[0615] With respect to one or more double bonds, the alkenyl group may optionally be present in cis or trans or E or Z orientation.

[0616] When the imide group is part of another (combined) group, such as in HO-C x-y imide-amino or H2N-C x-y The above definition for the alkenyl group also applies when the alkenyl group is in the form of an alkenyloxy group.

[0617] Unlike alkyl groups, acetylin It consists of at least two carbon atoms, wherein 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, in each case two hydrogen atoms on adjacent carbon atoms are formally removed and their free valences are saturated to form two additional bonds, the corresponding alkynyl group is formed.

[0618] Examples of alkynyl groups include ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, 1-methyl-prop-2-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, 3-methyl-but-1-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, etc.

[0619] Without further definition, the general terms propynyl, butynyl, penynyl, hexynyl, heptynyl, octyynyl, nonynyl, decynyl, etc., refer to all conceivable isomers having the corresponding number of carbon atoms. That is, propynyl includes prop-1-ynyl and prop-2-ynyl, and butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc.

[0620] If a hydrocarbon chain carries at least one double bond and at least one triple bond, it is defined as an alkynyl group.

[0621] If the alkynyl group is part of another (combined) group, such as in C... x-y alkynyl amino or C x-y The above definition for alkynyl groups also applies to alkynyl groups.

[0622] Unlike alkylene groups, Ethyne It consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C triple bond. If, in an alkylene group as defined above having at least two carbon atoms, in each case two hydrogen atoms on adjacent carbon atoms are formally removed and their free valences are saturated to form two additional bonds, the corresponding alkynylene group is formed.

[0623] Examples of ynyl groups include ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentyynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, and hexynylene.

[0624] Without further definition, the general terms propynyl, butynyl, pentylyl, hexynyl, etc., refer to all conceivable isomers having the corresponding number of carbon atoms, i.e., propynyl includes 1-methylethynyl, and butynyl includes 1-methylpropynyl, 2-methylpropynyl, 1,1-dimethylethynyl, and 1,2-dimethylethynyl.

[0625] If the ynyne group is part of another (combined) group, such as in HO-C x-y Imynylamino or H2N-C x-y In the case of alkynyloxy groups, the above definition for alkynyl groups also applies.

[0626] heteroatoms It refers to oxygen, nitrogen, and sulfur atoms.

[0627] Haloalkyl (haloalkenyl, haloynyl) Alkyl (alkenyl, ynyl) compounds derived from previously defined alkyl groups are obtained by independently replacing one or more hydrogen atoms in the hydrocarbon chain with halogen atoms, which may be the same or different. If the haloalkyl (haloalkenyl, haloynyl) is to be further substituted, the substitution may occur independently of each other in each case, either as a single substitution or multiple substitution, on all the hydrogen-carrying carbon atoms.

[0628] Examples of alkyl halogens (alkenyl halogens, alkynyl halogens) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCl=CH2, -CBr=CH2, -C≡C-CF3, -CHFCH2CH3, -CHFCH2CF3, etc.

[0629] Terms are also derived from the previously defined haloalkyl (haloalkenyl, haloynyl) groups. Halogenated alkylene (halogenated alkylene) (Alkenyl, Haloynyl) Unlike alkyl halogens (alkenyl halogens, alkynyl halogens), alkylene halogens (alkenylene halogens, alkynyl halogens) are divalent and require two bonding partners. Formally, the divalent form is achieved by removing a hydrogen atom from the alkyl halogen (alkenyl halogen, alkynyl halogen).

[0630] The corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF-, or >CFCH2F, etc.

[0631] The above definition also applies if the corresponding halogenated group is part of another (combined) group.

[0632] halogen It involves fluorine, chlorine, bromine and / or iodine atoms.

[0633] cycloalkyl It is composed of monocyclic cycloalkyl, bicyclic cycloalkyl, and spirocyclic cycloalkyl daughter groups. The ring system is saturated and formed by linked carbon atoms. In bicyclic cycloalkyl, two rings are linked together such that they share at least two carbon atoms. In spirocyclic cycloalkyl, one carbon atom (the spiro atom) belongs to both rings.

[0634] If a cycloalkyl group is to be substituted, the substitution can occur independently of each other in each case, either as a mono- or poly-substituted group, on all the hydrogen-carrying carbon atoms. The cycloalkyl group itself can act as a substituent attached to the molecule via each suitable position in the ring system.

[0635] Examples of cycloalkyl groups include 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 (octahydroindyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinel), spiro[2.5]octyl, spiro[3.3]heptyl, etc.

[0636] If the cycloalkyl group is part of another (combined) group, such as in C x-y Cycloalkylamino, C x-y Cycloalkyloxy or C x-y In the case of cycloalkyl groups, the above definition for cycloalkyl groups also applies.

[0637] If the free valence of cycloalkyl groups is saturated, then... Alicyclic .

[0638] Therefore, terminology Cycloalkylene It can be derived from the previously defined cycloalkyl group. Unlike cycloalkyl groups, hemicycloalkyl groups are divalent and require two bonding partners. Formally, the divalent value is obtained by removing a hydrogen atom from the cycloalkyl group. The corresponding groups are, for example:

[0639] Cyclohexyl and or or (Hydroxycyclohexyl).

[0640] If the cycloalkylene group is part of another (combined) group, such as in HO-C x-y Cycloalkylamino or H2N-C x-y In the case of cycloalkyloxy groups, the above definition for cycloalkyl groups also applies.

[0641] Cycloalkenyl It consists of monocyclic, bicyclic, and spirocyclic alkenyl groups. However, the system is unsaturated, meaning it contains at least one C-C double bond but no aromatic system. If, in a cycloalkyl group as defined above, two hydrogen atoms on adjacent ring carbon atoms are formally removed and their free valences are saturated to form a second bond, the corresponding cycloalkenyl group is obtained.

[0642] If the cycloalkenyl group is to be substituted, the substitution can occur independently of each other in each case, either as a mono- or poly-substituted group, on all the hydrogen-carrying carbon atoms. The cycloalkenyl group itself can be attached to the molecule as a substituent via each suitable position in the ring system.

[0643] Examples of cycloalkenyl groups include cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cycloheptyl-1-enyl, cycloheptyl-2-enyl, cycloheptyl-3-enyl, cycloheptyl-4-enyl, cyclobut-1,3-dienyl, cyclopentyl-1,4-dienyl, and cyclopentyl... -1,3-dienyl, cyclopent-2,4-dienyl, cyclohex-1,3-dienyl, cyclohex-1,5-dienyl, cyclohex-2,4-dienyl, cyclohex-1,4-dienyl, cyclohex-2,5-dienyl, bicyclo[2.2.1]hept-2,5-dienyl (norborn-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec-2-enyl, etc.

[0644] When the cycloalkenyl group is part of another (combined) group, such as in C... x-y cycloalkenylamino, C x-y cycloalkenyloxy or C x-y In the case of cycloalkenylalkyl groups, the above definition for cycloalkenyl also applies.

[0645] If the free valence of the cycloalkenyl group is saturated, then we obtain Unsaturated alicyclic rings .

[0646] Therefore, terminology Cycloalkenyl It can be derived from the previously defined cycloalkenyl group. Unlike cycloalkenyl groups, cycloalkylene groups are divalent and require two bonding partners. Formally, the second valence is obtained by removing a hydrogen atom from the cycloalkenyl group. The corresponding groups are, for example:

[0647] cyclopentenyl and or or or (cyclopentenyl) etc.

[0648] If the cycloene group is part of another (combined) group, such as in HO-C x-y cycloene-enylamino or H2N-C x-y In the case of cycloalkylene oxide, the above definition for cycloalkylene also applies.

[0649] Aryl It represents a monocyclic, bicyclic, or tricyclic carbon ring having at least one aromatic carbon ring. Preferably, it represents a monocyclic group (phenyl) having six carbon atoms 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 but may also be partially saturated.

[0650] If the aryl group is to be substituted, the substitution can occur independently of each other in each case, either as a mono- or poly-substitution, on all the hydrogen-carrying carbon atoms. The aryl group itself can be attached to the molecule as a substituent via each suitable position in the ring system.

[0651] Examples of aryl groups include phenyl, naphthyl, indanyl (2,3-dihydroindanyl), indanyl, anthraceneyl, phenanthryl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, naphthyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorene, etc. Phenyl is the most preferred.

[0652] The above definition of aryl also applies if the aryl group is part of another (combined) group, such as in an arylamino, aryloxy, or arylalkyl group.

[0653] If the free valence of the aryl group is saturated, then... Aromatic groups .

[0654] the term Aspartic It can also be derived from the previously defined aryl group. Unlike aryl, aryl derivatives are divalent and require two bonding partners. Formally, the second valence is formed by removing a hydrogen atom from the aryl group. The corresponding groups are, for example:

[0655] Phenyl and or or (ortho, meta, para-phenylene)

[0656] Naphthyl and or or wait.

[0657] If the arylene is part of another (combined) group, such as in HO-aryleneamino or H2N-aryleneoxy, then the above definition for the arylene also applies.

[0658] heterocyclic group This refers to a cyclic system derived from previously defined cycloalkyl, cycloalkenyl, and aryl groups by independently replacing one or more -CH2- groups in a hydrocarbon ring with groups -O-, -S-, or -NH-, or by replacing one or more =CH- groups with groups =N-. A total of no more than five heteroatoms may be present, at least one carbon atom must be present between the two oxygen atoms and between the two sulfur atoms, or between an oxygen atom and a sulfur atom, and the ring as a whole must be chemically stable. Heteroatoms may optionally be present in all possible oxidation stages (sulfoxide -SO-, sulfone -SO2-; nitrogen N-oxides). In heterocyclic groups... No The presence of heteroatom rings means that no heteroatom is not part of the aromatic system.

[0659] The direct result of the derivation from cycloalkyl, cycloalkenyl, and aryl groups is that heterocyclic groups are composed of monocyclic, bicyclic, tricyclic, and spirocyclic daughter groups, which can exist in saturated or unsaturated forms.

[0660] Unsaturated means that the ring system in question contains at least one double bond, but does not form a heteroaromatic system. In bicyclic heterocyclic groups, the two rings are linked together such that they share at least two (hetero)atoms. In spiroheterocyclic groups, a carbon atom (spiro atom) belongs to both rings.

[0661] If a heterocyclic group is substituted, substitution can occur independently of each other in each case, either as a monosubstituted or polysubstituted form, on all hydrogen-carrying carbon and / or nitrogen atoms. The heterocyclic group itself can be attached to the molecule as a substituent via each suitable position in the ring system. Substituents on the heterocyclic group are not counted in the number of members of the heterocyclic group.

[0662] Examples of heterocyclic groups include tetrahydrofuranyl, pyrrolyl, pyrrololinyl, imidazoalkyl, thiazoalkyl, imidazolinyl, pyrazolealkyl, pyrazolelinyl, piperidinyl, piperazine, ethylene oxide, aziridinyl, aziridine, aziridine, 1,4-dicyclohexacyclic, and 1,4-dicyclohexacyclic. Alkyl, heptyl alkyl, diazacycloheptyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxopentyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazylidene heptyl, tetrahydrothiophenyl, homothiomorpholinyl-S,S-dioxide Zyzolidinone, dihydropyrazolyl, dihydropyrrole, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuranyl, dihydropyranyl, tetrahydrothiophene-S-oxide, tetrahydrothiophene-S,S-dioxide, high-thiomorpholinyl-S-oxide, 2,3-dihydroazacyclobutadiene, 2H-pyrrole, 4H-pyranyl, 1,4-dihydropyridyl, 8-aza-bicyclo[3.2.1]octyl, 8-aza-bicyclo[5.1.0]octyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 2 ,5-diaza-bicyclo[2.2.1]heptyl, 1-diaza-bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl, 2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-diaza-spiro[4.5]decyl, 1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl, 2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2,8-diaza-spiro[4,5]decyl, etc.

[0663] Other examples are the structures shown below, which can be attached via each hydrogen-carrying atom (hydrogen exchange):

[0664]

[0665]

[0666]

[0667]

[0668] Preferably, the monocyclic heterocyclic group is 4 to 7 members and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0669] Preferred monocyclic heterocyclic groups are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, and azacyclic butyl.

[0670] The preferred bicyclic heterocyclic group is 6 to 10 members and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0671] The preferred tricyclic heterocyclic group is 9-membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0672] The preferred spiroheterocyclic group is 7 to 11 members and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0673] The above definition of a heterocyclic group also applies if the heterocyclic group is part of another (combined) group, such as in a heterocyclic amino, heterocyclic oxygen, or heterocyclic alkyl group.

[0674] If the free valence of the heterocyclic group is saturated, then... Heterocyclic .

[0675] the term Sub-heterocyclic It also derives from the previously defined heterocyclic groups. Unlike heterocyclic groups, subheterocyclic groups are divalent and require two bonding partners. Formally, the second valence is obtained by removing a hydrogen atom from the heterocyclic group. The corresponding groups are, for example:

[0676] Piperidinyl and or or ,

[0677] 2,3-Dihydro-1H-pyrrole and or or or wait.

[0678] The above definition of a heterocyclic group also applies if the heterocyclic group is part of another (combined) group, such as in HO-heterocyclic amino or H2N-heterocyclic oxy.

[0679] heteroaryl This refers to a monocyclic heteroaromatic ring or polycyclic ring having at least one heteroaromatic ring, which contains one or more identical or different heteroatoms, rather than one or more carbon atoms, compared to the corresponding aryl or cycloalkyl (cycloalkenyl) group, wherein the heteroatoms are independently selected from nitrogen, sulfur, and oxygen, and the resulting group must be chemically stable. The prerequisites for the presence of a heteroaryl group are heteroatoms and a heteroaromatic system.

