CA 3,000,063 NEW SPIRO[3H-INDOLE-3,2"-PYRROLIDIN]-2(1H)-ONE COMPOUNDS AND DERIVATIVES AS MDM2-P53 INHIBITORS The present invention relates to new spiro[3H-indole-3,2"-pyrrolidin1-2(1H)- one compounds and derivatives of formula (I) (124),NOkF NO I 3 = 6) R. - ..== n R ,y N,R1 (Rig V lAr N H wherein the groups R1 to R4, R7, A, D, E, F, V, W, X, Y, n, r and q have the meanings given in the claims and specification, their use as inhibitors of MDM2-p53 interaction, pharmaceutical compositions which contain compounds of this kind, their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases, lic) and synthetic intermediates. Background of the invention The tumor suppressor protein p53 is a sequence specific transcription factor and plays a central role in the regulation of several cellular processes, including cell cycle and growth arrest, apoptosis, DNA repair, senescence, angiogenesis, and innate immunity. The Mouse 15 Double Minute 2 (MDM2) protein (or its human homolog also known as HDM2) acts to down-regulate p53 activity in an auto-regulatory manner, and under normal cellular conditions (absence of stress), the MDM2 protein serves to maintain p53 activity at low levels. MDM2 directly inhibits the transactivation function of p53, exports p53 out of the nucleus, and promotes proteasome-mediated degradation of p53 through its E3 ubiquitin 20 ligase activity. Deregulation of the MDM2/p53 balance by overexpression of MDM2 or by p53 mutation or loss leads to malignant transformation of normal cells. Presently p53 is known to play a key role in practically all types of human cancers, and the mutation or loss of the p53 gene can 1 Date Recue/Date Received 2023-03-01 CA 3,000,063 be identified in more than 50 % of all human cancers worldwide. Analysis of 28 different types of human cancers in nearly 4,000 human tumor samples showed that MDM2 is amplified in 7 % of human cancers and that MDM2 overexpression by amplification and p53 mutations are largely mutually exclusive (Momand et aL, Nucleic Acid Res (1998) 26:3453- 3459). Because of the powerful tumor suppressor function of p53, reactivation of p53 has been long sought as a potentially novel cancer therapeutic strategy. In tumor harboring wild-type p53, MDM2 is the primary cellular inhibitor of p53 activity, and overexpression of MDM2 was found in many human tumors. Since MDM2 inhibits p53 through a direct protein-protein interaction, blocking this interaction using small molecules was pursued in several academic and industrial pharmaceutical laboratories in the last decade. A variety of non-peptide, drug- like small molecule as e.g. imidazole compounds (e.g. Nutlins or RG7112), benzodiazepinedione compounds, spirooxindole compounds (e.g. MI-219), substituted piperidines, pyrrolidinone compounds (e.g. PXN820-dl) and modifications thereof have been selected and designed in order to block MDM2/p53 interaction as a means to reactivate p53 in cells (Vassilev et al., Science (2004) 303:844-848; Grasberger et al., J Med Chem (2005) 48:909-912; Parks et al., Bioorg Med Chem Lett (2005) 15:765; Ding et J Am Soc (2005) 127:10130-10131; WO 2010/028862, US Patent 7,884,107, WO 2008/119741). A number of potent MDM2/p53 inhibitors have been evaluated in animal models of human cancer for their anti-tumor activity (Vassilev et al., Science (2004) 303:844-848; Tovar et al, Cancer Res (2013) 73 (8): 2587 ¨2597; Ding et a!, Journal of Medicinal Chemistry (2013) 56 (14): 5979 ¨5983; Rew eta!, Journal of Medicinal Chemistry (2012) 55: 4936 ¨4954; Sun eta!, Journal of Medicinal Chemistry (2014) 57 (4): 1454 ¨ 1472). In the pediatric preclinical testing program (PPTP) of the NCI, early evidence for high level anti-proliferative activity of RG7112, an inhibitor of the MDM2-p53 interaction, could be observed in vitro and in vivo. In particular, RG-7112 showed cytotoxic activity with lower median IC50 values for p53 wild-type vs. p53 mutant cell lines (Carol et al., Pediatric Blood and Cancer (2013) 60(4):633-641). Moreover, RG-7112 induced tumor growth inhibition in solid tumor xenograft models and was particularly efficacious in in acute lymphoblastic leukemia (ALL) xenograft models with mixed-lineage leukemia (MLL) rearrangement, (Carol etal., Pediatric Blood and Cancer (2013) 60(4):633-641). Additionally, the antiproliferative and proapoptotic activity of RG7112 has been observed in human acute myeloid leukemia 2 Date Recue/Date Received 2023-03-01 CA 3,000,063 (AML) and human prostate tumor xenograft models harboring p53 wild-type (Toyer et al, Cancer Res (2013) 73 (8): 2587 ¨ 2597). Accordingly, small molecule inhibitors of the MDM2 protein interactions offer an important approach towards cancer therapy, either as a single agent, or in combination with a broad variety of anti-tumor therapies and thus, there is the need for further MDM2 inhibitors which can be useful in the treatment of cancer. The following prior art documents disclose spiro oxindole compounds as inhibitors of MDM2-p53 interaction: WO 2007/104664; WO 2007/104714; WO 2008/141917; WO 2008/141975; WO 2009/077357; WO 2009/080488; WO 2010/084097; WO 2010/121995; WO 2011/067185; WO 2011/101297; WO 2011/134925; WO 2012/038307; WO 2012/022707; WO 2012/116989; WO 2006/091646; WO 2008/036168; WO 2011/060049; WO 2012/065022; WO 2012/155066; WO 2010/028862; WO 2011/153509, WO 2012/121361, WO 2015/155332, WO 2016/001376 and WO 2016/026937. The aim of the present invention is to provide new compounds which can be used for the prevention and/or treatment of a disease and/or condition characterised by excessive or abnormal cell proliferation, especially a disease and/or condition wherein the inhibition of the interaction between MDM2 and p53 is of therapeutic benefit. The compounds according to the invention are characterised by a powerful inhibitory effect on the interaction between MDM2 and p53 and in turn a high in vitro efficacy against tumour cells, e.g. osteosarcoma, ALL etc., which is mediated through the inhibition of the interaction between MDM2 and p53 and is the prerequisite for a corresponding efficacy in in vivo models and future patients. In addition to the inhibitory effect and cellular potency the compounds show good PK properties and selectivity against p53 mutant cell lines. Furthermore, they have good metabolic stability which is a pivotal requirement for an active pharmaceutical ingredient to reach its place of action and allow for a long- lasting efficacy. Finally, and in contrast to many compounds known in the prior art, the compounds have good chemical stability, i.e. they are for example less prone to epimerisation, a problem identified for many known representatives of Spiro oxindoles in the prior art (see e.g. Zhao et al. J. Am. Chem. Soc 2013, 135, 7223-7234; Shu et aL Org. Process Res. Dev. 2013, 17, 247-256; WO 2012/065022). It is also emphasized that building up the scaffolds of compounds (I), Le. the scaffolds of each subgroup (la), (lb) and (lc), is in itself 3 Date Recue/Date Received 2023-03-01 CA 3,000,063 unprecedented and needs highly sophisticated synthetic approaches to obtain these compounds of high structural complexity. Detailed description of the invention It has now been found that, surprisingly, compounds of formula (I) wherein the groups R1 to R4, R7, A, D, E, F, V, W, X, Y, n, r and q have the meanings given hereinafter act as inhibitors of the interaction of specific proteins which are involved in controlling cell proliferation. Thus, the compounds according to the invention may be used for example for the treatment of diseases connected with this protein-protein interaction and characterised by excessive or abnormal cell proliferation. The present invention therefore relates to a compound of formula (I) (Rir-i-k) NO I `D,E\ R3. 3 Wn FItia: --N R1 (Rig-1¨ w N V H (I) , wherein [AO] RI is a group, optionally substituted by one or more, identical or different Rbl and/or Rcl, selected from among Ci_salkyl, C2_6alkenyl, C2_6alkynyl, Ci_shaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_loaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each Rb1 is independently selected from among -ORcl, -NRclRci, halogen, -CN, -C(0)Rel , -C(0)OR, -C(0)NRG1Rcl , -S(0)2Rel , -S(0)2NRcl Rcl , -NHC(0)Rcl, -N(C1_4alkyl)C(0)Rel and the bivalent substituent =0, while =0 may only be a substituent in non-aromatic ring systems; each Rd independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rdl and/or RI, selected from among Cl_ salkyl, C2_6alkenyl, C2_6alkynyl, Cieshaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_ioaryl, 5- 10 membered heteroaryl and 3-10 membered heterocyclyl; 4 Date Recue/Date Received 2023-03-01 CA 3,000,063 each Rd.' is independently selected from among -0Re1, -NRelRel, halogen, -CN, -C(0)Rel, -C(0)0Rel, -C(0)NRelRel, -S(0)2Rel, -S(0)2NRelRel, -NHC(0)Rel, -N(Ci_4alkyl)C(0)Rel and the bivalent substituent =0, while =0 may only be a substituent in non-aromatic ring systems; each Re' independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rf1 and/or R91, selected from among Cl_ salkyl, C2_6alkenyl, C2_6alkynyl, Cl_shaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_loaryl, 5- membered heteroaryl and 3-10 membered heterocyclyl; each Rfi is independently selected from among -0Rg1, -NRoRgl, 10 halogen, -CN, -C(0)Rgl, -C(0)0Rgl, -C(0)NR1Rg1, -S(0)2Rg1, - S(0)2NRg1Rg1, -NHC(0)Rgl, -N(C1_4alkyl)C(0)Rgl and the bivalent substituent =0, while =0 may only be a substituent in non-aromatic ring systems; each Ro is independently selected from among hydrogen, Ci_salkyl, C2_6alkenyl, C2_6alkynyl, Cl_shaloalkyl, C3_7cycloalkyl, CaJcycloalkenyl, Cs_loaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; [BO] R2 and R3, each independently, is selected from among hydrogen, Cs_waryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein said Cs_loaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl is optionally substituted by one or more, identical or different Rb2 and/or V; each Rb2 is independently selected from among -0Re2, -NRc2Rc2, halogen, -CN, -C(0)Rc2, -C(0)0Rc2, -C(0)NRc2Rc2, -S(0)2Rc2, -S(0)2NRe2Re2, -NHC(0)Re2, -N(Cl_4alkyl)C(0)Rc2 and the bivalent substituent =0, while =0 may only be a substituent in non-aromatic ring systems; each Rc2 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rd2 and/or Re2, selected from among Cl_ salkyl, C2_6alkenyl, C2_6alkynyl, Ci_shaloalkyl, C3_6cycloalkyl, C4_6cycloalkenyl, C6.10aryl, 5- 10 membered heteroaryl and 3-10 membered heterocyclyl; each Rd2 is independently selected from among -0Re2, -NRe2Re2, halogen, -CN, -C(0)Re2, -C(0)0Re2, -C(0)NRe2Re2, -S(0)2Re2, -S(0)2NRe2Re2; -NHC(0)Re2, -N(Cl_4alkyl)C(0)Re2 and the bivalent substituent =0, while =0 may only be a substituent in non-aromatic ring systems; 5 Date Recue/Date Received 2023-03-01 CA 3,000,063 each Re2 independently of one another denotes hydrogen or a group selected from among Cl_salkyl, C2_6alkenyl, C2_6alkynyl, Ci_shaloalkyl, C3_6cycloalkyl, C4_6cycloalkenyl, Cs_ioaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; [CO] A is selected from among phenyl and 5-6 membered heteroaryl if F is carbon or A is 5-6 membered, nitrogen-containing heteroaryl if F is nitrogen; each R4 is independently selected from among Ra4 and Rb4; each Ra4 independently of one another is a group, optionally substituted by one or more, identical or different Rb4 and/or Rc4, selected from among Cl_salkyl, C2_6alkenyl, C2- salkynyl, Cieshaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_ioaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each Rb4 is independently selected from among -OR, -NRc4Rc4, halogen, -CN, -C(0)R', -C(0)OR, -C(0)NRc4Rc4, -C(0)NR0ORcA, -S(0)2R, -S(0)2NRc4Rc4, -NHSO2Rc4, -N(C1_4alkyl)S021V, -NHC(0)RG4, -N(Cl_4alkyl)C(0)Rc4 and the bivalent substituent =0, while =0 may only be a substituent in non- aromatic ring systems; each R" independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rd4 and/or Re4, selected from among Ci_ salkyl, C2_6alkenyl, C2_6alkynyl, Ci_shaloalkyl, C3_7cycloalkyl, C47cycloalkenyl, Cs_ioaryl, 5- 10 membered heteroaryl and 3-10 membered heterocyclyl; each Rd4 is independently selected from among -0Re4, -NRe4Re4, halogen, -CN, -C(0)R, -C(0)0R, -C(0)NRe4Re4, -C(0)NRg40Re4, -S(0)2R, -S(0)2NRe4Re4, -NHC(0)Ret -N(C14alkyl)C(0)Re4 and the bivalent substituent =0, while =0 may only be a substituent in non-aromatic ring systems; each Re4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different RT4 and/or Rg4, selected from among Cl_ salkyl, C2_6alkenyl, C2_6alkynyl, Ci_shaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_ioaryl, 5- 10 membered heteroaryl and 3-10 membered heterocyclyl; each 1214 is independently selected from among -ORg4, -NR94Rg4, halogen, -CN, -C(0)R94, -C(0)0R4, -C(0)NRg4Rg4, -C(0)NR00R94, -S(0)2R4, -S(0)2NR4Rg4, -NHC(0)Rg4, -N(C14alkyl)C(0)Rg4 and the bivalent substituent =0, while 6 Date Recue/Date Received 2023-03-01 CA 3,000,063 =0 may only be a substituent in non-aromatic ring systems; each Rg4 is independently selected from among hydrogen, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6haloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, C6_10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; r denotes the number 0, 1, 2 or 3; [DO] n denotes the number 1, 2 or 3; [EO] each R7 is independently selected from among halogen, Ci_zfalkyl, -CN, C1_4haloalkyl, -0Ci_ lci 4a1ky1 and -0C1_4haloalkyl; q denotes the number 0, 1, 2 or 3; [FO] W, X and Y is each independently selected from ¨N= and ¨CH= with the proviso that the hydrogen in each ¨CH= may be replaced by a substituent R7 if present and that a maximum of two of W, X and Y can be ¨N=; [GO] V is oxygen or sulfur; [HO] D is nitrogen, E is carbon and F is carbon; or D is carbon, E is nitrogen and F is carbon; or D is carbon, E is carbon and F is nitrogen; or a salt thereof. 