[0680] If a heteroaryl group is to be substituted, substitution can occur independently of each other in each case, either as a monosubstituted or polysubstituted group, on all hydrogen-carrying carbon and / or nitrogen atoms. The heteroaryl group itself can be attached to the molecule as a substituent via each suitable position (both carbon and nitrogen) in the ring system. Substituents on the heteroaryl group are not counted in the number of heteroaryl members.

[0681] Examples of heteroaryl groups are furanyl, thiophene, and pyrroleyl. azole group, thiazolyl group, iso- Azolyl, isothiazolyl, pyrazolyl, imidazole, triazolyl, tetrazolyl Diazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrroloyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, imidazole-N-oxide, iso azole-N-oxide, Azolyl-N-oxide, Thiazolyl-N-oxide, Diazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indole, isoindole, benzofuranyl, benzothiophene, benzo[] azole group, benzothiazolyl group, benzisocyanate Azolyl, benzisothiazolyl, benzimidazolyl, indazole, isoquinolinyl, quinolinyl, quinoxalinyl, cenolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indazinyl Azopyridyl, imidazopyridyl, naphridyl, benzo[] Azolium, pyridopyridyl, pyrimidopyridyl, purine, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N-oxide, isoquinolinyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, inazinyl-N-oxide, inazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide, etc.

[0682] Other examples are the structures shown below, which can be attached via each hydrogen-carrying atom (hydrogen exchange):

[0683]

[0684] 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.

[0685] The above definition of a heteroaryl group also applies if the heteroaryl group is part of another (combined) group, such as in a heteroarylamino, heteroaryloxy, or heteroarylalkyl group.

[0686] If the free valence of the heteroaryl group is saturated, then... heteroaryl groups .

[0687] the term Hybrid aryl It also derives from the previously defined heteroaryl group. Unlike heteroaryl groups, hypoaryl groups are divalent and require two bonding partners. Formally, the second valence is obtained by removing a hydrogen atom from the heteroaryl group. The corresponding groups are, for example:

[0688] pyrrole and or or or wait.

[0689] The above definition of a heteroaryl also applies if the heteroaryl group is part of another (combined) group, such as in HO-heteroarylamino or H2N-heteroaryloxy.

[0690] Replacement This refers to the substitution of a hydrogen atom directly bonded to the atom under consideration by another atom or another atomic group (substituent). Depending on the starting conditions (number of hydrogen atoms), monosubstitution or polysubstitution can occur on a single atom. A particular substituent can only be used if the permissible valences of the substituent and the atom to be substituted correspond and the substitution produces a stable compound (i.e., a compound that does not spontaneously transform, for example, through rearrangement, cyclization, or elimination).

[0691] Divalent substituents such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2, or the like can be substituents only on carbon atoms, while the divalent substituents =O and =NR can also be substituents on sulfur. Generally, substitution can be carried out by divalent substituents only in the ring system and requires the substitution of two twin hydrogen atoms, i.e., the hydrogen atom previously bonded to the same carbon atom as the saturated one. Therefore, substitution by divalent substituents can only occur at the -CH2- or sulfur atom group in the ring system (only the =O group or the =NR group, possibly one or two =O groups or, for example, one =O group and one =NR group, each group substituting a free electron pair).

[0692] Stereochemistry / solvents / hydrates: Unless explicitly stated otherwise, throughout the specification and appended claims, the given chemical formula or name shall encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and their racemates, as well as mixtures of different proportions of individual enantiomers, mixtures of diastereomers, or any mixtures of the foregoing forms (in the presence of such isomers and enantiomers), and salts (including pharmaceutically acceptable salts) and their solvates (e.g., hydrates, including solvates and hydrates of free compounds or solvates and hydrates of salts of compounds).

[0693] Typically, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, such as by separating the corresponding mixtures, by using stereochemically pure starting materials, and / or by stereoselective synthesis. Optically active forms are known in the art, such as by resolving racemic forms or by synthesis, for example, starting from optically active starting materials and / or by using chiral reagents.

[0694] The enantiomeric pure compounds or intermediates of the present invention can be prepared by asymmetric synthesis, for example by the preparation and subsequent separation of suitable diastereomeric compounds or intermediates, which can be separated by known methods (e.g., by chromatographic separation or crystallization) and / or by using chiral reagents (such as chiral starting materials, chiral catalysts or chiral auxiliaries).

[0695] Furthermore, those skilled in the art know how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on a chiral stationary phase or by resolving the racemic mixtures using suitable resolving agents, such as by forming diastereomer salts of the racemic compound with an optically active acid or base, subsequently resolving the salt and releasing the desired compound from the salt, or by derivatizing the corresponding racemic compound with an optically active chiral auxiliary agent, subsequently performing diastereomer separation and removing the chiral auxiliary group, or by kinetic resolution of the racemic mixture (e.g., by enzymatic resolution); by enantioselective crystallization from aggregates of enantiomorphic crystals under suitable conditions or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary agent.

[0696] Salts The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to a reasonable extent of medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0697] As used herein, a “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound in which the parent compound is modified by preparing its acid salt or base salt. Ions of pharmaceutically acceptable salts include (but are not limited to) inorganic or organic acid salts of basic residues such as amines; basic or organic salts of acidic residues such as carboxylic acids; and so on.

[0698] For example, such salts include those derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentian acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0699] Other pharmaceutically acceptable salts can be formed using cations from ammonia, L-arginine, calcium, 2,2'-iminodiethanol, L-lysine, magnesium, N-methyl-D-glucosamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0700] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts can be prepared by reacting the free acidic or basic form of these compounds with a sufficient amount of a suitable base or acid in water or in an organic diluent (such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or mixtures thereof).

[0701] Salts of other acids besides those mentioned above (which, for example, can be used to purify or isolate the compounds of the present invention) (e.g., trifluoroacetate) also constitute a part of the present invention.

[0702] In, for example, the following diagram

[0703] or or

[0704] The letter A has a ring designation function to make it easier, for example, to indicate the attachment of the ring in question to other rings.

[0705] For divalent groups, it is crucial to determine which adjacent groups they bind to and with which valence. The corresponding binding partners are indicated in parentheses for clarification, as shown in the following diagram:

[0706] or (R) 2 ) -C(=O)NH- or (R 2 ) -NHC(=O)-.

[0707] If such a specification is missing, the divalent groups can be bidirectionally bonded, i.e., for example, -C(=O)NH- also includes -NHC(=O)- (and vice versa).

[0708] Groups or substituents are typically selected from those having the corresponding group name (e.g., R). a R b Many alternative groups / substituents (etc.). If such groups are used repeatedly to define compounds according to the invention in different parts of the molecule, it should be noted that the various uses are considered to be completely independent of each other.

[0709] For the purposes of this invention, a therapeutically effective amount means an amount of substance that can eliminate or prevent or alleviate the symptoms of a patient, or prolong the survival of the treated patient.

[0710] The Ras family proteins used in this article are intended to include KRAS (V-Ki-ras2 Kirsten rat sarcoma virus oncogene homolog), NRAS (neuroblastoma RAS virus oncogene homolog), and HRAS (Harvey rat sarcoma virus oncogene) and any of their mutants.

[0711] As used herein, a RAS G12C inhibitor refers to a compound that combines one or more of the following: G12C mutant RAS protein KRAS G12C (= KRAS G12C inhibitor), NRAS G12C (= NRAS G12C inhibitor), and / or HRAS G12C (= HRAS G12C inhibitor), particularly KRAS G12C; and is capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS G12C and / or NRAS G12C and / or HRAS G12C, particularly KRAS G12C. While not wishing to be bound by theory, it is believed that the compounds of the present invention can selectively react with KRAS G12C and / or HRAS G12C and / or NRAS G12C proteins (preferably with KRAS G12C) by forming a covalent bond with the 12th cysteine ​​residue of KRAS G12C and / or HRAS G12C and / or NRAS G12C proteins (preferably with KRAS G12C), resulting in the regulation / inhibition of the enzymatic activity of the mutant Ras protein.

[0712] List of abbreviations

[0713]

[0714]

[0715]

[0716] Example

[0717] The features and advantages of the invention will become apparent from the following detailed embodiments, which illustrate the principles of the invention by way of example and do not limit its scope:

[0718] Preparation of compounds according to the present invention

[0719] General

[0720] Unless otherwise stated, all reactions are carried out in commercially available apparatus using methods typically used in chemical laboratories. Starting materials sensitive to air and / or moisture are stored under a protective gas, and the corresponding reactions and manipulations using them are carried out under a protective gas (nitrogen or argon).

[0721] If a compound can be represented by both its structural formula and its nomenclature, then in the event of a conflict, the structural formula is the determining factor.

[0722] The microwave reaction is preferably carried out under stirring in a sealed container (preferably 2, 5 or 20 mL) in an initiator / reactor manufactured by Biotage, or in a detector manufactured by CEM, or in a Synthos 3000 or Monowave 3000 manufactured by Anton Paar.

[0723] Chromatography

[0724] Thin-layer chromatography was performed on off-the-shelf silica 60 TLC plates on glass (with fluorescent indicator F-254) manufactured by Merck.

[0725] Preparative high-performance liquid chromatography (RP HPLC) of the compounds according to embodiments of the present invention was performed on an Agilent or Gilson system using columns manufactured by Waters (names: SunFire™ Preparative C18, OBD™ 10 µm, 50 x 150 mm or SunFire™ Preparative C18 OBD™ 5 µm, 30 x 50 mm or XBridge™ Preparative C18, OBD™ 10 µm, 50 x 150 mm or XBridge™ Preparative C18, OBD™ 5 µm, 30 x 150 mm or XBridge™ Preparative C18, OBD™ 5 µm, 30 x 50 mm) and columns manufactured by YMC (names: Actus-Triart Prep C18, 5 µm, 30 x 50 mm).

[0726] Different H2O / acetonitrile gradients were used to elute the compounds. For the Agilent system, 5% acid modifier (20 mL HCOOH to 1 L H2O / acetonitrile (1 / 1)) was added to the water (acidic conditions). For the Gilson system, 0.1% HCOOH was added to the water.

[0727] For chromatography under alkaline conditions, the Agilent system also uses an H2O / acetonitrile gradient, while making the water alkaline by adding 5% alkaline modifier (50 g NH4HCO3 + 50 mL NH3 (25%, in H2O) to 1 L (with H2O)). For the Gilson system, the water is made alkaline as follows: 5 mL NH4HCO3 solution (158 g, in 1 L H2O) and 2 mL NH3 (28%, in H2O) are added to make 1 L.

[0728] Supercritical fluid chromatography (SFC) of the intermediates and compounds of the present invention was performed on a JASCO SFC system using the following columns: Chiralcel OJ (250 x 20 mm, 5 µm), Chiralpak AD (250 x 20 mm, 5 µm), Chiralpak AS (250 x 20 mm, 5 µm), Chiralpak IC (250 x 20 mm, 5 µm), Chiralpak IA (250 x 20 mm, 5 µm), Chiralcel OJ (250 x 20 mm, 5 µm), Chiralcel OD (250 x 20 mm, 5 µm), and Phenomenex Lux C2 (250 x 20 mm, 5 µm).

[0729] Analytical HPLC (reaction control) of intermediates and final compounds was performed using a column manufactured by Waters (name: XBridge). TM C18, 2.5 µm, 2.1 x 20 mm or XBridge TM The analysis was performed using columns manufactured by YMC (name: Triart C18, 3.0 µm, 2.0 x 30 mm) and columns manufactured by Phenomenex (name: Luna C18, 5.0 µm, 2.0 x 30 mm). A mass detector was also provided in each case.

[0730] HPLC-mass spectrometry / UV-spectroscopy

[0731] Retention time / MS-ESI for characterizing compounds according to embodiments of the present invention + Produced using an HPLC-MS apparatus (high-performance liquid chromatography with a mass detector). The retention time t of the compound eluted at the injection peak is given. Ret. =0.00.

[0732] SFC-method (preparative)

[0733] Preparative SFC was performed in the Waters Thales SFC 80 system.

[0734] Column: Chiralpak AD-H (21 x 250 mm), 5µm

[0735] Flow rate: 25 g / min

[0736] Mobile phase: 75% CO2 + 25% MeOH (0.5% isopropylamine)

[0737] ABPR: 120 bar;

[0738] Temperature: 35ºC

[0739] UV: 220 nm

[0740] Stacking time: 8 min

[0741] HPLC Method (Analytical)

[0742] Method A

[0743] The samples were analyzed on an Agilent 1200 series LC system coupled with an Agilent 6140 mass spectrometer. Purity was determined by UV detection with a 170 nm bandwidth in the 230–400 nm range. LC parameters are as follows:

[0744]

[0745] Method B

[0746]

[0747] Method C

[0748]

[0749] Method D

[0750]

[0751] Method E

[0752]

[0753]

[0754] Method G

[0755]

[0756] The compounds and intermediates according to the invention are prepared by the synthetic methods described below, wherein the substituents of the general formula have the meanings given above. These methods are intended to illustrate the invention and not to limit its subject matter or the scope of the compounds claimed for these embodiments. Where the preparation of starting compounds is not described, they are commercially available or their synthesis is described in the prior art, or they can be prepared similarly to the known prior art compounds or methods described herein, i.e., the synthesis of these compounds is within the skill of an organic chemist. The substances described in the literature can be prepared according to the published synthetic methods. If the chemical structures depicted below do not have a precise configuration of the stereocenter, such as an asymmetrically substituted carbon atom, then both configurations should be considered to be included and disclosed in such illustrations. Stereocenter illustrations in racemic form should always be considered to include and disclose two enantiomers (if no other defined stereocenter exists) or all other potential diastereomers and enantiomers (if an additionally defined or undefined stereocenter exists).

[0757] Overview of general reaction schemes and synthetic routes for producing compound (I) according to the invention.

[0758] Option 1:

[0759]

[0760] Experimental procedure for synthesizing A-2a

[0761]

[0762] At 0–10°C, A-1a (93.46 mL, 587.5 mmol, 1.0 eq.) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 25.85 g, 646.3 mmol, 1.1 eq.) in THF (2.0 L). The mixture was stirred at 10°C for 30 min, and then iodomethane (55.11 mL, 881.3 mmol, 1.5 eq.) was added dropwise to the mixture at 10°C. The mixture was allowed to reach room temperature overnight. After complete conversion, the reaction mixture was cooled to 0°C and quenched with a saturated aqueous ammonium chloride solution. The product was extracted with EtOAc, and the organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give A-2a, which was used in the next step without further purification.

[0763] The following intermediate A-2 (Table 1) can be obtained in a similar manner using different cyclic β-keto esters A-1. If necessary, the crude product A-2 can be purified by chromatography.

[0764] Table 1

[0765]

[0766] Experimental procedure for synthesizing A-3a

[0767]

[0768] At room temperature, malononitrile (58.04 g, 879.3 mmol, 1.5 eq.) was added to a solution of A-2a (108.00 g, 586.2 mmol) in toluene (1.03 L), followed by the addition of ammonium acetate (9.04 g, 117.2 mmol, 0.2 eq.) and acetic acid (13.41 mL, 234.5 mmol, 0.4 eq.). The mixture was stirred at 110ºC for 16 h. After complete conversion, the mixture was diluted with EtOAc and washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give crude product A-3a. This crude product was used in the next step without further purification (see also Naumann et al., Pharmazie 51 (1996), 4).

[0769] The following intermediate A-3 (Table 2) can be obtained in a similar manner using different intermediates A-2. If necessary, the crude product A-3 can be purified by chromatography.

[0770] Table 2

[0771]

[0772] Experimental procedure for synthesizing A-4a

[0773]

[0774] Sulfur (68.9 g, 2.2 mol, 2.0 eq.) and L-proline (24.8 g, 0.22 mol, 0.2 eq.) were added to a solution of A-3a (250.0 g, 1.1 mol) in DMF (3.0 L), and the resulting mixture was stirred at 80ºC for 12 h. After complete conversion, the mixture was partitioned between EtOAc and water, and the organic layer was collected. The aqueous layer was further extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give A-4a.

[0775] The following intermediate A-4 (Table 3) can be obtained in a similar manner using different intermediates A-3. If necessary, the crude product A-4 can be purified by chromatography.

[0776] Table 3:

[0777]

[0778] Experimental procedure for synthesizing A-4d

[0779]

[0780] A stirred solution of A-1a (12.00 g, 70.5 mmol) in EtOH (60.0 mL) was treated with sulfur (2.26 g, 70.5 mmol, 1.00 eq.), morpholine (6.14 g, 70.5 mmol, 1.0 eq.), and malononitrile (4.66 g, 70.5 mmol, 1.0 eq.). The reaction mixture was then stirred at 55ºC for 1 h. After complete conversion, the reaction mixture was concentrated, diluted with water, extracted with EtOAc, and the extract was dried, filtered, and concentrated under reduced pressure to give a crude product. This crude product was purified by column chromatography (20%–30% EtOH in hexane) to give A-4d. (HPLC method A; t) ret = 1.10 min; [M+H] + =251).

[0781] Experimental procedure for synthesizing A-5a

[0782]

[0783] A-4a (78.0 mg, 0.3 mmol, 1.0 eq.) was dissolved in EtOH (1.5 mL), and potassium hydroxide (4 M in water, 0.37 mL, 1.5 mmol, 5.0 eq.) was added. The mixture was stirred at 78ºC for 16 h. After complete conversion, water and EtOAc were added to the mixture, the pH of the aqueous phase was adjusted to pH 4 using KHSO4 solution (10% in water), and the product was extracted using EtOAc. The combined organic layers were dried, filtered, and concentrated. The crude product was purified by acid reversed-phase chromatography (gradient elution: 20% to 90% acetonitrile in water) to give A-5a.

[0784] The following intermediate A-5 (Table 4) can be obtained in a similar manner using different esters A-4. If desired, the crude product A-5 can be purified by chromatography, and the enantiomers can be separated using preparative SFC chromatography as described herein, for example, separating A-5a and A-5b and their enantiomers.

[0785] Table 4

[0786]

[0787] Option 2a:

[0788]

[0789] Option 2b:

[0790]

[0791] Experimental procedure for synthesizing E-2a

[0792]

[0793] DIPEA (2.882 g, 22.3 mmol, 2.0 eq.) was added to a solution of (S)-1-((S)-1-methylpyrrolid-2-yl)-ethanol-1-ol (1.441 g, 11.15 mmol, 1.0 eq.) in DMSO, and the mixture was cooled to 10ºC. E-1a (2.0 g, 11.15 mmol, 97% purity, 1.0 eq.) was added, and the mixture was stirred at 10ºC for 45 min. The mixture was filtered, and the filtrate was purified by alkaline reversed-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give E-2a. (HPLC method A; t) ret = 1.36 min; [M+H] + = 267).

[0794] The other intermediate, E-2, can be obtained in a similar manner. If necessary, the crude product E-2 can be purified by chromatography.

[0795] Experimental procedure for synthesizing E-2b

[0796]

[0797] E-3a (3.50 g, 15.9 mmol) was dissolved in DMF (10 mL). 2-Dimethylaminoethyl chloride HCl salt (6.87 g, 47.72 mmol) was added, and the mixture was stirred at 150ºC for 25 min. The mixture was cooled to room temperature and filtered through a glass frit filter, followed by washing with EtOAc. The solvent was removed by lyophilization. The residue was purified by normal-phase chromatography (gradient elution: 0% to 20% MeOH in DCM) to give E-2b.

[0798] The intermediate E-2 (Table 5) can be obtained in a similar manner. If necessary, the crude product E-2 can be purified by chromatography.

[0799] Table 5

[0800]

[0801] Experimental procedure for synthesizing E-4a (Method A)

[0802]

[0803] 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.76 g, 13.73 mmol) and cesium carbonate (2.76 g, 13.73 mmol) were dissolved in DMA (10 mL). E-1b (2.50 g, 13.73 mmol) was added, and the mixture was stirred at 90ºC for 1 h. The reaction mixture was extracted from water into EtOAc, and the organic phase was dried over magnesium sulfate. The solvent was removed under vacuum, and the residue was purified by basic reversed-phase chromatography (gradient elution: 45% to 98% acetonitrile in water) to give E-4a.

[0804] Experimental procedure for synthesizing E-4b (Method B)

[0805]

[0806] tert-butyl piperazine-1-carboxylate (5.92 g, 31.79 mmol, 1.1 eq.) was added to a stirred solution of E-1b (5.00 g, 28.90 mmol) in DMSO (50.0 mL). DIPEA (11.21 g, 86.71 mmol, 3.0 eq.) was then added, and the reaction mixture was stirred at 60ºC for 1 h. After complete conversion, the mixture was dissolved in EtOAc and washed with water (3x). The organic phase was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc / hexane) to give E-4b.

[0807] Experimental procedure for synthesizing E-4c (Method C)

[0808]

[0809] To a stirred solution of E-1c (10.20 g, 57.22 mmol) in DCM (60.0 mL), tert-butyl piperazine-1-carboxylate (11.22 g, 57.22 mmol, 1.0 eq.) was added. Then DIPEA (20.71 g, 160.21 mmol, 2.8 eq.) was added, and the reaction mixture was stirred at 60ºC for 1 h. After complete conversion, the mixture was dissolved in EtOAc and washed with water (3 x). The organic phase was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH) to give E-4c.

[0810] Experimental procedure for synthesizing E-4d (Method D)

[0811]

[0812] N-(2-hydroxyethyl)-N-methylcarbamate tert-butyl ester (171 mg, 0.95 mmol, 1.1 eq.) was added to a stirred mixture of sodium hydride (22.8 mg, 0.95 mmol, 1.1 eq.) and THF (2 mL) under argon atmosphere, and the mixture was stirred for 5 min. E-1c (150 mg, 0.86 mmol, 1.0 eq.) was added, and the mixture was stirred for 1 h. The reaction was quenched by adding a few drops of water, and the solvent was removed under vacuum. The crude product was dissolved in DCM and purified by column chromatography (DCM / MeOH) to give E-4d.

[0813] Experimental procedure for synthesizing E-4e (Method E)

[0814]

[0815] E-1d (1.00 g, 6.62 mmol), piperazine-1-carboxylic acid tert-butyl ester (724.6 mg, 3.70 mmol, 0.8 eq.), sodium tert-butoxide (915.4 mg, 9.24 mmol, 2.0 eq.), 2-(di-tert-butylphosphino)biphenyl (275.7 mg, 0.92 mmol, 0.20 eq.), and tris(dibenzylideneacetone)palladium(0) (211.5 mg, 0.23 mmol, 0.05 eq.) were dissolved in anhydrous dihydrogen phosphate. The mixture was combined in alkane (9.00 mL) and stirred at room temperature for 1 h. After complete conversion, the mixture was concentrated, diluted with water, and the product was extracted with DCM. The combined organic layers were dried, filtered, and concentrated. The crude product was purified by basic reversed-phase chromatography (gradient elution: 35% to 98% acetonitrile in water) to give E-4e.

[0816] According to methods A through E, the following (additional) intermediate E-4 (Table 6) can be obtained in a similar manner using different amines PG-LH and intermediate E-1. If necessary, the crude product E-4 can be purified by chromatography.

[0817] Table 6

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824] Experimental procedure for synthesizing E-6a

[0825]

[0826] E-1b (500 mg, 2.83 mmol, 1.0 eq.) and cesium fluoride (1.72 g, 11.33 mmol, 4.0 eq.) were dissolved in DMA (5 mL) and heated to 110ºC by microwave radiation. The mixture was filtered and the solid was washed with a small amount of DMA to obtain a crude solution of E-5a in DMA.

[0827] Sodium hydride (158 mg, 3.97 mmol, 1.4 eq.) was added to a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (531 mg, 187.24 mmol, 1.0 eq.) in THF (5 mL), and the mixture was stirred for 30 min. This mixture was then slowly added to a freshly prepared solution of E-5a (397 mg, 140.09 mmol, 1.0 eq.) in DMA and stirred for 5 min, followed by the addition of water and EtOAc. The phases were separated, and the aqueous phase was extracted twice with EtOAc (30 mL). The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated. The mixture was dissolved in acetonitrile and water and purified by acidic reversed-phase chromatography to give the desired product E-6a.

[0828] The intermediate E-6 (Table 7) can be obtained in a similar manner. If necessary, the crude product E-7 can be purified by chromatography.

[0829] Table 7

[0830]

[0831] Experimental procedure for synthesizing E-6d

[0832]

[0833] E-1b (267 mg, 1.54 mmol, 1.0 eq.) and cesium fluoride (937 mg, 6.17 mmol, 4.0 eq.) were dissolved in DMA (3 mL) and heated to 110ºC by microwave irradiation. The mixture was filtered, and the solid was washed with a small amount of DMA to obtain a crude solution of E-5a in DMA. tert-butyl 5,8-diazaspiro[3.5]nonane-4-carboxylate (349 mg, 1.54 mmol, 1.0 eq.) and DIPEA (0.667 mL, 3.86 mmol, 2.5 eq.) were added to the mixture, and the mixture was stirred at 60ºC for 30 min. The mixture was filtered, and the filtrate was purified by alkaline reversed-phase chromatography to obtain the desired product E-6d.

[0834] The intermediate E-6 (Table 8) can be obtained in a similar manner. If necessary, the crude product E-6 can be purified by chromatography.

[0835] Table 8

[0836]

[0837] Experimental procedure for synthesizing E-6f

[0838]

[0839] Intermediate E-4ap (60 mg, 0.19 mmol, 1.0 eq.) and cesium fluoride (56 mg, 0.37 mmol, 2.0 eq.) were dissolved in DMSO (2 mL) and stirred overnight at 80ºC and cooled to room temperature. Cesium fluoride (56 mg, 0.37 mmol, 2.0 eq.) was then added, and the mixture was stirred at 110ºC to complete the reaction. Water and acetonitrile were added, and the mixture was purified by acid reversed-phase chromatography to give the desired product E-6f.

[0840] The following intermediate E-6 (Table 9) can be obtained from other intermediates E-4 in a similar manner. If necessary, the crude product E-6 can be purified by chromatography.

[0841] Table 9

[0842]

[0843] Various synthetic building blocks HR 5 Synthesis

[0844]

[0845] Experimental procedure for synthesizing G-2a

[0846] G-1a (500 mg, 2.33 mmol) was dissolved together with triethylamine (485 µL, 3.5 mmol, 1.5 eq.) in anhydrous THF (5.00 mL), and the mixture was cooled to 0ºC. Benzyl chloroformate (519 µL, 3.5 mmol, 1.5 eq.) was added in portions, and the mixture was stirred for 2 h and allowed to reach room temperature overnight. After complete conversion, water was added to the mixture, and the product was extracted with DCM. The combined extracts were dried, filtered, and concentrated. The crude product was used for the next step without further purification. (HPLC Method B, t) ret = 0.766 min, [M+H] + = 249 / 293).

[0847] Experimental procedure for synthesizing G-3a

[0848] G-2a (813 mg, 2.33 mmol) was dissolved in DCM (25.00 mL) and then dissolved in HCl (in a solution of 2,000 mL). The mixture was treated with 4 M alkylene (11.67 mL, 46.66 mmol, 20.0 eq.). The mixture was stirred at room temperature for 2 h. After complete conversion, the mixture was concentrated and the product was separated by alkaline reversed-phase chromatography (gradient elution: 10% to 70% acetonitrile in water). (HPLC method B, t) 停留 = 0.478 min, [M+H] + = 249).