7 Date Regue/Date Received 2023-03-01 CA 3,000,063 In one aspect the invention relates to a compound of formula (la) (R4), A N%I I N ,Nif N,R1 X o'" (R7)q--th V w N H (la) or a salt therof. In one aspect the invention relates to a compound of formula (lb) (124), A N.,N R3, ? (> )n RIN., ri)if 0"µ (R7)q---11-- V w N H (lb) or a salt therof. 8 Date Recue/Date Received 2023-03-01 CA 3,000,063 In one aspect the invention relates to a compound of formula (lc) (124), Nc:PD NJ ,Nif N,R1 X o'" (R7)q--tt¨ V 'IN N H (lc) or a salt therof. In one aspect the invention relates to a compound of formula (1a*) (114), A chiral NI I µ14 Ft: 1 Pn FtiNc, -.1s1 R1 ri)if 0"µ (R7)q--11¨ V 'IN N H (1a*) or a salt therof. 9 Date Recue/Date Received 2023-03-01 CA 3,000,063 In one aspect the invention relates to a compound of formula (1b*) (R4)r A chiral N N 3 E 6) X 0" (R7)q--th V 'w N H (1b1 or a salt therof. In one aspect the invention relates to a compound of formula (Ic*) (Rir chiral N Fr, E in RIN.:c, (II7)q--th V -w N H (1C*) or a salt therof. It is to be understood that compounds (la), (lb) and (lc) each are a subset of compounds (1) and that whenever the term "compound(s) (I)" is used this also includes compound(s) (la), (lb) and (lc) unless stated otherwise. to It is to be understood that compounds (1a*), (1b*) and (Ic*) each are a subset of compounds (la), (lb) and (lc), respectively, and that whenever (la), (lb) or (lc) is used this also includes compound(s) (1a*), (1b*) and (Ic*), respectively, unless stated otherwise. In another aspect [Al] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein 1.0 Date Recue/Date Received 2023-03-01 CA 3,000,063 R1 is a group, optionally substituted by one or more, identical or different Rbl and/or IV, selected from among Ci_salkyl, C2_6alkenyl, C2_6alkynyl, Ci_shaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_ioaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each Rbl is independently selected from among -ORcl, -NRciRcl, halogen, -CN, -C(0)R, -C(0)OR, -C(0)NRcfRel, -S(0)2R, -S(0)2NRcfRcl, -NHC(0)Rcl and -N(Ci_4alkyl)C(0)Rcl; each Rd l independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rdl and/or Re', selected from among C1_ salkyl, C2_6alkenyl, C2_6alkynyl, Ci_shaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_loaryl, 5- 10 membered heteroaryl and 3-10 membered heterocyclyl; each Rdl is independently selected from among -OR , -NRelRel, halogen, -CN, -C(0)Rel, -C(0)0Rel, -C(0)NRelRel, -S(0)2Rel, -S(0)2NRel R1, -NHC(0)Rel and -N(Cl_4alkyl)C(0)Rel; each Ref independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rfl and/or Ro, selected from among Cl_ salkyl, C2e6alkenyl, C2e6alkynyl, Cieshaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_ioaryl, 5- 10 membered heteroaryl and 3-10 membered heterocyclyl; each Rff is independently selected from among -ORgl, -NRoRgl, halogen, -CN, -C(0)R91, -C(0)0Rgl, -C(0)NRgfRo, -S(0)2Rgl, -S(0)2NR1Rg1, -NHC(0)Rg 1 and -N(Ci_4alkyl)C(0)Rgl; each Rgf is independently selected from among hydrogen, Ci_salkyl, C2_6alkenyl, C2_6alkynyl, Cl_shaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_loaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; or a salt thereof. In another aspect [A2] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (lc*), wherein 121 is a group, optionally substituted by one or more, identical or different Rbl and/or IV, selected from among Cl_salkyl, C2_6alkenyl, Cl_shaloalkyl and C3_7cycloalkyl; each Rbl is independently selected from among -ORcl, -NRcfRcl, halogen, -CN, -C(0)R, -C(0)OR, -C(0)NR R, -S(0)2R, -S(0)2NRel Rcl, 11 Date Recue/Date Received 2023-03-01 CA 3,000,063 -NHC(0)Rcl and -N(Ci_4alkyl)C(0)Rcl; each V independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rdl and/or RI, selected from among Cl_ salkyl, C3_7cycloalkyl, Cs_loaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each Rdl is independently selected from among -OR , - NRel Rel halogen, -CN, -C(0)Rel, -C(0)0Rel, -C(0)NRelRel, -S(0)2Rel , -S(0)2NRelRe1; -NHC(0)Rel and -N(Ci4alkyl)C(0)Rel; each RI independently of one another is selected from among hydrogen, Cl_salkyl, lo Ci_salkyl-O-Ci_salkyl, C3_7cycloalkyl, Cs_loaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; or a salt thereof. In another aspect [A3] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (lc*), wherein R1 is a group, optionally substituted by one or more, identical or different Rbl and/or Rcl, selected from among Cl_salkyl, C2_6alkenyl, Ci_shaloalkyl and C3_7cycloalkyl; each Rbl is independently selected from among -OR, halogen and -S(0)2Rcl; each Rd independently of one another is a group, optionally substituted by one or more, identical or different Rd1 and/or RI, selected from among Ci_salkyl, C3_7cycloalkyl, Cs_loaryl and 3-10 membered heterocyclyl; each Rdl is independently selected from among -OR , -CN and halogen; each RI independently of one another is Cl_salkyl or C1_6alky1-0-C1_6alkyl; or a salt thereof. In another aspect [A4] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (IC*), wherein R1 is a group, optionally substituted by one or more, identical or different Rbl and/or Rcl, selected from among Ci_salkyl, C2_6alkenyl and Cl_shaloalkyl; each Rb1 is independently selected from among -OR and -S(0)2Rcl; 12 Date Regue/Date Received 2023-03-01 CA 3,000,063 each Rcl independently of one another is a group, optionally substituted by one or more, identical or different Rai and/or Fe, selected from among Ci_salkyl, C3_7cycloalkyl and Cs_ioaryl; each Rdl is independently selected from among -OR , -CN and halogen; each Rel independently of one another is Ciesalkyl or Ciesalkyl-O-Ciesalkyl; or a salt thereof. In another aspect [A5] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein R1 is a group, optionally substituted by one or more, identical or different Rbl and/or Rcl, to selected from among Ci_salkyl, C2_6alkenyl and Ci_shaloalkyl; each Rbl is independently selected from among -OR el and -S(0)2Rcl; each Rd independently of one another is a group, optionally substituted by one or more, identical or different Rd1 and/or RI, selected from among Cl_salkyl, C3_7cycloalkyl and phenyl; each Rd.' is independently selected from among -OR , -CN and halogen; each Re1 independently of one another is Cl_salkyl or C1_6alky1-0-C1_6alkyl; or a salt thereof. In another aspect [A6] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein R1 is selected from among Cl_salkyl, C3_7cycloalkyl-C1_6alkyl and C2_6alkenyl; or a salt thereof. In another aspect [A7] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein R1 is C3_7cycloalkyl-C1_6alkyl; or a salt thereof. In another aspect [A8] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein 13 Date Regue/Date Received 2023-03-01 CA 3,000,063 R1 is cyclopropylmethyl; or a salt thereof. In another aspect [BI] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (lc*), wherein R2 and R3, each independently, is selected from among hydrogen, Cs_waryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein said Cs_loaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl is optionally substituted by one or more, identical or different Rb2 and/or IV; each Rb2 is independently selected from among -0Re2, -NRc2Rc2, halogen, -CN, -C(0)Rc2, -C(0)0Rc2, -C(0)NRc2Rc2, -S(0)2Rc2, -S(0)2NRc2Rc2, -NHC(0)Re2 and -N(Ci_4alkyl)C(0)Rc2; each IV independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rd2 and/or Re2, selected from among Ci_ salkyl, C2_6alkenyl, C2_6alkynyl, Cl_shaloalkyl, C3_6cycloalkyl, C4_6cycloalkenyl, Cs_loaryl, 5- 10 membered heteroaryl and 3-10 membered heterocyclyl; each Rd2 is independently selected from among -0R2, -NRe2Re2, halogen, -CN, -C(0)Re2, -C(0)0Re2, -C(0)NRe2Re2, -S(0)2Re2, -S(0)2NRe2Re2, -NHC(0)Re2 and -N(Ci_4alkyl)C(0)Re2; each Re2 independently of one another denotes hydrogen or a group selected from among Cl_salkyl, C2_6alkenyl, C2_6alkynyl, Cl_shaloalkyl, C3_6cycloalkyl, C4_6cycloalkenyl, Cs_ioaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; or a salt thereof. In another aspect [B2] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein one of R2 and R3 is hydrogen and the other is selected from among phenyl and 5- 6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl is optionally substituted by one or more, identical or different Rb2 and/or IV; each Rb2 is independently selected from among -OR , -NRe2Rc2, halogen, -CN, -C(0)Re2, -C(0)0Rc2, -C(0)NRG2Rc2, -S(0)2Rc2, -S(0)2NRc2Rc2, -NHC(0)1,2c2 and -N(Cl_4alkyl)C(0)Rc2; 14 Date Recue/Date Received 2023-03-01 CA 3,000,063 each Rc2 independently of one another denotes hydrogen or a group selected from among Cl_salkyl, C2_6alkenyl, C2_6alkynyl, Ci_shaloalkyl, C3_6cycloalkyl, C4_6cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocyclyl; or a salt thereof. In another aspect [B3] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (1c*), wherein one of R2 and R3 is hydrogen and the other is selected from among phenyl and 5- 6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl is optionally substituted by one or more, identical or different substituents selected from among -0C1_6alkyl, halogen, Ci_salkyl and Ci_shaloalkyl; or a salt thereof. In another aspect [B4] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (lc*), wherein one of R2 and R3 is hydrogen and the other is selected from among phenyl, thienyl and pyridyl, wherein said phenyl, thienyl and pyridyl is optionally substituted by one or more, identical or different substituents selected from among -0C1_6alkyl, halogen, Cl_salkyl and Cl_shaloalkyl; or a salt thereof. In another aspect [B5] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (IC*), wherein one of R2 and R3 is hydrogen and the other is selected from among 3-chloro phenyl, 3- chloro-2-fluoro phenyl and 3-bromo 2-fluoro phenyl; or a salt thereof. In further aspects [B6], [B7], [B8], [B9], [B10] and [B11] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) with structural aspects [BO], [B1], [B2] [B3], [B4] and [B5], wherein R3 is hydrogen; or a salt thereof. Date Regue/Date Received 2023-03-01 CA 3,000,063 In further aspects [B12], [B13], [B14], [B15], [B16] and [B17] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (lc*) with structural aspects [BO], [B1], [B2] [B3], [B4] and [B5], wherein R2 is hydrogen; or a salt thereof. In another aspect [C1] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein A is selected from among phenyl and 5-6 membered heteroaryl if F is carbon or A is 5-6 membered, nitrogen-containing heteroaryl if F is nitrogen; each R4 is independently selected from among Ra4 and Rb4; each Ra4 independently of one another is a group, optionally substituted by one or more, identical or different RIa4 and/or R`4, selected from among Ci_salkyl, C2e6alkenyl, C2- 6a1kyny1, C16haloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_loaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each Rb4 is independently selected from among -OR", -NR"R", halogen, -CN, -C(0)R", -C(0)0R", -C(0)NR"R", -C(0)NR0ORG4, -S(0)2R", -S(0)2NR"R04, -NHSO2R04, -N(Ci_4alkyl)S02R", -NHC(0)R" and - N(C1_4alkyl)C(0)R"; each R" independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rd4 and/or Re4, selected from among Cl_ salkyl, C2_6alkenyl, C2_6alkynyl, Cieshaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_ioaryl, 5- 10 membered heteroaryl and 3-10 membered heterocyclyl; each Rd4 is independently selected from among -0R4, -NRe4Re4, halogen, -CN, -C(0)R", -C(0)OR', -C(0)NRe4Re4, -C(0)NR4ORe4, -S(0)2R, -S(0)2NRe4Re4, -NHC(0)Re4 and -N(C1_4alkyl)C(0)Re4; each V independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rf4 and/or Rg4, selected from among Ci_ salkyl, C2_6alkenyl, C2_6alkynyl, Cl_shaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_loaryl, 5- 10 membered heteroaryl and 3-10 membered heterocyclyl; each Rf4 is independently selected from among -ORg4, -NR4Rg4, halogen, -CN, -C(0)R4, -C(0)0R4, -C(0)NRg4Rg4, -C(0)NR0ORg4, -S(0)2R4, 16 Date Recue/Date Received 2023-03-01 CA 3,000,063 -S(0)2NR4Rg4, -NHC(0)R0 and -N(Cl_4alkyl)C(0)R0; each Rg4 is independently selected from among hydrogen, Ci_salkyl, C2_6alkenyl, C2_6alkynyl, Cl_shaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_loaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; r denotes the number 0, 1, 2 or 3; or a salt therof. In another aspect [C2] the invention relates to a compound of formula (I), (la), (lb), (le) or (1b*), wherein A is phenyl and F is carbon; each R4 is independently selected from among Ra4 and R"; each Ra4 independently of one another is a group, optionally substituted by one or more, identical or different R" and/or R", selected from among Ciesalkyl, Ci_shaloalkyl, C3_7cycloalkyl and 3-10 membered heterocyclyl; each R" is independently selected from among -OR", -NR"Rc4, halogen, -C(0)R", -C(0)0R", -C(0)NR"R", -C(0)NR0OR", -S(0)2R" and -NHC(0)Ra4; each V independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rd4 and/or Re4, selected from among Cl_ salkyl, Cl_shaloalkyl, C3_7cycloalkyl and 3-10 membered heterocyclyl; each R" is independently selected from among -OR", -NR"Re4 and -S(0)2R"; each Re4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rm and/or Rg4, selected from among Ci_ salkyl and 3-10 membered heterocyclyl; each Rm is -ORg4; each Rg4 is independently selected from among hydrogen and Ci_salkyl; r denotes the number 0, 1, 2 or 3; or a salt therof. In another aspect [C3] the invention relates to a compound of formula (1), (la), (lb), (lc), 17 Date Recue/Date Received 2023-03-01 CA 3,000,063 (1a*), (1b*) or (1c*), wherein A is selected from among phenyl and 5-6 membered heteroaryl if F is carbon or A is 5-6 membered, nitrogen-containing heteroaryl if F is nitrogen; each R4 is independently selected from among Ra4 and Rb4; each Ra4 independently of one another is a group, optionally substituted by one or more, identical or different Rb4 and/or R", selected from among Cl_salkyl, C2_6alkenyl, C2- 6a1kyny1, Cieshaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_ioaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each