[0849] Experimental procedure for synthesizing G-4a (Method F)

[0850]

[0851] G-3a (4.0 g, 16.12 mmol) was dissolved in anhydrous DCM (50.00 mL) and treated with formaldehyde (37% in water, 1.21 mL, 16.12 mmol, 1.00 eq.) and acetic acid (92 µL, 1.61 mmol, 0.10 eq.). The mixture was stirred for 15 min, then sodium triacetoxyborohydride (6.335 g, 29.00 mmol, 1.80 eq.) was added, and the mixture was stirred at room temperature for 1 h. After complete conversion, water was added to the mixture, and the product was extracted with DCM. The combined extracts were dried, filtered, and concentrated. The crude product was purified by normal-phase chromatography (DCM / MeOH).

[0852] Experimental procedure for synthesizing G-4b (Method G)

[0853]

[0854] K₂CO₃ (0.303 g, 2.51 mmol, 2.50 eq.) was added to a stirred solution of G-3a (250.0 mg, 1.00 mmol) in anhydrous DMF (5.00 mL), followed by the addition of 1-bromo-2-methoxy-ethane (0.122 g, 1.00 mmol, 1.00 eq.). The reaction mixture was stirred at 80ºC for 16 h. After complete conversion, water was added to the mixture, and the product was extracted with EtOAc. The combined extracts were dried, filtered, and concentrated. The crude product was purified by normal-phase chromatography (DCM / MeOH).

[0855] According to method F or method G, using G-3a and different aldehydes or ketones as alkylating agents, the following (additional) intermediate G-4 (Table 10) can be obtained in a similar manner. If necessary, the crude product G-4 can be purified by chromatography.

[0856] Table 10

[0857]

[0858] Experimental procedure for synthesizing G-5a

[0859]

[0860] G-5a (3.00 g, 11.44 mmol) was dissolved in MeOH (20.0 mL) and palladium (10% on carbon, 360 mg) was added. The mixture was stirred in a hydrogenation reactor at room temperature under a hydrogen pressure of 5 bar for 16 h. After complete conversion, the catalyst was filtered off and the residue was concentrated. The crude product was used in the following steps without purification.

[0861] The following intermediate G-5 (≙ synthetic building block HR) 5 (Table 11) can be obtained in a similar manner using analogues of G-4 with different substitutions.

[0862] Table 11

[0863]

[0864] Experimental procedure for synthesizing G-7a

[0865]

[0866] G-6a (590.0 mg, 2.49 mmol) was dissolved in anhydrous THF (1.50 mL), and the mixture was cooled to 0ºC. LiAlH4 (2 M, 6.22 mL, 12.44 mmol, 5.00 eq. in THF) was added dropwise, and the mixture was stirred at 70ºC for 1.5 h in a sealed container. After complete conversion, the mixture was diluted with THF (15 mL), and potassium sodium tartrate tetrahydrate was slowly added, while the mixture was stirred at room temperature for 1.5 h. The mixture was filtered, the filtrate was concentrated, and the crude product was used unpurified in the following steps.

[0867] The following intermediate G-7 (≙ synthetic building block HR) 5 (Table 12) can be obtained in a similar manner from the corresponding N-Boc-aminoketone G-6.

[0868] Table 12

[0869]

[0870] Experimental procedure for synthesizing E-10a

[0871]

[0872] A solution of piperazine-1-carboxylate tert-butyl ester (505 mg, 2.71 mmol; 1.0 eq.) in acetone (11 mL) was added to a solution of E-9a (500 mg, 2.71 mmol; 1.0 eq.) in acetone (6 mL). An aqueous solution of sodium bicarbonate (225.00 mg, 2.12 mmol; 0.78 eq.) in water (5 mL) was added, and the reaction was stirred at 0ºC for 3 h. The reaction mixture was filtered, the solid was washed with water, and dried to give the desired compound E-10a (HPLC method A, t ret = 1.47 min, [M+H] + = 334).

[0873] Experimental procedure for synthesizing E-11a

[0874]

[0875] E-10a (1.04 g, 3.11 mmol, 1.0 eq.), (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (561.41 mg, 4.05 mmol, 1.3 eq.), and DIPEA (808.47 mg, 6.22 mmol, 2.0 eq.) were dissolved in anhydrous THF (12 mL) and stirred at room temperature for 3 h, followed by stirring at 40ºC for 1 h. The solvent was removed under vacuum, and the residue was purified by normal-phase chromatography (cyclohexane: EtOAc from 10:90 80:20) to obtain E-11a (HPLC method A, t ret = 1.54 min, [M+H] + = 427).

[0876] Experimental procedure for synthesizing E-8a

[0877]

[0878] E-11a (898 mg, 1.68 mmol, 1.0 eq.) and sodium cyanide (329.85 mg, 6.73 mmol, 4.0 eq.) were dissolved in DMSO (5 mL) and stirred at 60ºC for 3 h. The solvent was removed and the residue was purified by reversed-phase chromatography to obtain the desired compound E-8a (HPLC method A, t ret = 1.53 min; [M+H] + = 418)

[0879] Experimental procedure for synthesizing E-8b

[0880]

[0881] A solution of E-1a (1000 mg, 97% purity, 5.58 mmol, 1.0 eq.) in DMSO (3 mL) was slowly added to a solution of (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol (792 mg, 6.13 mmol, 1.1 eq.) and DIPEA (1.94 mL, 11.15 mmol, 2 eq.) in DMSO (3 mL). The mixture was stirred at room temperature for 30 min. After complete conversion of the starting material was observed, tert-butyl (R)-3-methylpiperazine-1-carboxylate (1.50 mg, 97% purity, 7.25 mmol, 1.3 eq.) and DIPEA (0.97 mL, 5.58 mmol, 1 eq.) were added to the mixture. The mixture was stirred at 60ºC for 60 min and DIPEA (0.97 mL, 5.58 mmol, 1 eq.) was added. The mixture was stirred at 70ºC for 50 min and then stirred overnight at room temperature. After complete conversion was observed, the reaction mixture was diluted with water and DCM and the phases were separated. The aqueous phase was extracted with DCM (3 x) and the organic phases were combined. The solvent was removed under vacuum to give crude product E-8a. The crude product was dissolved in acetonitrile and water, filtered, and purified by basic reversed-phase chromatography (gradient elution: 35% to 95% acetonitrile in water) to give the desired purified product E-8b.

[0882] The following intermediate E-8 (Table 13) can be obtained in a similar manner without separating the corresponding intermediate E-2. If necessary, the crude product E-8 can be purified by chromatography.

[0883] Table 13

[0884]

[0885] Experimental procedure for synthesizing E-8d

[0886]

[0887] Cesium fluoride (1.218 g, 8.02 mmol, 93% purity, 1.0 eq.) was added to a solution of E-1a (600 mg, 3.21 mmol, 93% purity, 1.0 eq.) in anhydrous DMSO (6 mL), and the resulting mixture was stirred at room temperature for 1 h until complete conversion of the starting material was observed. The resulting suspension was filtered, and the filtered solids were washed with anhydrous DMSO (2 mL). The filtrate (8 mL) was added to (S)-1-((S)-1-methylpyrrolid-2-yl)ethanol-1-ol (453 mg, 3.51 mmol, 1.1 eq.), and DIPEA (1.085 mL, 6.38 mmol, 2 eq.) was added. The mixture was stirred at room temperature for 1 h. After complete conversion of the starting material was observed, a solution of piperazine-1-carboxylic acid tert-butyl ester (674 mg, 3.51 mmol, 97% purity, 1.1 eq.) in anhydrous DMSO (3 mL) and DIPEA (1.085 mL, 6.38 mmol, 2 eq.) was added to the mixture. The mixture was stirred at room temperature for 30 min. After complete conversion was observed, the reaction mixture was diluted with acetonitrile and water, filtered, and purified by alkaline reversed-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give the desired product E-8d.

[0888] The following intermediate E-8 (Table 14) can be obtained in a similar manner without separating the corresponding intermediates E-5 and E-7 separately. If necessary, the crude product E-8 can be purified by chromatography.

[0889] Table 14

[0890]

[0891] Experimental procedure for synthesizing E-8g (Method A)

[0892]

[0893] E-4f (50.0 mg, 0.148 mmol), G-5a (115 mg, 0.740 mmol, 5.0 eq.), and DIPEA (25.78 µL, 0.15 mmol, 1.0 eq.) were combined with anhydrous NMP (10 µL), and the mixture was stirred at 120ºC for 1 h in a sealed container. The product was separated by alkaline reversed-phase chromatography (gradient elution: 40% to 98% acetonitrile in water) to give E-8 g.

[0894] Intermediate E-8, labeled “A” (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0895] Experimental procedure for synthesizing E-8h (Method B)

[0896]

[0897] E-4e (400.0 mg, 1.24 mmol), N-methylpiperazine (352.1 mg, 3.48 mmol, 2.8 eq.), sodium tert-butoxide (246.3 mg, 2.49 mmol, 2.0 eq.), 2-(di-tert-butylphosphino)biphenyl (74.18 mg, 0.25 mmol, 0.20 eq.), and tris(dibenzylacetone)palladium(0) (56.9 mg, 0.062 mmol, 0.05 eq.) were dissolved in anhydrous dimethyl ether. The mixture was combined in alkyl (2.50 mL) and stirred at 110ºC for 1 h. After complete conversion, the mixture was concentrated, diluted with water, and the product was extracted with DCM. The combined organic layers were dried, filtered, and concentrated. The crude product was purified by basic reversed-phase chromatography (gradient elution: 35% to 98% acetonitrile in water) to give E-8h.

[0898] Intermediate E-8, labeled “B” (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0899] Experimental procedure for synthesizing E-8i (Method C)

[0900]

[0901] E-4b (1.00 g, 3.10 mmol), (S)-1,3-dimethylpiperazine (0.99 g, 8.67 mmol, 2.80 eq.), tris(dibenzylacetone)palladium(0) (141.85 mg, 0.154 mmol, 0.05 eq.), xantphos (184.80 mg, 0.31 mmol, 0.10 eq.), cesium carbonate (2.019 g, 6.196 mmol, 2.00 eq.), and anhydrous dimethylacetone were added to the mixture. The alkyl groups (8.00 mL) were combined and stirred in a sealed container at 110ºC under an argon atmosphere for 16 h. After complete conversion, brine was added to the mixture, and the product was extracted with DCM. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by basic reversed-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give E-8i.

[0902] Intermediate E-8, labeled “C” (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0903] Experimental procedure for synthesizing E-8j (Method D)

[0904]

[0905] E-4g (3.035 g, 8.51 mmol), (S)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester (3.645 g, 17.01 mmol, 2.00 eq.), tris(dibenzylacetone)palladium(0) (778.82 mg, 0.850 mmol, 0.10 eq.), 1,3-bis(2,6-di-isopropylphenyl)imidazolium chloride (723.0 mg, 1.701 mmol, 0.20 eq.), cesium carbonate (8.313 g, 25.514 mmol, 3.00 eq.), and anhydrous dimethyl ether... The alkane (32.00 mL) were combined and stirred in a sealed vessel at 110ºC under an argon atmosphere for 16 h. After complete conversion, brine was added to the mixture, and the product was extracted with DCM. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by basic reversed-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give E-8j.

[0906] Intermediate E-8, labeled “D” (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0907] Experimental procedure for synthesizing E-8k (Method E)

[0908]

[0909] E-4b (400 mg, 1.239 mmol), 1-(1-methylpiperidin-4-yl)piperazine (273.0 mg, 1.49 mmol, 1.20 eq.), RuPhos Pd G3 (106.0 mg, 0.120 mmol, 0.10 eq.), tripotassium phosphate (553.0 mg, 2.605 mmol, 2.10 eq.), and anhydrous dihydrogen phosphate were added. The alkane (3.10 mL) were combined and stirred in a sealed container at 85ºC under an argon atmosphere for 2 h. After complete conversion, the mixture was diluted with DCM and filtered. The crude mixture was purified by normal-phase chromatography (DCM / MeOH / NH3) to give E-8k.

[0910] Intermediate E-8, labeled “E” (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0911] Experimental procedure for synthesizing E-8l (Method F)

[0912]

[0913] E-4b (100 mg, 0.31 mmol), pyridine-4-boronic acid (45.70 mg, 0.37 mmol, 1.20 eq.), RuPhos Pd G3 (27.3 mg, 0.031 mmol, 0.10 eq.), tripotassium phosphate (138.1 mg, 0.65 mmol, 2.10 eq.), and anhydrous dioxins were added. The alkane (0.9 mL) were combined and stirred in a sealed container at 80ºC under an argon atmosphere for 1 h. After complete conversion, the mixture was concentrated. The crude product was purified by basic reversed-phase chromatography to give E-8l.

[0914] Intermediate E-8, labeled “F” (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0915] Experimental procedure for synthesizing E-8m (Method G)

[0916]

[0917] To a mixture of DIPEA (736.3 µL, 4.23 mmol, 3 eq.) and E-4i (560 mg, 1.41 mmol, 85% purity, 1 eq.) in DMSO (1 mL), (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (922 mg, 5.64 mmol, 79% purity, 4.0 eq.) was added, and the mixture was stirred at 100ºC for 16 h. The mixture was cooled to room temperature, diluted with acetonitrile and water, filtered, and purified by acid reversed-phase chromatography (gradient elution: 10% to 98% acetonitrile in water) to give the desired product E-8m.

[0918] Intermediate E-8, labeled “G” (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0919] Experimental procedure for synthesizing E-8n (Method H)

[0920]

[0921] A mixture of E-4k (1.50 g, 4.44 mmol, 1.0 eq.) and (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (688 mg, 5.33 mmol, 1.2 eq.) in THF (45 mL) was cooled to 0ºC. Sodium tert-butoxide (854 mg, 8.88 mmol, 2.0 eq.) was added to the mixture at 0ºC. The mixture was slowly warmed to room temperature and stirred at room temperature for 2 h. The reaction was quenched by adding cold water and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and concentrated under vacuum. The crude product was purified by normal-phase chromatography (2% MeOH in DCM) to give the desired product E-8n.