Rb4 is independently selected from among -OR", -NR"Rc4, halogen, -CN, -C(0)R", -C(0)0R", -C(0)NR"R", -C(0)NHOR", -S(0)2R", -S(0)2NR"R", -NHSO2R", -N(C1_4alkyl)S02R", -NHC(0)R" and -N(Cl_4alkyl)C(0)R"; each R" independently of one another is selected from among hydrogen, Ci_salkyl, C2_6alkenyl, C2_6alkynyl, Ci_shaloalkyl, C3_7cycloalkyl, C4_7cycloalkenyl, Cs_ioaryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; r denotes the number 0, 1, 2 or 3; or a salt thereof. In another aspect [C4] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (lc*), wherein A is selected from among phenyl and pyridyl if F is carbon or A is pyridyl if F is nitrogen; each R4 is independently selected from among Ra4 and Rb4; each Ra4 independently of one another is Ci_salkyl optionally substituted by one or more, identical or different Rb4; each RI)4 is independently selected from among -OR", -NR"Rc4, halogen, -CN, -C(0)R", -C(0)0R", -C(0)NR"R", -C(0)NR0OR", -S(0)2R", -S(0)2NR"R", -NHSO2R", -N(Cl_4alkyl)S02R", -NHC(0)R" and -N(C1_4alkyl)C(0)R"; each R" independently of one another is selected from among hydrogen and Ci_salkyl; r denotes the number 0, 1, 2 or 3; 18 Date Recue/Date Received 2023-03-01 CA 3,000,063 or a salt thereof. In another aspect [C5] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (1c*), wherein A is selected from among phenyl and pyridyl if F is carbon or A is pyridyl if F is nitrogen; each R4 is independently selected from among Ra4 and Rb4; each Ra4 independently of one another is Ci_salkyl optionally substituted by one or more, identical or different Rb4; each Rb4 is independently selected from among -OR , halogen, -CN, -C(0)0R", -C(0)NRc4RcA and -S(0)2R; each V independently of one another is selected from among hydrogen and Cl_salkyl; r denotes the number 0, 1, 2 or 3; or a salt thereof. In another aspect [C6] the invention relates to a compound of formula (1), (la), (lb), (1a*) or (1b*), wherein A is phenyl and F is carbon; each R4 is independently selected from among Ra4 and Rb4; each Ra4 independently of one another is Ci_salkyl optionally substituted by one or more, identical or different Rb4; each Rb4 is independently selected from among -ORc4, halogen, -CN, -C(0)0R 4, -C(0)NRa4Ra4 and -S(0)2R'; each Rc4 independently of one another is selected from among hydrogen and Cl_salkyl; r denotes the number 0, 1, 2 or 3; or a salt thereof. In further aspects [C7], [C8], [C9], [C10], [C11], [C12] and [C13] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) with structural aspects [CO], [C1], [C2], [C3], [C4], [C5] and [C6], wherein 19 Date Regue/Date Received 2023-03-01 CA 3,000,063 r denotes the number 1 or 2; or a salt thereof. In another aspect [C14] the invention relates to a compound of formula (1), (la), (lb), (1a*) or (1b*), wherein A together with the r substituents R4 is R9 119 Rio R8 is selected from among hydrogen, Ci_salkyl, -0C1_6alkyl, halogen, -ON, -C(0)0H, -C(0)0Ci_6alkyl, -C(0)NH2, -C(0)NHCi_6alkyl, - C(0)N(Ci_6alkyl)2 and -S(0)2Ci_6alkyl; R9 is selected from among hydrogen, Ci_salkyl, halogen, -ON, -C(0)0H, -C(0)0C1_6alkyl, -C(0)NH2, -C(0)NHCi_6alkyl, - C(0)N(01_6a1ky1)2 and -S(0)2Ci_6alkyl; R19 is selected from among hydrogen, Ci_salkyl, -0C i_salkyl, halogen, -ON, -C(0)0H, -C(0)0Ci_6alkyl, -C(0)NH2, -C(0)NHCi_6alkyl, - C(0)N(C1_6alkyl)2 and -S(0)2Ci..6alkyl; with the proviso that at least one of R8 to R19 but not all of R8 to R19 is/are hydrogen; or a salt thereof. In another aspect [C15] the invention relates to a compound of formula (1), (la), (lb), (1a*) or (1b*), wherein A together with the r substituents R4 is R9 129 COI Rio ss, Date Recue/Date Received 2023-03-01 CA 3,000,063 R8 is -C(0)0H; one of R9 and R19 is Ci_aalkyl and the other is hydrogen; or a salt thereof. In another aspect [DI] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein n denotes the number 1 or 2; or a salt thereof. In another aspect [D2] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein nisi; or a salt thereof. In another aspect [03] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein n i52; or a salt thereof. In another aspect [El] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein each R7 independently is halogen or -CN and q is 1 or 2; or a salt thereof. In another aspect [E2] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein each R7 independently is chlorine or fluorine and q is 1 or 2; or a salt thereof. In another aspect [Fl] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein W, X and Y are ¨CH= with the proviso that the hydrogen in each ¨CH= may be replaced by 21 Date Regue/Date Received 2023-03-01 CA 3,000,063 a substituent R7 if present; or a salt thereof. In another aspect [EF1] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (1c*), wherein the 6-membered ring comprising W, X and Y together with the q substituents R7 has a substructure selected from among (i) and (ii) CI CI N (i) (ii) or a salt thereof. In another aspect [G1] the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*), wherein V is oxygen; or a salt thereof. All the above-mentioned structural aspects Al to A8, B1 to B17, Cl to C15, D1 to D3, El and E2, Fl, G1 and EF1 are preferred embodiments of the corresponding aspects AO, BO, CO, DO, EO, FO, EFO and GO, respectively, wherein EFO (EF) represents the combination of EO (E) and FO (F). The structural aspects AO to A8, BO to B17, CO to C15, DO to D3, EO to E2, FO and Fl, EFO and EF1, and GO and Cl relating to different molecular parts of the compounds (1), (la), (lb), (lc), (1a*), (1b*) and (Ic*) according to the invention may be permutated with one another as desired in combinations ABCDEFG, so as to obtain preferred compounds (1), (la), (lb), (lc), (1a*), (1b*) and (Ic*) (aspects E and F can be replaced by combination aspect EF). Each combination ABCDEFG represents and defines individual embodiments or generic subsets of compounds according to the invention. Preferred embodiments of the invention with structure (la) are example compounds la-1 to la-57. Preferred embodiments of the invention with structure (lb) are example compounds lb-1 to lb-254. 22 Date Recue/Date Received 2023-03-01 CA 3,000,063 Preferred embodiments of the invention with structure (lc) are example compounds lc-1 to 1c-38. All synthetic intermediates generically defined as well es specifically disclosed herein and their salts are also part of the invention. In a further aspect the invention also relates to synthetic intermediates of formula B-3 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (la*): OR 0211 R3, r+i 0 y NH (127)q ______________________________________ V B-3 The definitions of groups R2, R3, R7, V, W, X, Y, q and n in B-3 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (lc*) above, i.e. [BO] for R2/R3, [DO] for n, [EO] for R7/q, [FO] for WDUY and [GO] for V. R is a carboxyl protecting group, e.g. Cl_salkyl or t- Bu. Preferred intermediates B-3 are those which lead to preferred compounds (la) and (1a*) according to the invention, i.e. preferred embodiments of B-3 have structural aspects selected from [BO] to [B17] for R2/R3, [DO] to [D3] for n, [E0] to [E2] for R7/q, [FO] and [Fl] for WOUY, [GO] and [G1] for V and [EFO] and [EF1] for RTNNV/WY altogether. These structural aspects (including definitions of R) may be permutated with one another as desired in combinations BDEFGR, so as to obtain preferred intermediates B-3 (aspects E and F can be replaced by combination aspect EF). Each combination BDEFGR represents and defines individual embodiments or generic subsets of intermediates B-3. In a further aspect the invention also relates to the use of synthetic intermediates of formula 13-3 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to synthetic intermediates of formula 6-4 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): 23 Date Recue/Date Received 2023-03-01 CA 3,000,063 OR 02 Isl Rili 0 ",y t N....R1 X 1 (R7)q¨tr V N H B-4 The definitions of groups R'I, R2, R3, R7, V, W, X, Y, q and n in B-4 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (lc*) above, i.e. [AO] for RI, [BO] for R2/R3, [DO] for n, [EO] for R7/q, [FO] for W/X/Y and [GO] for V. R is a carboxyl protecting group, e.g. Cl.salkyl or t-Bu. Preferred intermediates B-4 are those which lead to preferred compounds (la) and (le) according to the invention, Le. preferred embodiments of B-4 have structural aspects selected from [AO] to [A8] for KI, [BO] to [B17] for R2/R3, [DO] to [D3] for n, [E0] to [E2] for R7/q, [FO] and [Fl] for W/XN, [GO] and [Cl] for V and [EFO] and [EF1] for R7/q/W/XN altogether. These structural aspects (including definitions of R) may be permutated with one another as desired in combinations ABDEFGR, so as to obtain preferred intermediates B- 4 (aspects E and F can be replaced by combination aspect EF). Each combination ABDEFGR represents and defines individual embodiments or generic subsets of intermediates B-4. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-4 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to synthetic intermediates of formula B-7 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): 24 Date Recue/Date Received 2023-03-01 CA 3,000,063 OH NO 14 I 2 ) )" Rii. N--R1 X 1µ" (R7)cr1t- V woo N H B-7 The definitions of groups RI, R2, R3, R7, V, W, X, Y, q and n in B-7 correspond to those as given for compound (I), (la), (lb), (lc), (1a*), (1b*) or (Ic*) above, i.e. [AO] for R1, [BO] for R2/R3, [DO] for n, [EO] for R7/q, [F0] for W/XN and [GO] for V. Preferred intermediates B-7 are those which lead to preferred compounds (la) and (le) according to the invention, i.e. preferred embodiments of B-7 have structural aspects selected from [AO] to [A8] for RI, [BO] to [B17] for R2/R3, [DO] to [D3] for n, [E0] to [E2] for 127/q, [F0] and [Fl] for W/XN, [GO] and [G1] for V and [EFO] and [EF1] for R7/q/W/X/Y altogether. These structural aspects may be permutated with one another as desired in combinations ABDEFG, so as to obtain preferred intermediates B-7 (aspects E and F can be replaced by combination aspect EF). Each combination ABDEFG represents and defines individual embodiments or generic subsets of intermediates B-7. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-7 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to synthetic intermediates of formula B-6 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (Ial: OH 0,1s1 R% - Riai: y NH X/ (R7)q %r V N H B-6 The definitions of groups R2, R3, R7, V, W, X, Y, q and n in B-6 correspond to those as given Date Recue/Date Received 2023-03-01 CA 3,000,063 for compound (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) above, i.e. [BO] for R2/R3, [DO] for n, [EO] for R7/q, [FO] for W/XN and [GO] for V. Preferred intermediates B-6 are those which lead to preferred compounds (la) and (le) according to the invention, Le. preferred embodiments of B-6 have structural aspects selected from [BO] to [B17] for R2/R3, [DO] to [D3] for n, [EO] to [E2] for R7/q, [FO] and [Fl] for W/XN, [GO] and [G1] for V and [EFO] and [EF1] for R7/q/W/XN altogether. These structural aspects may be permutated with one another as desired in combinations BDEFG, so as to obtain preferred intermediates B-6 (aspects E and F can be replaced by combination aspect EF). Each combination BDEFG represents and defines individual embodiments or generic subsets of intermediates B-6. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-6 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to synthetic intermediates of formula B-8 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): 0 NO2 nT: (SI) R4. y , N--R1 X = 0 (R7),i-t-- V w N H B-8 The definitions of groups R1, R2, R3, R7, V, W, X, Y, q and n in B-8 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) above, Le. [AO] for R1, [BO] for R2/F43, [DO] for n, [EO] for 127/q, [F0] for W/X/Y and [GO] for V. Preferred intermediates B-8 are those which lead to preferred compounds (la) and (le) according to the invention, Le. preferred embodiments of B-8 have structural aspects selected from [AO] to [A8] for R1, [BO] to [B17] for R2/R3, [DO] to [D3] for n, [EO] to [E2] for R7/q, [F0] and [Fl] for W/XN, [GO] and [G1] for V and [EFO] and [EF1] for R7/q/W/X/Y altogether. These structural aspects may be permutated with one another as desired in combinations ABDEFG, so as to obtain preferred intermediates B-8 (aspects E and F can 26 Date Recue/Date Received 2023-03-01 CA 3,000,063 be replaced by combination aspect EF). Each combination ABDEFG represents and defines individual embodiments or generic subsets of intermediates B-8. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-8 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to synthetic intermediates of formula B-10 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): (R4)r NO2 A / OH NO2 3: n R = y --N R1 X/ 111% V w N B-10 The definitions of groups R1, R2, R3, R4, R7, A, V, W, X, Y, r, q and n in B- 10 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (1c*) above, i.e. [AO] for R1, [BO] for R2/R3, [CO] for A/R4/r, [DO] for n, [EO] for R7/q, [FO] for W/XN and [GO] for V. Preferred intermediates B-10 are those which lead to preferred compounds (la) and (1a*) according to the invention, Le. preferred embodiments of B-10 have structural aspects selected from [AO] to [A8] for R1, [BO] to [B17] for R2/R3, [CO] to [C15] for A/R4/r, [DO] to [D3] for n, [EO] to [E2] for R7/q, [FO] and [Fl] for W/XN, [GO] and [G1] for V and [EFO] and [EF1] for R7/qNV/X/Y altogether. These structural aspects may be permutated with one another as desired in combinations ABCDEFG, so as to obtain preferred intermediates B- 10 (aspects E and F can be replaced by combination aspect EF). Each combination ABCDEFG represents and defines individual embodiments or generic subsets of intermediates B-10. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-10 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). 