[0922] Intermediate E-8, labeled “H” (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0923] Experimental procedure for synthesizing E-8o (Method I)

[0924]

[0925] A solution of (S)-1-((S)-1-methylpyrrolid-2-yl)ethanol-1-ol (312 mg, 2.42 mmol, 1.7 eq.) in THF (3 mL) was cooled to 0ºC, and sodium hydride (74 mg, 1.85 mmol, 1.3 eq.) was added in portions over 10 minutes. A solution of E-4l (500 mg, 1.42 mmol, 1.0 eq.) in THF (5 mL) was slowly added to the mixture, and the mixture was stirred for 18 h. The reaction was quenched by adding a saturated aqueous solution of ammonium chloride. The mixture was extracted with a mixture of DCM and MeOH (9:1). The phases were separated, and the organic layer was concentrated under vacuum. The crude product was purified by normal-phase chromatography (2% MeOH in DCM) to give the desired product E-8o.

[0926] Intermediate E-8, labeled “I” (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0927] Experimental procedure for synthesizing E-8p (Method J)

[0928]

[0929] Triethylamine (149.8 mg, 1.48 mmol, 2.5 eq.) was added to a mixture of E-4r (200 mg, 0.59 mmol, 1.0 eq.) and (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (91.8 mg, 0.71 mmol, 1.2 eq.) in acetonitrile (1.5 mL). The mixture was stirred at 40ºC for 2 h. The mixture was then stirred at 80ºC for 16 h. The solvent was removed under reduced pressure, and the crude product was purified by normal-phase chromatography (gradient elution: 0% to 90% MeOH (in DCM + ammonia)) to give the desired product E-8p.

[0930] Intermediate E-8, labeled “J” (Table 15), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0931] Table 15

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940] Experimental procedure for synthesizing intermediate E-8cc

[0941]

[0942] In the second E-2b (3.94 g, 20.93 mmol, 4.0 eq.), tert-butyl piperazine-1-carboxylate (1.76 g, 5.23 mmol, 1.0 eq.), sodium tert-butoxide (2.01 g, 20.93 mmol, 4.0 eq.), 2-(di-tert-butylphosphino)-biphenyl (624.45 mg, 0.21 mmol, 0.4 eq.), and tris-(dibenzylacetone)-dipalladium (479.05 mg, 0.052 mmol, 0.1 eq.) from alkyl groups (10 mL) were added to a sealed tube and shaken overnight at 45ºC under nitrogen. The reaction mixture was mixed with EtOAc and water and extracted into EtOAc. The resulting organic phase was dried over magnesium sulfate and purified by silica gel normal-phase chromatography (DCM:MeOH from 100:0 to 80:20).

[0943] The following intermediate E-8 (Table 16) can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0944] Table 16

[0945]

[0946] Experimental procedure for synthesizing E-8cf (method K)

[0947]

[0948] Sodium hydride (60% dispersed in mineral oil, 652.8 mg, 16.32 mmol, 5.0 eq.) was added to a solution of (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (1.335 g, 8.16 mmol, 2.5 eq.) in DMF (50 mL) at room temperature. The mixture was stirred at room temperature for 10 min and E-6 g (1.00 g, 3.26 mmol, 1.0 eq.) was added. The mixture was stirred at room temperature for 3 h. The reaction was quenched by adding water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, dried, filtered, and the solvent was removed under vacuum. The crude product was purified by basic reversed-phase chromatography to give E-8cf.

[0949] Intermediate E-8, labeled “K” (Table 17), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0950] Experimental procedure for synthesizing E-8cg (Method L)

[0951]

[0952] Potassium tert-butoxide (45.6 mg, 0.41 mmol, 5.0 eq.) was added to a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethanol-1-ol (52.6 mg, 0.41 mmol, 5.0 eq.) in THF (2 mL) at room temperature. The mixture was stirred at room temperature for 30 min and E-6b (25.0 mg, 0.081 mmol, 1.0 eq.) was added. The mixture was stirred at room temperature for 15 min. The reaction was quenched by adding water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The organic layers were combined and the solvent was removed under vacuum. The crude product was purified by acid reversed-phase chromatography to give E-8cg.

[0953] Intermediate E-8, labeled “L” (Table 17), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0954] Experimental procedure for synthesizing E-8ch (Method M)

[0955]

[0956] E-6h (100.0 mg, 0.31 mmol, 1.0 eq.) and (S)-1,3-dimethylpiperazine (42.5 mg, 0.37 mmol, 1.2 eq.) were dissolved in DMSO (1 mL) at room temperature, and DIPEA (115.0 µL, 0.62 mmol, 2.0 eq.) was added, and the mixture was stirred for 1 h. The mixture was diluted with acetonitrile and water and purified by acid reversed-phase chromatography to obtain E-8ch.

[0957] Intermediate E-8, labeled “M” (Table 17), can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0958] Table 17

[0959]

[0960] Experimental procedure for synthesizing E-8cn

[0961]

[0962] E-8j (2.404 g, 4.50 mmol) in DCM (41 mL) was dissolved in HCl (in a 2-dimethylformamide solution). The mixture was treated with 4 M (8.33 mL, 33.31 mmol, 7.4 eq.) in alkane and stirred at room temperature for 5 h. After complete conversion, the mixture was concentrated and the crude product was purified by basic reversed-phase chromatography (gradient elution: 25% to 100% acetonitrile in water) to give E-8cn.

[0963] The following intermediate E-8 (Table 18) can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0964] Table 18

[0965]

[0966] Experimental procedure for synthesizing E-8cq

[0967]

[0968] E-8cn (231 mg, 0.532 mmol) in DCM (10.72 mL) was treated with formaldehyde (37% in water, 79.89 µL, 1.06 mmol, 2.0 eq.), acetic acid (304.0 µL, 5.32 mmol, 10.0 eq.), and a small amount of molecular sieve was added. The mixture was stirred for 15 min. Sodium triacetoxyborohydride (232.3 mg, 1.06 mmol, 2.0 eq.) was added, and the mixture was stirred at room temperature for 2 h. After complete conversion, the mixture was diluted with brine, and the product was extracted with DCM. The combined organic extracts were dried, filtered, and concentrated. The crude product was purified by basic reversed-phase chromatography (gradient elution: 35% to 98% acetonitrile in water) to give E-8cq.

[0969] The following intermediate E-8 (Table 19) can be obtained in a similar manner. If necessary, the crude product E-8 can be purified by chromatography.

[0970] Table 19

[0971]

[0972] Option 3:

[0973]

[0974] Experimental procedure for synthesizing E-14a

[0975]

[0976] E-8i (240.0 mg, 0.60 mmol), hydroxylamine hydrochloride (110.48 mg, 1.56 mmol, 2.60 eq.), and sodium carbonate (81.79 mg, 0.78 mmol, 1.30 eq.) were dissolved in anhydrous EtOH (3.90 mL), and the mixture was stirred at 85ºC for 1 h. After complete conversion, the mixture was concentrated under reduced pressure to give E-14a, which was used in the next step without further purification.

[0977] The following intermediate E-14 (Table 20) can be obtained in a similar manner using different nitriles E-8. If necessary, the crude product E-14 can be purified by chromatography.

[0978] Table 20

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991] Experimental procedure for synthesizing E-15a

[0992]

[0993] Hydroxylamine hydrochloride (6.39 g, 91.98 mmol, 2.0 eq.) was added to a solution of E-1e (10.00 g, 45.99 mmol) in TEA (19.20 mL, 137.96 mmol, 3.0 eq.) and EtOH (100.0 mL), and the mixture was stirred at room temperature for 2 h. After complete conversion, the solvent was evaporated under reduced pressure, and the residue was partitioned between EtOAc and 10% Na2CO3 solution. The organic layer was collected, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure to give E-15a, which was used for the next step without further purification.

[0994] Experimental procedure for synthesizing E-16a

[0995]

[0996] Hydroxylamine (50% in water, 363 µL, 2.5 eq.) was added to a solution of E-4b (1.00 g, 3.10 mmol) in THF (0.50 mL) at room temperature. The mixture was stirred at room temperature for 3 h. After complete conversion, the mixture was concentrated under reduced pressure to give E-16a, which was used for the next step without further purification.

[0997] The following intermediate E-16 (Table 21) can be obtained in a similar manner using different nitriles E-4. If necessary, the crude product E-16 can be purified by chromatography.

[0998] Table 21

[0999]

[1000] Option 4:

[1001]

[1002] Experimental procedure for synthesizing B-1a

[1003]

[1004] DIPEA (13.99 mL, 80.85 mmol, 3.0 eq.) was added to a stirred solution of E-15a (6.75 g, 26.95 mmol) and A-5a (7.00 g, 29.64 mmol, 1.1 eq.) in DMF (70 mL) at room temperature. The mixture was cooled to 0ºC, and benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate (21.04 g, 40.42 mmol, 1.5 eq.) was added. The mixture was allowed to reach room temperature and stirred for 16 h. After complete conversion, the mixture was diluted with EtOAc and washed with water and brine, dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane / EtOAc) and then ground with DCM to obtain B-1a.

[1005] The reaction here can also be carried out using enantiomeric starting material A-5 to obtain enantiomeric product B-1.

[1006] Experimental procedure for synthesizing B-2a

[1007]

[1008] A benzyltrimethylammonium hydroxide solution (40 wt.%, 1.962 g; 11.73 mmol, 2.2 eq. in MeOH) was added to a stirred solution of B-1a (2.50 g, 5.33 mmol) in THF (250 mL) at 0ºC, and the mixture was stirred at room temperature for 6 min. The reaction was quenched by adding 25 mL of water and 25 mL of EtOAc. The layers were separated, and the organic phase was washed with water, dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane / EtOAc) to give B-2a.

[1009] Experimental procedure for synthesizing B-3a

[1010]

[1011] The reaction was carried out under an argon atmosphere. At room temperature, 160 µL of a 7:5 (v / v) mixture of trichlorotrimethylsilane (0.730 mL) and 1,2-dibromoethane (0.520 mL) was added dropwise over a 10-min time interval to a stirred mixture of zinc powder (497.22 mg, 7.60 mmol, 8.0 eq.) and anhydrous DMA (1.24 mL), and the resulting mixture was stirred at room temperature for another 15 min. A solution of tert-butyl 4-iodopiperidine-1-carboxylate (1.941 g, 6.05 mmol, 13.2 eq.) in anhydrous DMA (3.08 mL) was added in portions while maintaining the temperature below 35ºC. The resulting mixture was stirred for another 30 min while cooling to room temperature.

[1012] In a second flask, anhydrous DMA (1.4 mL) was added to a mixture of B-2a (200.0 mg, 0.44 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride, DCM (16.82 mg, 0.02 mmol, 0.09 eq.), and cuprous iodide(I) (9.61 mg, 0.05 mmol, 0.23 eq.). The mixture was degassed, and 1.14 mL of the previously prepared piperidinyl zinc iodide solution (21% solution prepared according to the above procedure) was added through a 0.45 µm syringe filter. The resulting solution was degassed again and stirred at 80ºC for 1 h. After complete conversion, DCM, water, and a saturated ammonium chloride solution were added, the layers were separated, and the aqueous layer was extracted with DCM. The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The crude product was purified by alkaline reversed-phase chromatography (gradient elution: 50% to 98% acetonitrile in water) to obtain B-3a (HPLC method B; t). ret = 0.88 min; [M+H] + = 499).

[1013] Experimental procedure for synthesizing B-4a

[1014]

[1015] B-3a (200.0 mg, 0.360 mmol) was treated with 1-methylpiperazine (799.30 µL, 7.21 mmol, 20 eq.) and DIPEA (92.99 µL, 0.54 mmol, 1.5 eq.) and stirred in a sealed container at 80ºC for 16 h. After complete conversion, DCM, water, and brine were added, and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined, dried, filtered, and concentrated under reduced pressure to give B-4a, which was used in the next step without further purification.

[1016] The following intermediate B-4 (Table 22) can be obtained in a similar manner using different piperazine analogs B-3. If necessary, the crude product B-4 can be purified by chromatography.

[1017] Table 22

[1018]

[1019] Experimental procedure for synthesizing B-4c

[1020]

[1021] B-3b (100.0 mg, 0.18 mmol) was treated with 1-pyrrolidine-3-ylpiperidine (277.39 mg, 1.80 mmol, 10 eq.) and DIPEA (154.7 µL, 0.90 mmol, 5.0 eq.) and stirred at 100ºC for 16 h in a sealed vessel. After complete conversion, DCM, water, and brine were added, the layers were separated, and the aqueous layer was extracted with DCM. The organic layers were combined, dried, filtered, and concentrated under reduced pressure to give B-4c, which was used in the next step without further purification.

[1022] The following intermediate B-4 (Table 23) can be obtained in a similar manner using different intermediates B-3. If necessary, the crude product B-4 can be purified by chromatography.

[1023] Table 23

[1024]

[1025]

[1026]

[1027]

[1028] Experimental procedure for synthesizing B-5a

[1029]

[1030] B-4a (111.5 mg, 0.18 mmol) in DCM (2.00 mL) was dissolved in HCl (in a 2-distillate solution). The mixture was treated with 4 M (900.8 µL, 3.60 mmol, 20.0 eq.) in alkanes and stirred at room temperature for 1 h. After complete conversion, the mixture was concentrated and the crude product was purified by alkaline reversed-phase chromatography (gradient elution: 15% to 90% acetonitrile in water) to give B-5a.

[1031] The following intermediate B-5 (Table 24) can be obtained in a similar manner using different piperazine analogs B-4. If necessary, the crude product B-5 can be purified by chromatography.

[1032] Table 24

[1033]

[1034] Option 5:

[1035]

[1036] Experimental procedure for synthesizing B-6a

[1037]

[1038] N,N-dimethylformamide dimethyl acetal (674.4 µL, 5.55 mmol, 10.0 eq.) was added to a solution of B-2b (250.0 mg, 0.56 mmol) in DMF (3.5 mL), and the reaction mixture was stirred at room temperature for 16 h. After complete conversion, the product was separated by alkaline reversed-phase chromatography (gradient elution: 50% to 98% acetonitrile in water) to give B-6a (HPLC method A; t ret = 1.61 min; [M+H] + = 505).