27 Date Recue/Date Received 2023-03-01 CA 3,000,063 In a further aspect the invention also relates to synthetic intermediates of formula B-11 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): (R4)r NO2 A/ 0 NO2 3 S 2 ( = )n R N,R1 X (R7),-i-tor V B-11 The definitions of groups RI, R2, R3, R4, R7, A, V, W, X, Y, r, q and n in B- 11 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (IC*) above, i.e. [AO] for RI, [BO] for R2/R3, [CO] for A/R4/r, [DO] for n, [EO] for R7/q, [FO] for W/X/Y and [GO] for V. Preferred intermediates B-11 are those which lead to preferred compounds (la) and (la*) according to the invention, i.e. preferred embodiments of B-11 have structural aspects selected from [AO] to [A8] for R1, [BO] to [B17] for R2/R3, [CO] to [C15] for PJR4/r, [DO] to [D3] for n, [ED] to [E2] for R7/q, [FO] and [Fl] for W/X/Y, [GO] and [G1] for V and [EFO] and [EF1] for 127/q/W/XN altogether. These structural aspects may be permutated with one another as desired in combinations ABCDEFG, so as to obtain preferred intermediates B- 11 (aspects E and F can be replaced by combination aspect EF). Each combination ABCDEFG represents and defines individual embodiments or generic subsets of intermediates B-11. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-11 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to synthetic intermediates of formula B-12 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): 28 Date Recue/Date Received 2023-03-01 CA 3,000,063 H2N A \ (R4)r HN 3 E Wri R RI 0 X N.-RI (R1 I:I¨tit( V N H B-12 The definitions of groups R1, R2, R3, R4, R7, A, V, W, X, Y, r, q and n in B- 12 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (1c*) above, i.e. [AO] for R1, [BO] for R2/R3, [CO] for A/R4/r, [DO] for n, [EO] for R7/q, [FO] for W/X/Y and [GO] for V. Preferred intermediates B-12 are those which lead to preferred compounds (la) and (1a*) according to the invention, i.e. preferred embodiments of B-12 have structural aspects selected from [AO] to [A8] for R1, [BO] to [B17] for R2/R3, [CO] to [C15] for A/R4/r, [DO] to [D3] for n, [EO] to [E2] for R7/q, [FO] and [Fl] for W/X/Y, [GO] and [G1] for V and [EFO] and [EF1] for R7/q/W/XN altogether. These structural aspects may be permutated with one another as desired in combinations ABCDEFG, so as to obtain preferred intermediates B- 12 (aspects E and F can be replaced by combination aspect EF). Each combination ABCDEFG represents and defines individual embodiments or generic subsets of intermediates B-12. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-12 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to synthetic intermediates of formula B-16 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): 29 Date Recue/Date Received 2023-03-01 CA 3,000,063 (Rir nO ---4( A N µ H ` Br B-16 The definitions of group R4, A and r in B-16 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) above, i.e. [CO] for A/R4/r. Preferred intermediates B-16 are those which lead to preferred compounds (la) and (le) according to the invention, i.e. preferred embodiments of B-16 have structural aspects selected from [CO] to [C15] for AVM each defining individual embodiments or generic subsets of intermediates B-16. Preferred intermediates B-16 are selected from intermediates B-16a to B-16f (see table 15-2 below), including their salts. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-16 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B-16 (R4),. nO ---1 A N µ H ` Br B-16 , or a salt thereof, comprising bromination of a compound of formula B-15 (R4)r 0 --"A A N µ H N B-15 , or a salt thereof, wherein Date Recue/Date Received 2023-03-01 CA 3,000,063 the reaction is performed in a solvent with a source of electrophilic bromine in the presence of a palladium catalyst and an acidic additive, and R4, A and r is as hereinbefore defined. (STEP A) Embodiments/conditions for STEP A: The solvent to be chosen can be an organic solvent, preferably chosen from the group consisting of a carboxylic acid, a carboxylic ester, an alkane and an aromatic solvent, or a mixture thereof. More preferably the solvent is chosen from the group consisting of AcOH, nBuOAc, iPrOAc, MCH, nHep, toluene and xylol (or a mixture thereof, e.g. nBuOAc/AcOH (9:1), iPrOAc/AcOH (9:1), toluene/AcOH (9:1)). Most preferred is AcOH. The source of electrophilic bromine can, e.g., be selected from the group consisting of NBS, N-bromosaccharine and 1,3-dibromo-5,5-dimethylhydantoine. Preferably, NBS is chosen as source of electrophilic bromine. Preferably, the palladium catalyst to be used can be a Pd(II) catalyst, e.g., a Pd(II) catalyst chosen from the group consisting of Pd(OAc)2 and Pd(OC(0)CF3)2. The preferred Pd(II) catalyst is Pd(OAc)2. As far as the acidic additive is concerned this is preferentially an aromatic acid, preferably an aromatic sulfonic acid. Most preferred acidic additive is Ts0H or a hydrate thereof. The reaction can be performed at a temperature range of about 70 C to about 100 C, preferably at about 60 C to about 90 C. Most preferably, the temperature range is about 60 C to about 80 C. Preferred intermediates B-16 which may be synthesized by this method are selected from any one of intermediates B-16a to B-16f (see table 15-2 below), including their salts. The advantage of the bromination step as described herein is its efficiency and high yield due to almost complete control of regiochemistry for the subsequent installation of the linker between substituted ring system A and the isatin (oxindole) scaffold which is also positively influenced by the anilide protecting group, the temperature range applied and the choice of AcOH as reaction solvent. In addition, the use of NBS is process friendly. In a further aspect the invention also relates to synthetic intermediates of formula B-17 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): 31 Date Recue/Date Received 2023-03-01 CA 3,000,063 (Rir nO ----Lk A N \ H s II BocNH B-17 The definitions of group R4, A and r in B-17 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (1c*) above, i.e. [CO] for PJR4/r. Preferred intermediates B-17 are those which lead to preferred compounds (la) and (1a*) according to the invention, i.e. preferred embodiments of B-17 have structural aspects selected from [CO] to [C15] for A/R4/r each defining individual embodiments or generic subsets of intermediates B-17. Preferred intermediates B-17 are selected from intermediates B-17a to B-17f (see table 15-3 below), including their salts. In a further aspect the invention also relates to the use of synthetic intermediates of formula lci B-17 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B-17 (R4)r nO --Ak A N µ H s II BocNH B-17 , or a salt thereof, comprising reacting a compound of formula B-16 32 Date Recue/Date Received 2023-03-01 CA 3,000,063 (Rir 110 N Br B-16 , or a salt thereof, with prop-2-ynyl-carbamic acid tert-butyl ester 0 40AN , wherein the reaction is performed in a solvent in the presence of a palladium catalyst, a ligand, a base and, optionally, a copper co-catalyst, and R4, A and r is as hereinbefore defined. (STEP B) Embodiments/conditions for STEP B: The solvent to be chosen can be an organic solvent, preferably chosen from the group consisting of DMSO, DMF, ACN, THF, dioxane, NMP, iPrOAc, toluene, nBuOH, or a mixture thereof. Most preferred is DMSO. Preferably, the palladium catalyst to be used is a Pd(II) or a Pd(0) catalyst, e.g., a palladium catalyst chosen from the group consisting of Pd(OAc)2 and Pd2(dba)3. The preferred palladium catalyst is Pd2(dba)3. The ligand to be used in the reaction is preferably an organophosphorous compound, e.g. is a ligand selected from the group consisting of [(tBu)3PH]BF4, RuPhos and Xphos. The preferred ligand to be used is [(tBu)3PH]BF4. The copper co-catalyst, if present, preferably is a copper salt, more preferably a Cu(I) salt, e.g. selected from the group consisting of Cul, CuCI and Cu2O. The preferred copper co- catalyst is Cul. The base to be used is preferably an organic base, more preferably an amine base, e.g. a secondary amine. Most preferred is the use of DIPA. The reaction can be performed at a temperature range of about 20 C to about 70 C, preferably at about 20 C to about 40 C. Most preferably, the temperature range is about 33 Date Recue/Date Received 2023-03-01 CA 3,000,063 20 C to about 30 C. Preferred intermediates B-17 which may be synthesized by this method are selected from any one of intermediates B-17a to B-17f (see table 15-3 below), including their salts. In a further aspect the invention also relates to synthetic intermediates of formula B-18 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): (R4)r A H2N 0 H2N B-18 The definitions of group R4, A and r in B-18 correspond to those as given for compound (I), (la), (lb), (lc), (1a*), (1b*) or (Ic*) above, i.e. [CO] for A/R4/r. im Preferred intermediates B-18 are those which lead to preferred compounds (la) and (1a*) according to the invention, i.e. preferred embodiments of B-18 have structural aspects selected from [CO] to [C15] for A/R4/r each defining individual embodiments or generic subsets of intermediates B-18. Preferred intermediates B-18 are selected from intermediates B-18a to B-181 (see tables 15-4 and 15-5 below), including their salts. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-18 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B-18 34 Date Recue/Date Received 2023-03-01 CA 3,000,063 (114),. H2N A 0 H2N B-18 , or a salt thereof, comprising hydration and deprotectionof a compound of formula B-17 (R4)r nO II A N H BocNH B-17 , or a salt thereof, wherein the hydration step is performed in the presence of a palladium catalyst in a solvent and the deprotection step is performed in the presence of an acid, and R4, A and r is as hereinbefore defined. (STEP C) Embodiments/conditions for STEP C: The solvent to be chosen can be an organic solvent, preferably a carboxylic acid. Most preferred is AcOH. Preferably, the palladium catalyst to be used is a Pd(II) catalyst, e.g., a Pd(II) catalyst chosen from the group consisting of Pd(OAc)2, PdC12 and Pd(OC(0)CF3)2. The preferred Pd(II) catalyst is Pd(OAc)2. The acid to be used in the deprotection step is preferably an aqueous inorganic acid, e.g. selected from the group consisting of aqueous HCI, HBr and H2SO4. Most preferred is aqueous HCl. The hydration step can be performed at a temperature range of about 20 C to about 80 C, preferably at a range of about 20 C to about 50 C. Most preferred is a range of about 20 C to about 30 C. Date Recue/Date Received 2023-03-01 CA 3,000,063 The deprotection step can be performed at a temperature range of about 20 C to about 80 C. Preferred intermediates B-18 which may be synthesized by this method are selected from any one of intermediates B-18a to B-181 (see table 15-4 and 15-5 below) and their salts. The intermediate product obtained after the hydration step, i.e. B-18 still bearing the acetyl and Boc protecting group, is also part of the invention. In a further aspect the invention also relates to synthetic intermediates of formula B-19 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): (R4)r A H2N 0 Xµ( (1:27)q cr V B-19 The definitions of groups R4, R7, A, V, W, X, Y, rand q in B-19 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (lc*) above, i.e. [CO] for A/R4/r, [ED] for R7/q, [FO] for W/XN and [GO] for V. Preferred intermediates B-19 are those which lead to preferred compounds (la) and (le) according to the invention, i.e. preferred embodiments of B-19 have structural aspects selected from [CO] to [C151 for A/R4/r, [ED] to [E2] for R7/q, [FO] and [Fl] for W/X/Y, [GO] and [G1] for V and [EFO] and [EF1] for R7/q/VV/XN altogether. These structural aspects may be permutated with one another as desired in combinations CEFG, so as to obtain preferred intermediates B-19 (aspects E and F can be replaced by combination aspect EF). Each combination CEFG represents and defines individual embodiments or generic subsets of intermediates B-19. Preferred intermediates B-19 are selected from intermediates B-19a to B-19f (see table 15-6 below), including their salts. In a further aspect the invention also relates to the use of synthetic intermediates of formula 36 Date Recue/Date Received 2023-03-01 CA 3,000,063 B-19 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B-19 (Rir A H2N 0 (R7)q¨tor V B-19 , or a salt thereof, comprising reacting a compound of formula B-18 (R4), H2N A 0 H2N B-18 , or a salt thereof, with a compound of formula S-1 0 X (R7)q¨cr V S-1 , or a salt thereof, wherein the reaction is performed in a solvent in the presence of an acid and a base, and R4, R7, A, V, W, X, Y, r and q is as hereinbefore defined. (STEP D) 37 Date Recue/Date Received 2023-03-01 CA 3,000,063 Embodiments/conditions for STEP D: The solvent to be chosen can be an organic solvent, preferably chosen from the group consisting of Me0H, DMF, ACN, NMP and THF, or a mixture thereof. Most preferred is a mixture of Me0H and DMF. The acid to be used is preferably an organic acid, more preferably a carboxylic acid. Most preferred is the use of AcOH. The base to be used is preferably an organic base, more preferably an amine base, e.g. a tertiary amine. The tertiary amine is preferably selected from the group consisting of TEA, DIPEA and N-ethyl-dicyclohexyl amine. Most preferred is the use of TEA. The reaction can be performed at a temperature range of about - 10 C to about 50 C, preferably at about 10 C to about 20 C. Preferred intermediates B-19 which may be synthesized by this method are selected from any one of intermediates B-19a to B-191 (see table 15-6 below) including their salts. In a further aspect the invention also relates to synthetic intermediates of formula B-20 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): (R4)r H2N A 02N, 0 Faõ, NH V R2 / (Rig B-20 The definitions of groups R2, R3, R4, R7, A, V, W, X, Y, r and q in B-20 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) above, i.e. [BO] for R2/R3, [CO] for A/R4/r, [EO] for R7/q, [FO] for W/XN and [GO] for V. Preferred intermediates B-20 are those which lead to preferred compounds (la) and (1a*) 38 Date Recue/Date Received 2023-03-01 CA 3,000,063 according to the invention, Le. preferred embodiments of B-20 have structural aspects selected from [BO] to [B17] for R2/R3, [CO] to [C15] for A/R4/r, [EO] to [E2] for 1,17/q, [F0] and [Fl] for W/XN, [GO] and [G1] for V and [EFO] and [EF1] for FVIONIXN altogether. These structural aspects may be permutated with one another as desired in combinations BCEFG, so as to obtain preferred intermediates B-20 (aspects E and F can be replaced by combination aspect EF). Each combination BCEFG represents and defines individual embodiments or generic subsets of intermediates B-20. Preferred intermediates B-20 are selected from intermediates B-20a to B-20f (see table 15-7 below), including their salts. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-20 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B-20 (R4),. H2N A 02N, if o /44 NH (Rig B-20 , or a salt thereof, comprising reacting a compound of formula B-2 R2(R3 NO2 B-2 , or a salt thereof, with a compound of formula B-19 39 Date Recue/Date Received 2023-03-01 CA 3,000,063 (R4)r H2N A 0 (127)q¨cr V B-19 , or a salt thereof, wherein the reaction is performed in a solvent in the presence of a base, and R2, R3,R4, R7, A, V, W, X, Y, r and q is as hereinbefore defined. (STEP E) Embodiments/conditions for STEP E: The solvent to be chosen is an organic solvent or a mixture of an organic solvent and water. Preferably, the organic solvent is selected from the group consisting of MeTHF, dioxane, DCM, ACN, toluene, 2-methyl-2-butanol and iPrOH, or a mixture thereof, or a mixture of the organic solvent(s) with water. Most preferred is a mixture of toluene and water. The base to be used is preferably an organic base, more preferably an amine base. The to amine base is preferably selected from the group consisting of N- methylpyrrolidine, N- ethylpyrrolidine, N-methylpiperidine, 1-(2-hydroxyethyl)-pyrrolidine, 3- quinuclidinol and DABCO. Most preferred is the use of N-methylpyrrolidine. The reaction can be performed at a temperature range of about 35 C to about 110 C, preferably at about 40 C to about 85 C. Preferred intermediates B-20 which may be synthesized by this method are selected from any one of intermediates B-20a to B-20f (see table 15-7 below) including their salts. In a further aspect the invention also relates to a method for chiral separation of a mixture comprising both enantiomers of an intermediate of formula B-20 Date Recue/Date Received 2023-03-01 CA 3,000,063 (R4)r H2N A 02N, rzoir R34,õ NH V R2 ,li (.1 (Rig B-20 comprising precipitating a salt of one enantiomer formed with a chiral acid. Embodiments/conditions for chiral separation: The chiral acid to be used is, e.g., preferably selected from among (+)-Di- 0,0'-dibenzoyl- D-tartaric acid, (-)-Di-0,0'-dibenzoyl-L-tartaric acid, (+)-Di-0,0'-p-toluoyl- D-tartaric acid, (-)-Di-0,0'-p-toluoyl-L-tartaric acid, (1S)-(+)-camphor-10-sulfonic acid, (1R)- (-)-camphor- 10-sulfonic acid, (R)-(-)-mandelic acid, (S)-(+)-mandelic acid, L-pyroglutamic acid, D- pyroglutamic acid L-(+)-tartaric acid and D-(-)-tartaric acid. Most preferred is (1R)-(-)- and (1S)-(+)-camphor-10-sulfonic acid. The salt of the enantiomer is precipitated from a solution or suspension of compounds B-20 in an appropriate solvent, preferably ACN. Without wishing to be bound by theory, it is assumed that the formation of labile acetonitrile solvates of the precipitating camphor-10-sulfonic acid salt may be responsible for the resolution of racemic mixtures of the most preferred compounds. The salt precipitates selectively, i.e. one enantiomer precipitates as a salt of the chiral acid whereas the other enantiomer remains/is substantially dissolved under the conditions applied. The free enantiomer can be recovered from the salt by ion exchange. The method described hereinbefore can also be applied for the enrichment of one enantiomer in relation to the other if complete separation can not be achieved or the steps can be repeated several times to achieve complete separation. Separation means that the respective enantiomer/salt is obtained in a form that is substantially free of the other enantiomer. Preferably, the chiral acid is used in sub- stoichiometric amounts in relation to the enantiomer being separated, i.e. preferably in a range of 0.5 ¨ 0.9 eq. (about 0.6 eq. being most preferred). The total concentration of racemate in the solution/suspension before separation is preferably in a range of 50 ¨ 150 41 Date Recue/Date Received 2023-03-01 CA 3,000,063 g/L, about 100 g/L being most preferred. Preferred chiral intermediates B-20 which may be separated from their enantiomer by this method are selected from any one of intermediates B-20g to B-201 (see table 15- 7 below) including their salts. In a further aspect the invention also relates to synthetic intermediates of formula B-21 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (la*): (R4), H2N HO, R2 A .1 X,Y=+I` V NH (R7)q---t w N chiral B-21 The definitions of groups R2, R3, R4, R7, A, V, W, X, Y, r and q in B-21 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) above, i.e. [BO] for R2/R3, [CO] for A/124/r, [EO] for 127/q, [F0] for W/X/Y and [GO] for V. Preferred intermediates 13-21 are those which lead to preferred compounds (la) and (le) according to the invention, i.e. preferred embodiments of B-21 have structural aspects selected from [BO] to [B17] for R2/R3, [CO] to [C15] for A/R4/r, [EO] to [E2] for R7/q, [F0] and [Fl] for W/X/Y, [GO] and [G1] for V and [EFO] and [EF1] for 127/q1W/YJY altogether. These structural aspects may be permutated with one another as desired in combinations BCEFG, so as to obtain preferred intermediates B-21 (aspects E and F can be replaced by combination aspect EF). Each combination BCEFG represents and defines individual embodiments or generic subsets of intermediates 13-21. Preferred intermediates 13-21 are selected from intermediates B-21a to B-21f (see table 15-8 below), including their salts. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-21 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (1a) and (1a*). 42 Date Recue/Date Received 2023-03-01 CA 3,000,063 In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B-21 (R4)r A H2N \ HO, -N R2R ! 1 _Y NH A \ too (Rig cr v N H chiral B-21 , or a salt thereof, comprising hydrogenating a compound of formula B-20, (R4), H2N \A 02N, 1 0 Rt.õ, 34ore.rneir NH V R2 $ )XliN chiral (127)q B-20 , or a salt thereof, wherein the reaction is performed in a solvent in the presence of a Pt catalyst, and R2, R3,R4, R7, A, V, W, X, Y, r and q is as hereinbefore defined. Embodiments/conditions for this step: The solvent to be chosen can be an organic solvent. Preferably, the organic solvent is selected from the group consisting of MeTHF, THF, Me0H, nBuOAc and iPrOAc, or a mixture thereof. Most preferred is MeTHF. Preferably, the Pt catalyst to be used is Pt/C. 43 Date Recue/Date Received 2023-03-01 CA 3,000,063 The reaction can be performed at a temperature range of about 20 C to about 100 C, preferably at about 20 C to about 30 C. The Hz-pressure applied for hydrogenation is preferably in the range of about 20 bar to about 70 bar. Most preferred the Hz-pressure is in the range of about 60 bar to about 70 bar Preferred intermediates B-21 which may be synthesized by this method are selected from any one of intermediates B-21a to B-21f (see table 15-8 below) including their salts. In a further aspect the invention also relates to synthetic intermediates of formula B-22 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): (R4)r A H2N \ 3HN , .. R% - R2ai. X NH (117)q¨t- v W N H chiral io B-22 The definitions of groups R2, R3, R4, R7, A, V, W, X, Y, r and q in B-22 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (lc*) above, i.e. [BO] for R2/R3, [CO] for A/R4/r, [EO] for 127/q, [F0] for W/XN and [GO] for V. Preferred intermediates B-22 are those which lead to preferred compounds (la) and (1a*) according to the invention, i.e. preferred embodiments of B-22 have structural aspects selected from [BO] to [B17] for R2/R3, [CO] to [C15] for A/R4/r, [EO] to [E2] for 117/q, [F0] and [Fl] for W/XN, [GO] and [G1] for V and [EFO] and [EFI] for R7/qNV/XJY altogether. These structural aspects may be permutated with one another as desired in combinations BCEFG, so as to obtain preferred intermediates B-22 (aspects E and F can be replaced by combination aspect EF). Each combination BCEFG represents and defines individual embodiments or generic subsets of intermediates B-22. Preferred intermediates B-22 are selected from intermediates B-22a to B-22f (see table 15-8 below), including their salts. 44 Date Recue/Date Received 2023-03-01 CA 3,000,063 In a further aspect the invention also relates to the use of synthetic intermediates of formula B-22 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B-22 (114)r A H2N \ H 3 tl , R2R% XX` NH (R7)q _______________________ cr v al.... N H chiral B-22 , or a salt thereof, comprising hydrogenating a compound of formula B-21, (R4)r A H2N \ HO, N R2 = X,Yr NH (R7)q --tvi, v N H chiral B-21 , or a salt thereof, wherein The reaction is performed in a solvent in the presence of a Pt catalyst and a V catalyst, and R2, R3,R4, R7, A, V, W, X, Y, r and q is as herein before defined. Embodiments/conditions for this step: The solvent to be chosen can be an organic solvent. Preferably, the organic solvent is Date Recue/Date Received 2023-03-01 CA 3,000,063 selected from the group consisting of MeTHF, THF, Me0H, nBuOAc and iPrOAc, or a mixture thereof. Most preferred is MeTHF. Preferably, the Pt catalyst to be used is Pt/C. Preferably, the V catalyst to be used is a V(IV) catalyst. Most preferred is VO(acac)2. The reaction can be performed at a temperature range of about 20 C to about 60 C, preferably at about 20 C to about 30 C. The H2-pressure applied for hydrogenation is preferably in the range of about 3 to about 70 bar. Most preferred the H2-pressure is in the range of about 60 bar to about 70 bar. Preferred intermediates B-22 which may be synthesized by this method are selected from any one of intermediates B-22a to B-22f (see table 15-8 below) including their salts. In a further aspect the invention also relates to a method for chiral separation of a mixture comprising both enantiomers of an intermediate of formula B-22 (R4)i. H2N A HN RLJT ,Y X NH too (R7)q¨t V W N B-22 comprising precipitating a salt of one enantiomer formed with a chiral acid. Embodiments/conditions for chiral separation: The chiral acid to be used is, e.g., preferably selected from among (+)-Di- 0,0'-dibenzoyl- D-tartaric acid, (-)-Di-0,0'-dibenzoyl-L-tartaric acid, (+)-Di-0,0'-p-toluoyl- D-tartaric acid, (-)-Di-0,0'-p-toluoyl-L-tartaric acid, (1S)-(+)-camphor-10-sulfonic acid, (1R)- (-)-camphor- 10-sulfonic acid, (R)-(-)-mandelic acid, (S)-(+)-mandelic acid, L-pyroglutamic acid, D- pyroglutamic acid, L-(+)-tartaric acid, D-(-)-tartaric acid, L-(+)-lactic acid and L-(+)-lactic acid. Most preferred is (+)-Di-0,0'-p-toluoyl-D-tartaric acid and (-)-Di-0,0'- p-toluoyl-L- 46 Date Recue/Date Received 2023-03-01 CA 3,000,063 tartaric acid. The salt of the enantiomer is precipitated from a solution or suspension of compounds B-22 in an appropriate solvent, preferably ACN. The salt precipitates selectively, i.e. one enantiomer precipitates as a salt of the chiral acid whereas the other enantiomer remains/is substantially dissolved under the conditions applied. The free enantiomer can be recovered from the salt by ion exchange. The method described hereinbefore can also be applied for the enrichment of one enantiomer in relation to the other if complete separation can not be achieved or the steps can be repeated several times to achieve complete separation. Separation means that the respective enantiomer/salt is obtained in a form that is substantially free of the other enantiomer. Preferably, the chiral acid is used in sub-stoichiometric amounts in relation to the enantiomer being separated, i.e. preferably in a range of 0.5 ¨ 1 eq. (1 eq. being most preferred). The total concentration of racemate in the solution/suspension before separation is preferably in a range of 50 ¨ 150 g/L, about 100 g/L being most preferred. Preferred chiral intermediates B-22 which may be separated from their enantiomer by this method are selected from any one of intermediates B-22a to B-22f (see table 15- 7 below) including their salts. In a further aspect the invention also relates to synthetic intermediates of formula B-23 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (la) and (1a*): (R4), A / I 3 E 1 R1.7z NH X (R7),-i¨tw V H chiral B-23 The definitions of groups R2, R3, R4, R7, A, V, W, X, Y, r and q in B-23 correspond to those as given for compound (I), (la), (lb), (lc), (1a*), (1b*) or (Ic*) above, i.e. [BO] for R2/R3, [CO] for A/124/r, [EO] for 127/q, [FO] for W/X/Y and [GO] for V. 47 Date Recue/Date Received 2023-03-01 CA 3,000,063 Preferred intermediates B-23 are those which lead to preferred compounds (la) and (1a*) according to the invention, i.e. preferred embodiments of B-23 have structural aspects selected from [BO] to [B17] for R2/R3, [CO] to [C15] for A/R4/r, [EO] to [E2] for R7/q, [FO] and [Fl] for W/X/Y, [GO] and [G1] for V and [EFO] and [EF1] for 127/qNV/XN altogether. These structural aspects may be permutated with one another as desired in combinations BCEFG, so as to obtain preferred intermediates B-23 (aspects E and F can be replaced by combination aspect EF). Each combination BCEFG represents and defines individual embodiments or generic subsets of intermediates B-23. Preferred intermediates B-23 are selected from intermediates B-23a to B-23f (see table 15-9 below), including their salts. In a further aspect the invention also relates to the use of synthetic intermediates of formula B-23 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (la) and (1a*). In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B-23 (R4)r A 14," I R3 R2 11 y NH (117)ci¨tvir V H chiral B-23 , or a salt thereof, comprising oxidation of a compound of formula B-22, 48 Date Recue/Date Received 2023-03-01 CA 3,000,063 (R4), H2N A HN R` X,Ytio% NH (R7)q¨k- V w N H chiral B-22 , or a salt thereof, wherein the reaction is performed in a solvent in the presence of a catalyst and an oxidizing agent, and R2, R3,R4, R7, A, V, W, X, Y, r and q is as hereinbefore defined. Embodiments/conditions for this step: The solvent to be chosen is an organic solvent or a mixture of an organic solvent and water. Preferably, the organic solvent is selected from the group consisting of DCM and toluene, or a mixture thereof, or a mixture of the organic solvent(s) with water. Most preferred is a mixture of DCM and water. The catalyst to be used can be a Mo-, V- or W-catalyst. Preferably, the catalyst is selected from the group consisting of (NH4)2Mo04, Na2Mo04, VO(acac)2, Mo02(acac)2, Na2W04*2H20. Most preferred is Na2W04*2H20. As far as the oxidizing agent is concerned H202 is preferably used, in particular H202 in water. The reaction can be performed at a temperature range of about 0 C to about 50 C, preferably at about 35 C to about 40 C. Preferred intermediates B-23 which may be synthesized by this method are selected from any one of intermediates B-23a to B-23f (see table 15-9 below) including their salts. Synthetic steps B-20 4 B-21, B-21 4 B-22 and B-22 4 B-23 can also be performed with racemic intermediate B-20, B-21 and B-22, respectively (if chiral separation of B-20 is not performed). Racemic B-21, B-22 and B-23 and the corresponding reaction steps with the racemic intermediates are also part of the invention. 