[1039] Experimental procedure for synthesizing B-7a

[1040]

[1041] The procedure was performed in a glove box under a nitrogen atmosphere. B-6a (1.00 g, 1.785 mmol), (S)-1-((S)-1-methylpyrrolidone-2-yl)ethanol-1-ol (369.0 mg, 2.86 mmol, 1.6 eq.), sodium tert-butoxide (257.3 mg, 2.68 mmol, 1.5 eq.), and [BrettPhos Pd(crotonyl)]OTf (151.4 mg, 0.18 mmol, 0.1 eq.) were combined and anhydrous dimethyl ether was added. Alkane (15.0 mL) was added, and the mixture was stirred in a sealed vessel at room temperature for 16 h. After complete conversion, the mixture was poured into water, the pH was adjusted to 10 by adding 8 N NaOH, the product was extracted with DCM, and the combined organic layers were dried, filtered, and concentrated. The crude product was purified by alkaline reversed-phase chromatography (gradient elution: 60% to 98% acetonitrile in water) to give B-7a (HPLC method A; t ret = 1.74 min; [M+H]+ = 598).

[1042] Experimental procedure for synthesizing B-8a

[1043]

[1044] The procedure was performed in a glove box under a nitrogen atmosphere. B-7a (135.0 mg, 0.23 mmol), tert-butyl 3-hydroxyazacyclobutane-1-carboxylate (78.1 mg, 0.45 mmol, 2.0 equiv.), potassium phosphate (143.6 mg, 0.68 mmol, 3.0 eq.), palladium(II) acetate (5.1 mg, 0.023 mmol, 0.1 eq.), and 5-[bis(1-adamantyl)phosphino]-1',3',5'-triphenyl-1'H-[1,4]bipyrazole (29.9 mg, 0.045 mmol, 0.2 eq.) were combined, anhydrous toluene (2.7 mL) was added, and the mixture was stirred in a sealed container at 90ºC for 16 h. After complete conversion, the mixture was poured into water, the product was extracted with DCM, and the combined organic layers were dried, filtered, and concentrated. The crude product was purified by alkaline reversed-phase chromatography (gradient elution: 5% to 98% acetonitrile in water) to obtain B-8a.

[1045] The following intermediate B-8 (Table 25) can be obtained in a similar manner using different alcohols. If necessary, the crude product B-8 can be purified by chromatography.

[1046] Table 25

[1047]

[1048] Experimental procedure for synthesizing B-5c

[1049]

[1050] B-8a (112.2 mg, 0.16 mmol) was dissolved in EtOH (2.75 mL) and treated with concentrated HCl (37% in water, 94.1 µL, 1.137 mmol, 7.0 eq.). The mixture was stirred at 100ºC for 1 h, and after complete conversion, the mixture was concentrated, and the crude product was purified by basic reversed-phase chromatography (gradient elution: 15% to 98% acetonitrile in water) to give B-5c.

[1051] The following intermediate B-5 (Table 26) can be obtained in a similar manner using different analogues B-8. If necessary, the crude product B-5 can be purified by chromatography.

[1052] Table 26

[1053]

[1054] Option 6:

[1055]

[1056] Experimental procedure for synthesizing B-9a

[1057]

[1058] A-5a (67.09 mg, 0.28 mmol, 0.90 eq.) in DMSO (1.0 mL) was treated with HATU (125.9 mg, 0.32 mmol, 1.05 eq.) and TEA (89.2 µL, 0.62 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 20 min. E-16a (110.0 mg, 0.31 mmol, 1.0 eq.) was then added, and the mixture was stirred at room temperature for 2 h. The mixture was poured into water, and the precipitate was collected, washed with water, and dried to obtain B-9a, which was used in the next step without further purification.

[1059] The reaction can also be carried out using enantiomeric starting material A-5 to give a single stereoisomer of product B-9.

[1060] The following intermediate B-9 (Table 27) can be obtained in a similar manner using different intermediates E-16 and acid A5. If necessary, the crude product B-9 can be purified by chromatography.

[1061] Table 27

[1062]

[1063]

[1064]

[1065] Experimental procedure for synthesizing B-3b

[1066]

[1067] Tetrabutylammonium hydroxide solution (0.152 mL, 0.23 mmol, 0.75 eq. in 40% water) was added dropwise to a stirred solution of B-9a (180 mg, 0.31 mmol) in 1.0 mL of THF, and the mixture was stirred at room temperature for 16 h. After complete conversion, the mixture was concentrated under reduced pressure, and the crude product was purified by basic reversed-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give B-3b.

[1068] The following intermediate B-3 (Table 28) can be obtained in a similar manner using different intermediates B-9. If necessary, the crude product B-3 can be purified by chromatography.

[1069] Table 28

[1070]

[1071]

[1072] Experimental procedure for synthesizing B-10a

[1073]

[1074] The process is carried out in a similar manner to the preparation of B-6 from B-2 (see, for example, procedure B-6a B-2a).

[1075] The following intermediate B-10 (Table 29) can be obtained in a similar manner from different intermediates B-3. If necessary, the crude product B-10 can be purified by chromatography.

[1076] Table 29

[1077]

[1078] Experimental procedure for synthesizing B-8c

[1079]

[1080] The procedure was performed in a glovebox under a nitrogen atmosphere. B-10a (25.0 mg, 0.041 mmol), (1S)-1-[(2S)-1-methylpyrrolidone-2-yl]prop-1-ol (11.70 mg, 0.08 mmol, 2.0 eq.), sodium tert-butoxide (5.89 mg, 0.06 mmol, 2.0 eq.), and BrettPhos Pd (crotonyl) OTf (3.46 mg, 0.004 mmol, 0.1 eq.) were combined. Degassed dimethyl ether was added. The mixture was stirred in a sealed container at 60ºC for 16 h under an inert atmosphere (0.5 mL) with alkylene. The reaction mixture was filtered and the crude product was purified by acid reversed-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give B-8c.

[1081] The following intermediate B-8 (Table 30) can be obtained in a similar manner from different intermediates B-10. If necessary, the crude product B-8 can be purified by chromatography.

[1082] Table 30

[1083]

[1084]

[1085]

[1086]

[1087] Experimental procedure for synthesizing B-5e

[1088]

[1089] B-8c (140.0 mg, 0.195 mmol) was dissolved in EtOH (3 mL), and concentrated aqueous HCl (134 mg, 1.36 mmol) was added. The mixture was stirred at 100ºC under an inert atmosphere for 2 h. The reaction mixture was concentrated under vacuum, and the crude product was purified by basic reversed-phase chromatography (gradient elution: 30% to 90% acetonitrile in water) to give B-5e.

[1090] The following intermediate B-5 (Table 31) can be obtained in a similar manner using different intermediates B-8. If necessary, the crude product B-5 can be purified by chromatography.

[1091] Table 31

[1092]

[1093] Option 7:

[1094]

[1095] Experimental procedure for synthesizing B-11a

[1096]

[1097] A-5a (454.0 mg, 1.91 mmol, 1.0 eq.) in DMF (11.8 mL) was treated with HATU (724.5 mg, 1.91 mmol, 1.0 eq.) and DIPEA (0.923 mL, 5.72 mmol, 3.0 eq.), and the mixture was stirred at room temperature for 20 min. E-14a (874.8 mg, 1.48 mmol, 0.78 eq.) was then added, and the mixture was stirred at room temperature for 16 h. The crude mixture was purified by alkaline reversed-phase chromatography (gradient elution: 30% to 98% acetonitrile in water) to give B-11a.

[1098] The reaction can also be carried out using enantiomeric starting material A-5 to give a single stereoisomer of product B-11.

[1099] The following intermediate B-11 (Table 32) can be obtained in a similar manner using different intermediates E-14 and acid A-5. If necessary, the crude product B-11 can be purified by chromatography.

[1100] Table 32

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116] Experimental procedure for synthesizing B-4y

[1117]

[1118] Tetrabutylammonium fluoride solution (1 M, 2.168 mL, 2.17 mmol, 1.50 eq. in THF, 1.50 mL) was added dropwise to a stirred solution of B-11a (1.570 g, 1.45 mmol) in THF (16.0 mL), and the mixture was stirred at room temperature for 16 h. After complete conversion, the mixture was filtered, concentrated under reduced pressure, and the crude product was purified by basic reversed-phase chromatography (gradient elution: 40% to 98% acetonitrile in water) to give B-4y.

[1119] The following intermediate B-4 (Table 33) can be obtained in a similar manner using different intermediates B-11. If necessary, the crude product B-4 can be purified by chromatography.

[1120] Table 33

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139]

[1140] Experimental procedure for synthesizing B-5j

[1141]

[1142] B-4cn (400 mg, 0.50 mmol, 1 eq.) was dissolved in MeOH and then hydrogenated at 50ºC using an H-Cube apparatus with a palladium hydroxide cartridge. The solvent was removed under vacuum, and the residue was purified by reversed-phase chromatography to obtain B-5j (HPLC method A; t ret = 1.34 min; [M+H] + = 606).

[1143] Experimental procedure for deprotection of Boc and Cbz in synthetic building block B-4 (B-4 B-5)

[1144] The following intermediate B-5 (Table 34) can be obtained by deprotecting Boc or Cbz similar to that of the synthetic building block B-4 described herein (see B-4a, B-5a and B-4cn, B-5e).

[1145] Table 34

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152]

[1153]

[1154]

[1155]

[1156]

[1157]

[1158]

[1159]

[1160]

[1161]

[1162]

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169]

[1170]

[1171]

[1172]

[1173] Synthesis of the final compound (I) according to the present invention:

[1174] Option 8:

[1175]

[1176] Experimental procedure for synthesizing Ia-1

[1177]

[1178] B5-a (29.5 mg, 0.057 mmol), TEA (23.7 µL, 0.171 mmol, 3.0 eq.), and DMSO (900.0 µL) were dissolved in DCM (1.0 mL). Acryloyl chloride (5.5 µL, 0.068 mmol, 1.2 eq.) dissolved in DCM (1 mL) was added dropwise over a 10-min time interval, and the mixture was stirred at room temperature for 30 min. Acryloyl chloride (3.2 µL, 0.04 mmol, 0.7 eq.) dissolved in DCM (0.2 mL) was then added dropwise, and the mixture was stirred for another 30 min. After complete conversion, the mixture was concentrated, and the crude product was purified by acidic reversed-phase chromatography (gradient elution: 5% to 60% acetonitrile in water) to give Ia-1.

[1179] The following compounds (I) (Table 35) belonging to subclass Ia according to the present invention can be obtained in a similar manner using different analogs B-5. If necessary, the crude product Ia can be purified by chromatography.

[1180] Table 35

[1181]

[1182] Experimental procedure for synthesizing Ia-3

[1183]

[1184] Acryloyl chloride solution (1 M, 336.0 µL, 0.34 mmol, 3.0 eq. in acetone) was added to a mixture of potassium carbonate (46.4 mg, 0.34 mmol, 3.0 eq.), acetone (1.75 mL), and water (0.35 mL). The mixture was stirred at room temperature for 10 min, and then B-5c (60.0 mg, 0.11 mmol) dissolved in acetone (1.75 mL) and water (0.35 mL) was added. The mixture was stirred at room temperature for 15 min. After complete conversion, the mixture was concentrated, and the crude product was purified by basic reversed-phase chromatography (gradient elution: 10% to 98% acetonitrile in water) to give Ia-3.

[1185] The following compounds (I) (Table 36) belonging to subclass Ia according to the present invention can be obtained in a similar manner using different analogs B-5. If necessary, the crude product Ia can be purified by chromatography.

[1186] In some cases, the synthesis is carried out using a mixture of diastereomers as starting materials, and the enantiomeric final compound is separated by chiral SFC if necessary.

[1187] Table 36

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194]

[1195]

[1196]

[1197]

[1198]

[1199]

[1200]

[1201]

[1202]

[1203]

[1204]

[1205]

[1206]

[1207]

[1208]

[1209]

[1210]

[1211]

[1212]

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219] Compound Ia, as depicted in Table 37 below, can be obtained from different intermediates B-5 and the corresponding carboxylic acids in a manner similar to the conversion of C-5a to Ic-8 described further below. If necessary, the crude product Ia can be purified by chromatography.

[1220] Table 37

[1221]

[1222]

[1223] Compound Ia, as depicted in Table 38 below, can be obtained from different intermediates B-5 and 2-butynedic acid, in a manner similar to the conversion of C-5a to Ic-8 described further below. If necessary, the crude product Ia can be purified by chromatography.

[1224] Table 38

[1225]

[1226]

[1227] Experimental procedure for synthesizing Ia-169

[1228]

[1229] B-5f (70.0 mg, 0.13 mmol) in anhydrous DMF (0.75 mL) was treated with TEA (46.0 µL, 0.32 mmol, 2.5 eq.), followed by treatment with (2E)-4-bromo-N,N-dimethylbut-2-enamine (33.63 mg, 0.14 mmol, 1.1 eq.) dissolved in DMF (0.75 mL). The mixture was stirred at room temperature for 48 h. After complete conversion, the product was separated by alkaline reversed-phase chromatography (gradient elution: 15% to 52% acetonitrile in water) to give Ia-169 (HPLC method A; t ret=1.23 min; [M+H] + = 661).

[1230] Table 39

[1231]

[1232] Experimental procedure for synthesizing Ia-170

[1233]

[1234] Ia-155 (84 mg, 0.13 mmol, 1 eq.) was dissolved in DCM (1 mL) and trifluoroacetic acid (145 mg, 1.27 mmol, 10 eq.) was added. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum and then purified by basic reversed-phase chromatography (acetonitrile:water = 30:70 90:10). Then it was purified by acidic reversed-phase chromatography (acetonitrile:water = 5:95 60:40). The product containing fractions was lyophilized to obtain Ia-170.