49 Date Recue/Date Received 2023-03-01 CA 3,000,063 In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B-18 comprising STEP A as hereinbefore described (VARIANT 1). In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B- 18 comprising STEP A and STEP B as hereinbefore described (VARIANT 2). In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B- 18 comprising STEP A and STEP B and STEP C as hereinbefore described (VARIANT 3). Syntheses according to VARIANTS 1 to 3 are advantageous over alternative approaches that may be considered and allow for an improved overall synthetic efficiency and througput, lower costs and reduced solvents and waste. o In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B-20 comprising STEP D as hereinbefore described (VARIANT 4). In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B- 20 comprising STEP D and STEP E as hereinbefore described (VARIANT 5). In a further aspect the invention also relates to a method for synthesizing an intermediate of formula B- 20 comprising STEP A and STEP B and STEP C and STEP D and STEP E as hereinbefore described (VARIANT 6). In a further aspect the invention also relates to a method for synthesizing a compound of formula (la) and (1a*) comprising a variant selected from VARIANT 1 to 6. All STEPS as referred to hereinbefore include all embodiments/conditions of how the STEPS can be performed as disclosed hereinbefore. In a further aspect the invention also relates to synthetic intermediates of formula A-12 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (lb) and (1b*): 0[41 3 5 n R2 N X (Rig II V N A-12 The definitions of groups R2, R3, R7, V, W, X, Y, n and q in A-12 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (1c*) above, i.e. [BO] for R2/R3, [DO] for Date Recue/Date Received 2023-03-01 CA 3,000,063 n, [EO] for R7/q, [FO] for W/X/Y and [GO] for V. Preferred intermediates A-12 are those which lead to preferred compounds (lb) and (1b*) according to the invention, i.e. preferred embodiments of A-12 have structural aspects selected from [BO] to [B17] for R2/R3, [DO] to [D3] for n, [EO] to [E2] for R7/q, [FO] and [Fl] for WOUY, [GO] and [G1] for V and [EFO] and [EF1] for R7/qNV/X/Y altogether. These structural aspects may be permutated with one another as desired in combinations BDEFG, so as to obtain preferred intermediates A-12 (aspects E and F can be replaced by combination aspect EF). Each combination BDEFG represents and defines individual embodiments or generic subsets of intermediates A-12. In a further aspect the invention also relates to the use of synthetic intermediates of formula A-12 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (lb) and (1b*). In a further aspect the invention also relates to synthetic intermediates of formula A-13 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (lb) and (1b*): (R4)r 02N \A 0 ()). R X (R7)q-11-- V -w N A-13 The definitions of groups R2, R3, R4, R7, A, V, W, X, Y, n, q and r in A-13 correspond to those as given for compound (I), (la), (lb), (lc), (1a*), (1b*) or (1c*) above, i.e. [BO] for R2/R3, [CO] for A/R4/r, [DO] for n, [EO] for R7/q, [FO] for W/XN and [GO] for V. Preferred intermediates A-13 are those which lead to preferred compounds (lb) and (1b*) according to the invention, i.e. preferred embodiments of A-13 have structural aspects selected from [BO] to [B17] for R2/R3, [CO] to [C15] for A/R4/r, [DO] to [D3] for n, [EO] to 51 Date Regue/Date Received 2023-03-01 CA 3,000,063 [E2] for R7/q, [FO] and [Fl] for W/X/Y, [GO] and [G1] for V and [EFO] and [EF1] for R7/q/W/XN altogether. These structural aspects may be permutated with one another as desired in combinations BCDEFG, so as to obtain preferred intermediates A-13 (aspects E and F can be replaced by combination aspect EF). Each combination BCDEFG represents and defines individual embodiments or generic subsets of intermediates A-13. In a further aspect the invention also relates to the use of synthetic intermediates of formula A-13 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (lb) and (1b*). In a further aspect the invention also relates to synthetic intermediates of formula A-14 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (lb) and (1b*): (114), A - \ R3, E R N--% X2(' (R7)q 11 V w N A-14 The definitions of groups R2, R3, R4, R7, A, V, W, X, Y, n, q and r in A-15 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (1c*) above, i.e. [BO] for R2/R3, [CO] for A/R4/r, [DO] for n, [ED] for R7/q, [FO] for W/X/Y and [GO] for V. Preferred intermediates A-14 are those which lead to preferred compounds (lb) and (1b*) according to the invention, i.e. preferred embodiments of A-14 have structural aspects selected from [BO] to [B17] for R2/R3, [CO] to [C15] for A/124/r, [DO] to [D3] for n, [ED] to [E2] for R7/q, [FO] and [Fl] for W/XN, [GO] and [G1] for V and [EFO] and [EF1] for 127/q/W/X/Y altogether. These structural aspects may be permutated with one another as desired in combinations BCDEFG, so as to obtain preferred intermediates A-14 (aspects E and F can be replaced by combination aspect EF). Each combination BCDEFG represents and defines individual embodiments or generic subsets of intermediates A-14. 52 Date Recue/Date Received 2023-03-01 CA 3,000,063 In a further aspect the invention also relates to the use of synthetic intermediates of formula A-14 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (lb) and (1b*). In a further aspect the invention also relates to synthetic intermediates of formula A-15 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (lb) and (1b*): (R4), A N R3, On 2' R' ,y NH X (R7)q¨t¨ V w N A-15 The definitions of groups R2, R3, R4, R7, A, V, W, X, Y, n, q and r in A-15 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (IC*) above, Le. [BO] for R2/R3, [CO] for A/R4/r, [DO] for n, [E0] for R7/q, [FO] for W/XN and [GO] for V. Preferred intermediates A-15 are those which lead to preferred compounds (lb) and (1b*) according to the invention, Le. preferred embodiments of A-15 have structural aspects selected from [BO] to [B17] for R2/R3, [CO] to [C15] for A/R4/r, [DO] to [D3] for n, [EO] to [E2] for 127/q, [FO] and [Fl] for W/XN, [GO] and [G1] for V and [EFO] and [EF1] for R7/q/W/X/Y altogether. These structural aspects may be permutated with one another as desired in combinations BCDEFG, so as to obtain preferred intermediates A-15 (aspects E and F can be replaced by combination aspect EF). Each combination BCDEFG represents and defines individual embodiments or generic subsets of intermediates A-15. In a further aspect the invention also relates to the use of synthetic intermediates of formula A-15 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (lb) and (1b*). In a further aspect the invention also relates to synthetic intermediates of formula A-17 and their salts, which can be used as key intermediates in the synthesis of compounds of 53 Date Recue/Date Received 2023-03-01 CA 3,000,063 formula (lb) and (1b*): (R4)r A 0 NH2 ¨ H R2 A-17 The definitions of groups R2, R3, R4, A and r in A-17 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (lc*) above, Le. [BO] for R2/R3 and [CO] for A/124/r. Preferred intermediates A-17 are those which lead to preferred compounds (lb) and (1b*) according to the invention, i.e. preferred embodiments of A-17 have structural aspects selected from [BO] to [B17] for R2/R3 and [CO] to [C15] for A/124/r. These structural aspects may be permutated with one another as desired in combinations BC, so as to obtain preferred intermediates A-17. Each combination BC represents and defines individual embodiments or generic subsets of intermediates A-17. In a further aspect the invention also relates to the use of synthetic intermediates of formula A-17 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (lb) and (1b*). In a further aspect the invention also relates to synthetic intermediates of formula A-18 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (lb) and (1b*): A I N \)¨R (R4 r H R2 A-18 The definitions of groups R2, R3, R4, A and r in A-18 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) above, i.e. [BO] for R2/R3 and [CO] for A/R4/r. Preferred intermediates A-18 are those which lead to preferred compounds (lb) and (1b*) according to the invention, i.e. preferred embodiments of A-18 have structural aspects selected from [BO] to [B17] for R2/R3 and [CO] to [C15] for A/R4/r. These structural aspects may be permutated with one another as desired in combinations BC, so as to obtain 54 Date Recue/Date Received 2023-03-01 CA 3,000,063 preferred intermediates A-18. Each combination BC represents and defines individual embodiments or generic subsets of intermediates A-18. In a further aspect the invention also relates to the use of synthetic intermediates of formula A-18 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (lb) and (1b*). In a further aspect the invention also relates to synthetic intermediates of formula A-20 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (lb) and (1b*): A I \> ¨ ¨ N R3 (R4 r R2 NH tBu0-1 A-20 0 The definitions of groups R2, R3, R4, A, n and r in A-20 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (lc*) above, i.e. [BO] for R2/R3, [CO] for A/R4/r and [DO] for n. Preferred intermediates A-20 are those which lead to preferred compounds (lb) and (1b*) according to the invention, i.e. preferred embodiments of A-20 have structural aspects selected from [BO] to [B17] for R2/R3, [CO] to [C15] for A/R4/r and [DO] to [D3] for n. These structural aspects may be permutated with one another as desired in combinations BCD, so as to obtain preferred intermediates A-20. Each combination BCD represents and defines individual embodiments or generic subsets of intermediates A-20. In a further aspect the invention also relates to the use of synthetic intermediates of formula A-20 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (lb) and (1b*). In a further aspect the invention also relates to synthetic intermediates of formula A-21 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (lb) and (1b*): Date Recue/Date Received 2023-03-01 CA 3,000,063 A I \>¨$¨ N R3 (R4 r R2 NH2 A-21 The definitions of groups R2, R3, R4, A, n and r in A-21 correspond to those as given for compound (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) above, i.e. [BO] for R2/R3, [CO] for A/R4/r and [DO] for n. Preferred intermediates A-21 are those which lead to preferred compounds (lb) and (1b*) according to the invention, Le. preferred embodiments of A-21 have structural aspects selected from [BO] to [B17] for R2/R3, [CO] to [C15] for A/R4/r and [DO] to [D3] for n. These structural aspects may be permutated with one another as desired in combinations BCD, so as to obtain preferred intermediates A-21. Each combination BCD represents and defines individual embodiments or generic subsets of intermediates A-21. In a further aspect the invention also relates to the use of synthetic intermediates of formula A-21 or their salts (and the various embodiments and sub-groups as described and/or defined herein) in the synthesis of compounds (lb) and (1b*). The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, isomers and prodrugs of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (1c*). Compounds of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) which e.g. bear ester groups are potential prodrugs the ester being cleaved under physiological conditions. The present invention further relates to a pharmaceutically acceptable salt of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*). The present invention further relates to a co-crystal, preferably a pharmaceutically acceptable co-crystal, of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*). In one aspect compounds (1), (la), (lb), (lc), (1a*), (1b*) or (1c*) according to the invention are in amorphous form. The present invention further relates to a pharmaceutically acceptable salt of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) with inorganic or organic acids or bases. 