[1235] Table 40

[1236]

[1237] The following examples describe the biological activities of the compounds according to the present invention, but the invention is not limited to these examples.

[1238] KRAS::SOS1 AlphaScreen binding assay

[1239] This assay can be used to examine the efficacy of compounds according to the invention that bind to KRAS G12C in inhibiting protein-protein interactions between SOS1 and KRAS G12C. This inhibits the GEF function of SOS1 and locks KRAS G12C into its inactive GDP-binding state. The low IC50 value in this assay setting... 50 The values ​​indicate that the protein-protein interaction between SOS1 and KRAS is strongly inhibited.

[1240] Reagents:

[1241] • SOS1 with GST label (564_1049_GST_TEV_ECO), internally manufactured

[1242] • GST-TEV-SOS1 (564-1049), purchased from Viva Biotech Ltd.

[1243] The expression construct containing the C-terminal avi tag of KRAS G12C (amino acids 1-169 of the reference sequence P01116-2 (uniprot), with additional mutations: C51S, C80L, and C118S) was obtained through gene synthesis in the donor vector (pDONR-221) (GeneArt, Thermo Fisher) and transferred to the pDEST17 vector with an N-terminal His6 tag via recombinant cloning. The protein was expressed in E. coli, and the purified protein was biotinylated with E. coli biotin ligase (BirA) before use.

[1244] GDP (Sigma catalog number G7127)

[1245] • AlphaLISA glutathione receptor beads (PerkinElmer, catalog number AL109)

[1246] • AlphaScreen streptavidin donor beads (PerkinElmer catalog number 6760002)

[1247] • Test plate: Proxiplate-384 PLUS, white (PerkinElmer, catalog number 6008289)

[1248] Assay buffer:

[1249] 1 x PBS

[1250] 0.1% BSA

[1251] 0.05% Tween 20

[1252] KRAS::SOS1 GDP mixture:

[1253] Before use, mix 7.5 nM (final assay concentration) KRAS G12C, 10 µM (final assay concentration) GDP and 5 nM (final assay concentration) GST-SOS1 in assay buffer and keep at room temperature.

[1254] Bead mixture:

[1255] Before use, mix the AlphaLISA glutathione receptor beads and AlphaScreen streptavidin donor beads in the assay buffer at a concentration of 10 μg / mL (final assay concentration) and keep at room temperature.

[1256] Measurement protocol:

[1257] Dilute the compound to a final starting concentration of 100 µM and test in duplicate. Generate assay preparation plates (ARPs) using an Access Labcyte workstation with a Labcyte Echo 550 or 555 acoustic dispenser. For compounds with a starting concentration of 100 µM, transfer 150 nL of compound solution per well in duplicate at 11 consecutive 1:5 dilutions.

[1258] The assay was performed using a fully automated robotic system in a dark room at less than 100 lux. 10 µL of KRAS::SOS1 GDP mixture was added to column 1-24 to 150 nL of compound solution (final dilution 1:100 for assay, final DMSO concentration 1%).

[1259] After a 30-minute incubation period, 5 µL of the bead mixture was added to column 1-23. The plates were kept in a dark incubator at room temperature. After a further 60-minute incubation, the signal was measured using a PerkinElmer Envision HTS multi-label reader with AlphaScreen specifications from PerkinElmer. Each plate contained the following controls:

[1260] • Diluted DMSO + KRAS::SOS1 GDP mixture + bead mixture

[1261] • Diluted DMSO + KRAS::SOS1 GDP mixture

[1262] Result calculation:

[1263] Calculating and analyzing ICs using a 4-parameter logic model 50 value.

[1264] The compounds disclosed in this article contain IC values ​​determined using the above assay method. 50 value.

[1265] Ba / F3 cell model generation and proliferation assay

[1266] Ba / F3 cells were ordered from DSMZ (ACC300, Lot 17) and grown at 37ºC in RPMI-1640 (ATCC 30-2001) + 10% FCS + 10 ng / mL IL-3 under a 5% CO2 atmosphere. Plasmids containing the KRASG12 mutant were obtained from GeneScript. To generate a KRASG12-dependent Ba / F3 model, Ba / F3 cells were transduced with a retrovirus containing a vector with the KRASG12 isotype. Platinum-E cells (Cell Biolabs) were used for retrovirus packaging. The retrovirus was added to the Ba / F3 cells. To ensure infection, 4 μg / mL polyglobulin was added and the infected cells were rotated. Infection efficiency was confirmed by measuring GFP-positive cells using a cell analyzer. Cells with an infection efficiency of 10% to 20% were further incubated and selection was initiated with 1 μg / mL puromycin. Parental Ba / F3 cells were used as a control to demonstrate the selection status. Selection was considered successful when the parental Ba / F3 cell cultures died. To evaluate the transformation potential of the KRASG12 mutation, IL-3 was no longer supplemented in the growth medium. Ba / F3 cells with the empty vector were used as a control. Puromycin was discontinued approximately ten days prior to the experiment.

[1267] For proliferation assays, Ba / F3 cells were grown in growth medium (RPMI-1640 + 10% FCS) at a concentration of 1 x 10⁻⁶ cells / mL. 3 60 μL of cells were seeded into 384-well plates. Compounds were added using an AccessLabcyte workstation equipped with a Labcyte Echo 550 or 555 acoustic dispenser. All treatments were performed technically in duplicate. Assays were performed using a fully automated robotic system. Treated cells were incubated at 37ºC and 5% CO2 for 72 h. The reactive dye AlamarBlue™ (ThermoFisher) was added, and fluorescence was measured in a PerkinElmer Envision HTS multi-label reader. Raw data were imported into Boehringer Ingelheim proprietary software MegaLab and analyzed (based on curve fitting of the PRISM program, GraphPad Inc.).

[1268] IC50 of the representative compound (I) according to the present invention, measured using this assay method 50 The values ​​are presented in Table 41.

[1269] Table 41

[1270]

[1271]

[1272]

[1273] Further proliferation assays of G12C mutant cancer cell lines

[1274] • SW 837 CTG proliferation assay (CRC)

[1275] SW837 cells (ATCC #CCL-235) were cultured in a 175 cm⁻¹ cell culture flask containing L-15 10% FCS, 1% L-Glu, 1xNEAA, and 1x Na-Pyrovat. 2 Cultures were grown in a humid atmosphere at 37ºC and 0% CO2, with medium changes or subculturing performed 2-3 times per week. Materials used for assays were sterile, tissue culture-treated white opaque 384-well microplates (Perkin Elmer #6007680), Leibovitz L15 medium, and FBS # SH30071.03 (HyClone).

[1276] Proliferation assays were initiated on day 1 by seeding cells at a density of 500 cells / well in 90 µL of L-15 10% FCS, 1% L-Glu, 1xNEAA, and 1x Na-Pyrovat in a flat-bottomed 384-well microtiter plate. Any other luminescently compatible plate format was acceptable. On day 2, 10 µL of a dilution of the test compound covering a concentration range between approximately 0.1 and 10,000 nM was added to the cells. Cells were incubated for 5 days at 37ºC in a humidified, CO2-controlled (CO2-free) incubator. On day 7, 100 µL of Cell Titer Glow reagent (Cell titer Glo Luminescent catalog number G7571, Promega) was added to each well, and the cells were incubated for an additional 10 min at room temperature (with stirring). Luminescence was measured using a standard luminescence readout on a Wallac Victor. IC50 was calculated using the standard Levenberg Marquard algorithm (GraphPad Prism). 50 value.

[1277] IC50 of the representative compound (I) according to the present invention, measured using this assay method 50 The values ​​are presented in Table 42.

[1278] • MiaPaCa-2 CTG proliferation assay (pancreatic cancer)

[1279] MiaPaCa-2 cells (ATCC® CRM-CRL-1420™) were cultured in a 175 cm⁻¹ cell culture flask containing DMEM medium supplemented with 10% fetal bovine serum. 2 Cultures were grown in a humid atmosphere at 37ºC and 5% CO2, with medium changes or subculturing performed 2-3 times per week. Materials used for assays were CulturPlate-384 sterile, tissue culture-treated white opaque 384-well microplates (Perkin Elmer #6007680), DMEM medium, and FBS #SH30071.03 (HyClone).

[1280] Proliferation assays were initiated on day 1 by seeding cells at a density of 500 cells / well in 90 µL of DMEM medium supplemented with 10% FBS in a flat-bottomed 384-well microtiter plate. Any other luminescently compatible plate format was acceptable. On day 2, 10 µL of a dilution of the test compound covering a concentration range between approximately 0.1 and 10,000 nM was added to the cells. Cells were incubated for 5 days at 37ºC in a humidified incubator containing 5% CO2. On day 7, 100 µL of Cell Titer Glow reagent (Cell titer Glo Luminescent catalog number G7571, Promega) was added to each well, and the cells were incubated for an additional 10 min at room temperature (with stirring). Luminescence was measured using a standard luminescence readout on a Wallac Victor. IC50 was calculated using the standard Levenberg Marquard algorithm (GraphPad Prism). 50 value.

[1281] IC50 of the representative compound (I) according to the present invention, measured using this assay method 50 The values ​​are presented in Table 42.

[1282] • NCI-H358 CTG proliferation assay (120 h) (NSCLC)

[1283] NCI-H358 cells (ATCC No. CRL-5807) were partitioned at a density of 2000 cells per well into 100 µL of RPMI-1640 ATCC-prepared (Gibco #A10491) + 10% FCS in opaque white-bottomed 96-well plates (Perkin Elmer catalog No. 5680). Cells were incubated overnight at 37ºC in a humidified tissue culture incubator with 5% CO2. The compound (10 mM stock solution in DMSO) was added in logarithmic dose series using an HP digital dispenser D300 (Tecan) (normalized against the amount of DMSO added). For measurements at the T0 time point, untreated cells were analyzed at the time of compound addition. The plates were incubated for 120 h, and cell viability was measured using the CellTiter-Glo luminescent cell viability assay (Promega product code G7570). Viability (expressed as a percentage of control) was defined as the relative luminescent units (RLU) per well divided by the RLU of cells in the DMSO control. IC 50 The values ​​were determined from the vitality measurement using a four-parameter model via nonlinear regression.

[1284] IC50 of the representative compound (I) according to the present invention, measured using this assay method 50 The values ​​are presented in Table 42.

[1285] • NCI-H2122 CTG proliferation assay (120 h) (NSCLC)

[1286] The CTG assay was designed to quantitatively measure the proliferation of NCI-H2122 cells (ATCC CRL-5985) using the CellTiter Glow Assay Kit (Promega G7571). Cells were grown in RPMI medium (ATCC) supplemented with fetal bovine serum (Life Technologies, Gibco BRL, catalog number 10270-106). On Day 0, 1000 NCI-H2122 cells were seeded in 60 µL of RPMI ATCC + 10% FCS + Penstrep in 384-well flat-bottomed plates. Cells were then incubated overnight in a CO2 incubator at 37ºC. On Day 1, compounds, including a DMSO control, were added using the ECHO Acoustic Liquid Handling System (Beckman Coulter). The plates were incubated for 120 hours, and cell viability was measured using the CellTiter-Glo luminescent cell viability assay kit (Promega product code G7570). Viability (expressed as a percentage of the control) is defined as the relative luminescence units (RLU) per well divided by the RLU of cells in the DMSO control. IC 50 The values ​​were determined from the vitality measurement using a four-parameter model via nonlinear regression.

[1287] Table 42

[1288]

[1289] ERK phosphorylation assay

[1290] The ERK phosphorylation assay was used to examine the efficacy of the compound in in vitro in inhibiting KRAS G12C-mediated signal transduction in a KRAS G12C mutant human cancer cell line. This demonstrated the molecular mode of action of the compound according to the invention by interfering with the RAS G12C protein signal transduction cascade. The low IC50 value in this assay setting... 50 The values ​​demonstrate the high potency of the compounds according to the invention. The compounds according to the invention were observed to inhibit ERK phosphorylation in KRAS G12C mutant human cancer cell lines, thus confirming the molecular mechanism of action of the compounds on RAS G12C protein signaling.

[1291] ERK phosphorylation assays were performed using the following human cell lines:

[1292] NCI-H358 (ATCC (ATCC CRL-5807): human lung cancer with a KRAS G12C mutation (Assay 1), and NCI-H358_Cas9_SOS2, the same cell line but with SOS2 knocked out (Assay 2). A vector containing a designed DNA sequence for generating gRNA for SOS2 protein knockout was obtained from Sigma-Aldrich. To generate the NCI-H358 SOS2 knockout cell line, NCI-H358 cells expressing the Cas9 endonuclease were transfected with XtremeGene9 reagent and the corresponding plasmid. Transfection efficiency was confirmed by measuring GFP-positive cells using a cell analyzer. GFP-positive cells were collected and further amplified. These GFP-positive cell libraries were single-cell dilutions, and SOS2 knockout clones were identified by Western blotting and genomic DNA sequencing analysis.

[1293] Materials used for measurement:

[1294] RPMI-1640 medium (ATCC® 30-2001™)

[1295] Fetal bovine serum (FBS) from HyClone (SH30071.03)

[1296] Non-essential amino acids (11140035) from Thermo Fischer Scientific

[1297] Pyruvate (11360039) from Thermo Fischer Scientific

[1298] Glutamax (35050061) from Thermo Fischer Scientific

[1299] 384 plates (781182) from Greiner Bio-One

[1300] Proxiplate™ 384 (6008280) from PerkinElmer Inc.

[1301] AlphaLISA SureFire Ultra p-ERK1 / 2 (Thr202 / Tyr204) Assay Kit (ALSU-PERK-A500)

[1302] EGF (E4127) from Sigma

[1303] Receptor mixture: Protein A receptor beads (6760137M) from PerkinElmer.

[1304] Donor mixture: AlphaScreen streptavidin-coated donor beads (6760002) from PerkinElmer.

[1305] trametinib

[1306] Staurosporine (S6942) from Sigma Aldrich

[1307] Measurement setup:

[1308] Cells were seeded at 40,000 cells / well in 60 µL of RPMI containing 10% FBS, non-essential amino acids, pyruvate, and glutamax in Greiner TC 384 plates. Cells were incubated at room temperature for 1 h, followed by overnight incubation at 37ºC and 5% CO2 under humidified conditions. Then, 60 nL of compound solution (10 mM DMSO stock solution) was added using a Labcyte Echo 550 device. After 1 h of incubation in the above incubator, the medium was removed by centrifugation, and cells were lysed by adding 20 µL of 1.6-fold lysis buffer from the AlphaLISA SureFire Ultra pERK1 / 2 (Thr202 / Tyr204) assay kit containing protease inhibitors, 100 nM trametinib, and 100 nM asteroidin. After incubating with shaking at room temperature for 20 minutes, 6 µL of each lysate sample was transferred to a 384-well Proxiplate, and pERK (Thr202 / Tyr204) was analyzed using the AlphaLISA SureFire Ultra pERK1 / 2 (Thr202 / Tyr204) assay kit. 3 µL of acceptor mixture and 3 µL of donor mixture were added under dimmed light and incubated in the dark at room temperature for 2 h, followed by signal measurement on a PerkinElmer Envision HTS multilabel reader. The raw data were imported into the Boehringer Ingelheim proprietary software MegaLab and analyzed (based on curve fitting of the PRISM program, GraphPad Inc.).

[1309] The IC50 of the representative compound (I) according to the present invention was measured using this method. 50 The values ​​are presented in Table 57 (IC values ​​for determination 2). 50 All others marked with * are from determination 1).

[1310] Table 42

[1311]

[1312]

[1313]

[1314]

[1315] The following examples of formulations illustrate the invention but do not limit its scope:

[1316] Pharmaceutical formulation examples

[1317]

[1318] Finely ground active ingredient, lactose, and some corn starch are mixed together. The mixture is sieved, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated, and dried. The granules, remaining corn starch, and magnesium stearate are sieved and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

[1319]

[1320] Finely ground active ingredients, some corn starch, lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixed together. The mixture is sieved and processed with the remaining corn starch and water to form granules. The granules are dried and sieved again. Sodium carboxymethyl starch and magnesium stearate are added and mixed in, and the mixture is compressed to form tablets of suitable size.

[1321]

[1322] The active ingredient, lactose, and cellulose are mixed together. The mixture is sieved, then moistened with water, kneaded, wet-granulated, and dried or dry-granulated, or directly blended with magnesium stearate and compressed into tablets of suitable shape and size. When wet-granulating, additional lactose or cellulose and magnesium stearate are added, and the mixture is compressed into tablets of suitable shape and size.

[1323]

[1324] The active ingredient is dissolved in water at its own pH or optionally at pH 5.5 to 6.5, and sodium chloride is added to make it isotonic. The resulting solution is filtered to remove pyrogens, and the filtrate is aseptically transferred to ampoules, which are then sterilized and melt-sealed. The ampoules contain 5 mg, 25 mg, and 50 mg of active ingredient.

Claims

1. A compound of formula (I) ,in R 1a and R 1b All are independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-5 cycloalkyl and 3-5 membered heterocyclic groups; R 2a and R 2b All are independently selected from hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-5 cycloalkyl and 3-5 membered heterocyclic groups; And / or, optionally, R 1a Or R 1b One of them and R 2a Or R 2b One of them, together with the carbon atoms to which they are attached, forms a cyclopropane ring; Z is -(CR 6a R 6b ) n -; Each R 6a and R 6b Independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-5 cycloalkyl and 3-5 membered heterocyclic groups; n is selected from 0, 1, and 2; R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -CN, C 3-5 cycloalkyl and 3-5 membered heterocyclic groups; Ring A is Diazole or thiadiazole; U is selected from nitrogen (=N-) and R. A Substituted carbon (=C(R) A )-); V is selected from nitrogen (=N-) and R. B Substituted carbon (=C(R) B )-); W is selected from nitrogen (=N-) and R. C Substituted carbon (=C(R) C )-); R A R B and R C Each is independently selected from hydrogen and C. 1-6 Halogenated alkyl, optionally C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2; R 5 Selected from R a1 and R b1 ; R a1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups. b1 and / or R c1 replace; 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 Alkyl)C(=O)R c1 -NHS(=O)2R c1 -N(C 1-4 alkyl)S(=O)2R c1 -NHC(=O)OR c1 -N(C 1-4 Alkyl)C(=O)OR c1 and divalent substituent = O; Each R c1 Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups. d1 and / or R e1 replace; Each R d1 Independently selected from -OR e1 -NR e1 R e1 Halogen, -CN, -C(=O)R e1 -C(=O)OR e1 -C(=O)NR e1 R e1 -S(=O)2R e1 -S(=O)2NR e1 R e1 -NHC(=O)R e1 -N(C 1-4 Alkyl)C(=O)R e1 -NHS(=O)2R c1 -N(C 1-4 alkyl)S(=O)2R c1 -NHC(=O)OR e1 -N(C 1-4 Alkyl)C(=O)OR e1 and divalent substituent = O; Each R e1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl groups, 3-11 membered heterocyclic groups—which may optionally be substituted by one or more of the same or different of the following groups: C 1-4 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, halogen, -CN, -NH2, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group (2) and divalent substituent = O; L is -L 1 -L 2 -L 3 -, where L 1 Connect to E; L 1 Selected from bonds, -NH-, -N(C 1-4 Alkyl group, -O group, -C(=O) group, -NH-C(=O) group, -N(C) group 1-4 Alkyl)-C(=O)-, -C(=O)-NH-, -C(=O)-N(C 1-4 Alkyl)-, -C(=O)-, C 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4-12 membered heterocyclic alkylene and 5-10 membered heteroarylalkylene; L 2 Selected from C 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4-12 membered heterocyclic alkylene and 5-10 membered heteroarylalkylene; L 3 Selected from bonds, -NH-, -N(C 1-4 Alkyl group, -O group, -C(=O) group, -NH-C(=O) group, -N(C) group 1-4 Alkyl)-C(=O)-, -C(=O)-NH-, -C(=O)-N(C 1-4 Alkyl)-, -C(=O)-, C 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4-12 membered heterocyclic alkylene and 5-10 membered heteroarylalkylene; Where L 1 L 2 and L 3 Each C in 1-6 Alkylene, C 3-7 Cycloalkylene, phenylene, 4-12-membered heterocyclic and 5-10-membered heteroaryl groups are optionally and independently substituted by one or more identical or different substituents selected from the following: C 2-6 Alkyne group, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 5-6 heteroaryl, halogen, -OH, -CN, C 1-6 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)-OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl group 2, divalent substituent =O, and C group optionally substituted with one or more identical or different substituents selected from the following. 1-6 Alkyl groups: halogens, -OH, -CN, C 1-4 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)-OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2; E is Indicates a double or triple bond; Q 1 Selected from bonds, -CH2-, -CH(OH)-, -C(=O)-, -C(=O)N(R) G1 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G1 - and -C(=NR) H1 )-; Each R G1 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, cyano-C 1-6 Alkyl, (C 1-4 Alkyl)HN-C 1-6 Alkyl, (C 1-4 (alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3-11 membered heterocyclic groups; Each R H1 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl; if To represent a double bond, then R D Selected from hydrogen, C 3-7 Cycloalkyl, phenyl, halogen, -CN, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -NHC(=O)-C 1-6 Alkyl groups and C groups optionally substituted with one or more identical or different substituents selected from the following 1-6 Alkyl groups: phenyl, 3-11 membered heterocyclic groups, C 1-6 Alkoxy, halogen, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)NH(C) 1-6 Alkyl), -NHC(=O)-C 1-6 Alkyl, -OC(=O)-C 1-6 Alkyl and phenyl-C 1-6 Alkoxy; R E and R F Each independently selected from R a2 and R b2 ; R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups. b2 and / or R c2 replace; 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 -S(=O)2R c2 -S(=O)2NR c2 R c2 -NHC(=O)R c2 -N(C 1-4 Alkyl)C(=O)R c2 -NHC(=O)OR c2 -N(C 1-4 Alkyl)C(=O)OR c2 and divalent substituents = O; Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3-11 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, -OH, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-(C 1-6 -alkyl), -C(=O)-N(C 1-6 -alkyl)2 and divalent substituents =O; or R D and R E Together with the carbon atoms attached to them, they form 4-7 membered unsaturated alicyclic rings or 4-7 membered unsaturated heterocyclic rings, wherein the 4-7 membered unsaturated alicyclic rings or 4-7 membered unsaturated heterocyclic rings and R F Optionally substituted by one or more identical or different substituents selected from the following: C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OH, C 1-6 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -NH2, -CN, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2, halogen, -C(=O)OC 1-6 Alkyl group and divalent substituent = O; or If Q 1 It is -C(=O)N(R) G1 )-, then -C(=O)N(R G1 )- of R G1 and R F Together they form a connector selected from the following: -C(=O)-, -CH2-, -CH2-C(=O)-, -C(=O)-CH2- and -C2H4-; if To represent a triple bond, then R D and R E None of them exist; R F It is R a2 ; R a2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more identical or different R groups. b2 and / or R c2 replace; 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 -S(=O)2R c2 -S(=O)2NR c2 R c2 -NHC(=O)R c2 -N(C 1-4 Alkyl)C(=O)R c2 -NHC(=O)OR c2 -N(C 1-4 Alkyl)C(=O)OR c2 and divalent substituents = O; Each R c2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; or E is Q 2 Selected from bonds, -CH2-, -CH(OH)-, -C(=O)-, -C(=O)N(R) G2 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G2 - and -C(=NR) H2 )-; Each R G2 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, cyano-C 1-6 Alkyl, (C 1-4 Alkyl)HN-C 1-6 Alkyl, (C 1-4 Alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 Cycloalkyl and 3-11 membered heterocyclic groups; Each R H2 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl; R I Selected from hydrogen and halogens; R J It is hydrogen; or R I and R J Together with the carbon atoms attached to them, they form cyclopropane or ethylene oxide rings; R K Selected from hydrogen, C 1-6 Alkyl groups, -CN groups, and halogens; R L Selected from hydrogen, C 1-6 Alkyl groups, -CN, halogens, and -C(=O)-C 1-6 alkyl; or E is Q 3 Selected from -C(=O)- and -C(=O)N(R) G3 )-, -C(=O)O-, -S(=O)2-, -S(=O)2N(R G3 - and -C(=NR) H3 )-; Each R G3 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, H2N-C 1-6 Alkyl, cyano-C 1-6 Alkyl, (C 1-4 Alkyl)HN-C 1-6 Alkyl, (C 1-4 Alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-7 Cycloalkyl and 3-11 membered heterocyclic groups; Each R H3 Independently selected from hydrogen, -OH, C 1-6 Alkoxy, -CN and C 1-6 alkyl; R M Selected from halogens, -CN and -OC(=O)-C 1-6 alkyl; or E is Q 4 Selected from bonds, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(C 1-4 Alkyl group, -S(=O)2- and -S(=O)2NH-; Ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and 5-membered heteroaryl; q is selected from 1, 2, 3, and 4; Each R N Selected independently from C 1-4 Alkyl, C 1-4 Halogenated alkyl, vinyl, ethynyl, halogen, -CN, nitro and C 1-4 Alkoxy; Or its salt.

2. The compound or salt according to claim 1, having formula (Ia) ,in R 1a R 1b R 2a R 2b Z, R 3 U, V, W, R 5 L and E are as defined in claim 1.

3. A compound of formula (II) ,in R 1a R 1b R 2a R 2b Z, R 3 Ring A, U, V, W, R 5 And L as defined in claim 1 for formula (I) or its salts.

4. The compound or salt according to any one of claims 1 to 3, wherein R 1a and R 1b Both are independently selected from hydrogen and C 1-4 alkyl; R 2a and R 2b They are all independently selected from hydrogen and halogens.

5. The compound or salt according to any one of claims 1 to 4, wherein R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, cyano-C 1-4 Alkyl, halogen, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2 and -CN.

6. The compound or salt according to any one of claims 1 to 5, wherein Ring A is selected from 7. The compound or salt according to any one of claims 1 to 6, wherein U is R A Substituted carbon (=C(R) A )-); V is R B Substituted carbon (=C(R) B )-); W stands for nitrogen (=N-); R A and R B Each is independently selected from hydrogen and C. 1-6 Halogenated alkyl, optionally C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2.

8. The compound or salt according to any one of claims 1 to 6, wherein U is R A Substituted carbon (=C(R) A )-); V is R B Substituted carbon (=C(R) B )-); W was R C Substituted carbon (=C(R) C )-); R A R B and R C Each is independently selected from hydrogen and C. 1-6 Halogenated alkyl, optionally C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2.

9. The compound or salt according to any one of claims 1 to 6, wherein U is nitrogen (=N-); V is R B Substituted carbon (=C(R) B )-); W stands for nitrogen (=N-); R B Selected from hydrogen, C 1-6 Halogenated alkyl, optionally C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, and C groups optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2.

10. The compound or salt according to any one of claims 1 to 6, wherein U is R A Substituted carbon (=C(R) A )-); V is nitrogen (=N-); W stands for nitrogen (=N-); R A Selected from hydrogen, C 1-6 Halogenated alkyl, optionally C 3-5 Cycloalkyl-substituted C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl, 3-5 membered heterocycles, and C-membered rings optionally substituted with substituents selected from the following 1-6 Alkyl: C 1-6 Alkoxy, -CN, -OH, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl) and -C(=O)N(C 1-4 Alkyl)2.

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