56 Date Recue/Date Received 2023-03-01 CA 3,000,063 The present invention is directed to compounds of formula (1), (la), (lb), (lc), (1a*), (1b*) or (1c*) which are useful in the prevention and/or treatment of a disease and/or condition wherein the inhibition of the interaction between MDM2 and p53 is of therapeutic benefit, including but not limited to the treatment and/or prevention of cancer. In another aspect the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically acceptable salt thereof ¨ for use as a medicament. In another aspect the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (1c*) ¨ or a pharmaceutically acceptable salt thereof ¨ for use in a method for treatment of the human or animal body. In another aspect the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically acceptable salt thereof¨ for use in the treatment and/or prevention of a disease and/or condition wherein the inhibition of the interaction between MDM2 and p53 is of therapeutic benefit. In another aspect the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically acceptable salt thereof¨ for use in the treatment and/or prevention of cancer, infections, inflammations or autoimmune diseases. In another aspect the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically acceptable salt thereof ¨ for use in a method for treatment and/or prevention of cancer, infections, inflammations or autoimmune diseases in the human and animal body. In another aspect the invention relates to the use of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically acceptable salt thereof ¨ for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammations or autoimmune diseases. In another aspect the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically acceptable salt thereof¨ for use in the treatment and/or prevention of cancer. In another aspect the invention relates to the use of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically acceptable salt thereof ¨ for preparing a pharmaceutical composition for the treatment and/or prevention of cancer. In another aspect the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), 57 Date Recue/Date Received 2023-03-01 CA 3,000,063 (1b*) or (1c*) ¨ or a pharmaceutically acceptable salt thereof ¨ for use in a method for treatment and/or prevention of cancer in the human or animal body. In another aspect the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (IC*) ¨ or a pharmaceutically acceptable salt thereof¨ for use in the treatment and/or prevention of acute myeloid leukaemia (AML), prostate cancer or lung cancer, wherein the cancer cells have functional p53, preferably wherein the cancer cells are p53 wild-type. In another aspect the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically acceptable salt thereof¨ for use in the treatment and/or prevention of acute myeloid leukaemia (AML), prostate cancer or lung cancer, wherein the cancer cells preferably have functional p53, more preferably wherein the cancer cells are p53 wild-type. In another aspect the invention relates to the use of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (1c*) ¨ or a pharmaceutically acceptable salt thereof ¨ for preparing a pharmaceutical composition for the treatment and/or prevention of acute myeloid leukaemia (AML), prostate cancer or lung cancer, wherein the cancer cells have functional p53, preferably wherein the cancer cells are p53 wild-type. In another aspect the invention relates to the use of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (lc*) ¨ or a pharmaceutically acceptable salt thereof ¨ for preparing a pharmaceutical composition for the treatment and/or prevention of acute myeloid leukaemia (AML), prostate cancer or lung cancer, wherein the cancer cells preferably have functional p53, more preferably wherein the cancer cells are p53 wild-type. In another aspect the invention relates to a method for the treatment and/or prevention of a disease and/or condition wherein the inhibition of the interaction between MDM2 and p53 is of therapeutic benefit comprising administering a therapeutically effective amount of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*)¨ or a pharmaceutically acceptable salt thereof¨ to a human being. In another aspect the invention relates to a method for the treatment and/or prevention of cancer comprising administering a therapeutically effective amount of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (1c*) ¨ or a pharmaceutically acceptable salt thereof ¨ to a human being. In another aspect the invention relates to a pharmaceutical composition comprising at least one compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically 58 Date Recue/Date Received 2023-03-01 CA 3,000,063 acceptable salt thereof¨ and a pharmaceutically acceptable carrier. In another aspect the invention relates to a pharmaceutical preparation comprising a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (1c*)¨ or a pharmaceutically acceptable salt thereof ¨ and at least one other cytostatic and/or cytotoxic active substance. In another aspect the invention relates to a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically acceptable salt thereof¨ for use in the treatment and/or prevention of cancer, infections, inflammations or autoimmune diseases wherein said compound is administered before, after or together with at least one other cytostatic or cytotoxic active substance. In another aspect the invention relates to the use of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically acceptable salt thereof ¨ for preparing a medicament for the treatment and/or prevention of cancer, infections, inflammations or autoimmune diseases wherein said compound is administered before, after or together with at least one other cytostatic or cytotoxic active substance. In another aspect the invention relates to a cytostatic or cytotoxic active substance prepared for being administered before, after or together with a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (1c*) ¨ or a pharmaceutically acceptable salt thereof ¨ for use in the treatment and/or prevention of cancer, infections, inflammations or autoimmune diseases. In another aspect the invention relates to a method for the treatment and/or prevention of cancer, infections, inflammations or autoimmune diseases comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) ¨ or a pharmaceutically acceptable salt thereof ¨ before, after or together with at least one other cytostatic or cytotoxic active substance. Definitions Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to: The use of the prefix Cx.y, wherein x and y each represent a natural number (x < y), indicates that the chain or ring structure or combination of chain and ring structure as a whole, specified and mentioned in direct association, may consist of a maximum of y and a 59 Date Recue/Date Received 2023-03-01 CA 3,000,063 minimum of x carbon atoms. The indication of the number of members in groups that contain one or more heteroatom(s) (e.g. heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycylalkyl) relates to the total number of atoms of all the ring members or chain members or the total of all the ring and chain members. The indication of the number of carbon atoms in groups that consist of a combination of carbon chain and carbon ring structure (e.g. cycloalkylalkyl, arylalkyl) relates to the total number of carbon atoms of all the carbon ring and carbon chain members. Obviously, a ring structure has at least three members. In general, for groups comprising two or more subgroups (e.g. heteroarylalkyl, heterocycylalkyl, cycloalkylalkyl, arylalkyl) the last named subgroup is the radical attachment point, for example, the substituent aryl-Ci_salkyl means an aryl group which is bound to a Ci_salkyl group, the latter of which is bound to the core or to the group to which the substituent is attached. Alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono- or polysubstitution in each case, on all the hydrogen-carrying carbon atoms. The term "Ci_salkyl" includes for example H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C- CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-. Further examples of alkyl are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (i-Pr; iso-propyl; -CH(CH3)2), 1-butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-1-propyl (iso-butyl; i-Bu; -CH2CH(CH3)2), 2- butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl; t-Bu; - C(CH3)3), 1-pentyl (n-pentyl; -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 3-methyl-1-butyl (iso-pentyl; -CH2CH2CH(CH3)2), 2-methyl-2- butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethyl-l-propyl (neo-pentyl; -CH2C(CH3)3), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (n-hexyl; -CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl Date Recue/Date Received 2023-03-01 CA 3,000,063 (-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-dimethy1-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethy1-2-butyl (- CH(CH3)C(CH3)3), 2,3-dimethy1-1-butyl (-CH2CH(CH3)CH(CH3)CH3), 2,2-dimethyl-l-butyl (-CH2C(CH3)2CH2CH3), 3,3-dimethy1-1-butyl (-CH2CH2C(CH3)3), 2-methyl-1-pentyl (-CH2CH(CH3)CH2CH2CH3), 3-methyl-1-pentyl (-CH2CH2CH(CH3)CH2CH3), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethy1-1-pentyl, 2,3-dimethy1-1-pentyl, 2,4-dimethy1-1-pentyl, 3,3-dimethy1-1-pentyl, 2,2,3- trimethy1-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl) etc. By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included. The above definition for alkyl also applies if alkyl is a part of another (combined) group such as for example Cx_yalkylamino or Cx_yalkyloxy. The term alkylene can also be derived from alkyl. Alkylene is bivalent, unlike alkyl, and requires two binding partners. Formally, the second valency is produced by removing a hydrogen atom in an alkyl. Corresponding groups are for example -CH3 and -CH2- , -CH2CH3 and -CH2CH2- or >CHCH3 etc. The term "Ci_aalkylene" includes for example -(CH2)-, -(CH2-CH2)-, -(CH(CH3))- , -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))- , -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-CH2-CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2-CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CH(CH(CH3))2)- and -C(CH3)(CH2CH3)-. Other examples of alkylene are methylene, ethylene, propylene, 1- methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene etc. By the generic terms propylene, butylene, pentylene, hexylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propylene includes 1-methylethylene and butylene includes 61 Date Recue/Date Received 2023-03-01 CA 3,000,063 1-methylpropylene, 2-methyl propylene, 1,1-dimethylethylene and 1,2- dimethylethylene. The above definition for alkylene also applies if alkylene is part of another (combined) group such as for example in HO-Calkyleneamino or H2N-Calkyleneoxy. Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond and a carbon atom can only be part of one C-C double bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl is formed. Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, ally! (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1- enyl, 1-methyl-prop-2-enyl, 1 -methyl-prop-1-enyl, 1 -methyl idene propyl , pent-1 - enyl , pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2- enyl, 3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5- enyl, 2,3-d imethyl-but-3-enyl, 2,3-d imethyl-but-2-enyl, 2-methylidene-3-methyl butyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl, 2,3-dimethylbuta-1,3-diene etc. By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, Le. propenyl includes prop-1-enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl etc. Alkenyl may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s). The above definition for alkenyl also applies when alkenyl is part of another (combined) group such as for example in Cx_yalkenylamino or Cx_yalkenyloxy. Unlike alkylene, alkenvlene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond and a carbon atom can only be part of one C-C double bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenylene is formed. 62 Date Recue/Date Received 2023-03-01 CA 3,000,063 Examples of alkenylene are ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene etc. By the generic terms propenylene, butenylene, pentenylene, hexenylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, Le. propenylene includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene. Alkenylene may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s). The above definition for alkenylene also applies when alkenylene is a part of another (combined) group as for example in HO-Cx_yalkenyleneamino or H2N- Cx_yalkenyleneoxy. Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl is formed. Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2- ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent- 4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5- ynyl etc. By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynyl includes prop-1- ynyl and prop-2-ynyl, butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1 -ynyl , 1 -methyl-prop-2-ynyl, etc. If a hydrocarbon chain carries both at least one double bond and also at least one triple bond, by definition it belongs to the alkynyl subgroup. The above definition for alkynyl also applies if alkynyl is part of another (combined) group, as for example in Cx_yalkynylamino or Cx_yalkynyloxy. Unlike alkylene, allrynylene consists of at least two carbon atoms, wherein at least two 63 Date Recue/Date Received 2023-03-01 CA 3,000,063 adjacent carbon atoms are joined together by a C-C triple bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynylene is formed. Examples of al kynylene are ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1 ,1-dimethyl pro pynylene, 2,2-di methyl propynylene, 1 ,2- dimethylpropynylene, 3-dimethyl pro pynylene, hexynylene etc. By the generic terms propynylene, butynylene, pentynylene, hexynylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynylene includes 1 -methylpro pynylene, 2-methylpropynylene, 1 ,1-dimethylethynylene and 1 ,2-d imethylethynylene. The above definition for alkynylene also applies if alkynylene is part of another (combined) group, as for example in HO-Cx_yalkynyleneamino or H2N-Cx_yalkynyleneoxy. By heteroatoms are meant oxygen, nitrogen and sulphur atoms. Haloalkvl (haloalkenvl, haloalkvnvI) is derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If a haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCI=CH2, -CBr=CH2, -CC-CF3, -CHFCH2CH3, -CHFCH2CF3 etc. From the previously defined haloalkyl (haloalkenyl, haloalkynyl) are also derived the terms haloalkvlene (haloalkenvlene, haloalkvnvIenel. Haloalkylene (haloalkenylene, haloalkynylene), unlike haloalkyl (haloalkenyl, haloalkynyl), is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from a haloalkyl (haloalkenyl, haloalkynyl). Corresponding groups are for example -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or 64 Date Recue/Date Received 2023-03-01 CA 3,000,063 >CFCH2F etc. The above definitions also apply if the corresponding halogen-containing groups are part of another (combined) group. Halogen relates to fluorine, chlorine, bromine and/or iodine atoms. Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they have at least two carbon atoms together. In spiro-hydrocarbon rings one carbon atom (spiroatom) belongs to two rings together. If a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molecule via every suitable position of the ring system. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc. The above definition for cycloalkyl also applies if cycloalkyl is part of another (combined) group as for example in Cx_ycycloalkylamino, Cx_ycycloalkyloxy or Cx_ycycloalkylalkyl. If the free valency of a cycloalkyl is saturated, then an acyclic group is obtained. The term cycloalkylene can thus be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are for example: --(R cyclohexyl and ' ' or -' or '-- (cyclohexylene). The above definition for cycloalkylene also applies if cycloalkylene is part of another (combined) group as for example in HO-Ccycloal kyleneamino or H2N-Ccycloalkyleneoxy. Date Recue/Date Received 2023-03-01 CA 3,000,063 Cycloalkenvl is also made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However, the systems are unsaturated, i.e. there is at least one C-C double bond but no aromatic system. If in a cycloalkyl as hereinbefore defined two hydrogen atoms at adjacent cyclic carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding cycloalkenyl is obtained. If a cycloalkenyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkenyl itself may be linked as a substituent to the molecule via every suitable position of the ring system. Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1 - enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3- dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl, cyclohexa- 2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl, bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec- 2-enyl etc. The above definition for cycloalkenyl also applies when cycloalkenyl is part of another (combined) group as for example in Cx_ycycloalkenylamino, Cx_ycycloalkenyloxy or Cx_ycycloalkenylalkyl. If the free valency of a cycloalkenyl is saturated, then an unsaturated alio/clic group is obtained. The term cycloalkenylene can thus be derived from the previously defined cycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are for example: .. e. ¨ H 5) cyclopentenyl and ' or --- --- or ' or ' (cyclopentenylene) etc. The above definition for cycloalkenylene also applies if cycloalkenylene is part of another (combined) group as for example in HO-Cx_ycycloalkenyleneamino or H2N-Cx_ycycloalkenyleneoxy. 66 Date Recue/Date Received 2023-03-01 CA 3,000,063 Aryl denotes mono-, bi- or tricyclic carbocycles with at least one aromatic carbocycle. Preferably, it denotes a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or, however, may also be partially saturated. If an aryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen- carrying carbon atoms. Aryl itself may be linked as a substituent to the molecule via every suitable position of the ring system. Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2- dihydronaphthyl), fluorenyl etc. The above definition of aryl also applies if aryl is part of another (combined) group as for example in arylamino, aryloxy or arylalkyl. If the free valency of an aryl is saturated, then an aromatic group is obtained. The term arvlene can also be derived from the previously defined aryl. Arylene, unlike aryl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups are for example: phenyl and ' ' or / or -'- (o, m, p-phenylene), naphthyl and = ' or ' or ' .. etc. The above definition for arylene also applies if arylene is part of another (combined) group as for example in HO-aryleneamino or H2N-aryleneoxy. Heterocyclvl denotes ring systems, which are derived from the previously defined cycloalkyl, cycloalkenyl and aryl by replacing one or more of the groups -CH2- independently of one another in the hydrocarbon rings by the groups -0-, -S- or -NH- or by replacing one or more of the groups =CH- by the group =N-, wherein a total of not more than five heteroatoms may be present, at least one carbon atom must be present between 67 Date Recue/Date Received 2023-03-01 CA 3,000,063 two oxygen atoms and between two sulphur atoms or between an oxygen and a sulphur atom and the ring as a whole must have chemical stability. Heteroatoms may optionally be present in all the possible oxidation stages (sulphur 4 sulphoxide -SO-, sulphone -SO2-; nitrogen 4 N-oxide). In a heterocyclyl there is no heteroaromatic ring, i.e. no heteroatom is part of an aromatic system. A direct result of the derivation from cycloalkyl, cycloalkenyl and aryl is that heterocyclyl is made up of the subgroups monocyclic heterorings, bicyclic heterorings, tricyclic heterorings and spiro-heterorings, which may be present in saturated or unsaturated form. By unsaturated is meant that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In bicyclic heterorings two rings are linked together so that they have at least two (hetero)atoms in common. In spiro-heterorings one carbon atom (spiroatom) belongs to two rings together. If a heterocyclyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heterocyclyl itself may be linked as a substituent to the molecule via every suitable position of the ring system. Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4Foxazepanyl, tetrahydrothienyl, homothiomorpholinyl- S,S- dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetra hydrothienyl-S,S-d ioxide, homothiomorpholinyl-S-oxide, 2, 3-d i hydroazet, 2H-pyrrolyl, 4H-pyranyl, 1 ,4-dihydropyridinyl, 8-aza-bicyclo[3.2.1]octyl, 8-aza- bicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-d iaza-bicyclo[3.2.1]octyl, 2,5-d iaza-bicyclo [2.2.1]heptyl, 1 -aza- bicyclo[2.2.21octyl, 3,8-d iaza-bicyclo[3.2.1]octyl, 3,9-d iaza-bicyclo[4.2.1 ]nonyl, 2,6-d iaza- bicyclo[3.2.2]nonyl, 1,4-d ioxa-spiro[4.5]decyl, 1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza- spiro[3.3]heptyl, 2,7-d iaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]0cty1, 3,9-diaza- spiro[5.5]undecyl, 2.8-diaza- 68 Date Recue/Date Received 2023-03-01 CA 3,000,063 spiro[4,5]decyl etc. Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen): 0 H H ,0 II N 11) FT 11 FT' TT=0 H 0 N H ii 0õ0 ) N, c ) c (S N H 171H H H 0 H ri N ) N ) C) 0 KN C ) S, S=0 c __ ) H \ __ S \O 01 0 S 0 0. c o) a c-? H N --. 0 S, S=0 S II S=0 II µ0 0 S 0 H 0 N 7 H H II iC4sC) N II S N 0 0' '0 H H H ($0 00 L 7 0 7S) 7 .vN 7N II /S. ,S. 0"S 0 a' 0 S) 00 0 H II v0 N 0 S S ICI"S ( _________________________ ) ( _______ ) ( ) ( ) 69 Date Recue/Date Received 2023-03-01 CA 3,000,063 0 0 õ 0 H 1 1 o". H N (S) \ ____________________ N \ __ N \ ___ N N \ __ N H H H H H 0 õ 0 1 1 S S (0 ) ( ) ( ___________________________________________________________ ) rss.) rs) Q 0 0 0 a s H H N N 0 0 S S 0 0 eN II II 0,. '' Q S0 0 , ,0 S ' S ' S' > (_*7 N N H \-- H H N H N, 0 0 HI71H c __ .? N c __ ) ¨ N O H c ) ( rµl N ) S ________ S H \ __ S S s , \ o b H H N N N 0s ____________________________________________________ , ,p=0 Is=o 6 0_-0 r\ ) \\_ i o 0 o \--0 s 0, ,o, H H H S / = 0 I , o o ----... ---.....====- - ........ ---...,--- H I 1 Date Recue/Date Received 2023-03-01 CA 3,000,063 H H tN H r .11=1 sN NH "..A.,..-- H H H H :1µ13 1=1 N N) II , N H 0 0,S, s 0 H NH 1 iiIIIrIIII 0 0 0 S S 0 e NH S=0 S,. IIIrI8 :i c;ILIIN H 0 0 0 S 0 6 H N H H S 9, $ N> di NI) di N> ' 0 H l'W 0 grl S H H 0 0 N> * N> 0 0 5>s S j0 \O 0 S 0 0 osss,0 H N H > S > 14. ,S. 0 Nj N. ci0 71 Date Recue/Date Received 2023-03-01 CA 3,000,063 ) 0 0õ0 = sS5 0 = S, 0 0' .0 0', µ0 Preferably, heterocyclyls are 4 to 8 membered, monocyclic and have one or two heteroatoms independently selected from oxygen, nitrogen and sulfur Preferred heterocyclyls are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, tetra hydropyranyl, tetra hydrofuranyl. The above definition of heterocyclyl also applies if heterocyclyl is part of another (combined) group as for example in heterocyclylamino, heterocyclyloxy or heterocyclylalkyl. If the free valency of a heterocyclyl is saturated, then a heterocyclic croup is obtained. The term heterocyclylene is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups are for example: \NH __ \NH : __ (NH piperidinyl and : ' Or Or .= TN, TN N 2,3-dihydro-1 H-pyrrolyl and H or ¨I- - - or H or H etc. The above definition of heterocyclylene also applies if heterocyclylene is part of another (combined) group as for example in HO-heterocyclyleneamino or H2N-heterocyclyleneoxy. 72 Date Recue/Date Received 2023-03-01 CA 3,000,063 Heteroarvl denotes monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring, which compared with the corresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of one or more carbon atoms, one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, wherein the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic system. If a heteroaryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heteroaryl itself may be linked as a substituent to the molecule via every suitable position of the ring system, both carbon and nitrogen. Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N- oxide, pyrimidinyl-N- oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl- N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N- oxide, triazolyl-N- oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N- oxide, quinoxalinyl- N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N- oxide, benzimidazolyl-N-oxide etc. Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen): H 0 H QS . 'CI H H O 0 0 co C N N 0 .._.,? /171 c s,/ 0 S S ' , 0 0, iiN N ________________________________________________ N ________ N __ H H 0, ,O, S, N= N ,S, S 0 0, S, cc N N N c'r Nc_iii\iN N ))c() t oN IN N jj \\ // \\ # µ N N-N \\ ii N-N N-N i\i N--il 73 Date Recue/Date Received 2023-03-01 CA 3,000,063 0- H f\1 71µ1 N 1=1 N+ 71\1 .1\1 11 zs, zN -1/ N ,..-- -..., r .... ,.. 1 1 ) (ni- N v H 1 m N N-N ',-.% NN",,e !õ.. '--re .,,,N1 ii J/N \ \ \ \ \ S S. N \\ H 0 S 0 6 '0 N N N \ N\) la , N N \,N1 H 0 S H 0 \ N \\,N S' N ,o ,s N , S H N N H ,-------- rn N =='_--- 1 =,----- 1 -_., - I 1\1---NJ N'N N Th\1N N'-N H H H H H ----\, \ N N \\ 1 ,N k " ,H N 'N NH H H ,.-------y-\ n -....."-T. .....-=------... r- .1.-___-N N- N ----"7",-___NI / / NN 'f\I 0 71\1-N NN /".--N HN.--N H 4--"\eµ _...õ..õNµ 0 __ \ Nr\j/ N H /r\l'INI NN \ NN) H H H m HNI HN --- NI\ HN'µ N S N N N H N Preferably, heteroaryls are 5-6 membered monocyclic or 9-10 membered bicyclic, each with 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. 74 Date Recue/Date Received 2023-03-01 CA 3,000,063 The above definition of heteroaryl also applies if heteroaryl is part of another (combined) group as for example in heteroarylamino, heteroaryloxy or heteroarylalkyl. If the free valency of a heteroaryl is saturated, a heteroaromatic group is obtained. The term heteroarviene is also derived from the previously defined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are for example: N N N N pyrrolyl and H or H or H or - etc. The above definition of heteroarylene also applies if heteroarylene is part of another (combined) group as for example in HO-heteroaryleneamino or H2N- heteroaryleneoxy. By substituted is meant that a hydrogen atom which is bound directly to the atom under consideration, is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place on one atom. Substitution with a particular substituent is only possible if the permitted valencies of the substituent and of the atom that is to be substituted correspond to one another and the substitution leads to a stable compound (Le. to a compound which is not converted spontaneously, e.g. by rearrangement, cyclisation or elimination). Bivalent substituents such as =S, =NR, =NOR, =NNRR, =NN(R)C(0)NRR, =N2 or the like, may only be substituents on carbon atoms, wherein the bivalent substituent =0 may also be a substituent on sulphur. Generally, substitution may be carried out by a bivalent substituent only at ring systems and requires replacement of two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom that is saturated prior to the substitution. Substitution by a bivalent substituent is therefore only possible at the group - CH2- or sulphur atoms (=0 only) of a ring system. Stereochemistry/solvates/hydrates: Unless specifically indicated, throughout the specification and appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, EIZ isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically Date Recue/Date Received 2023-03-01 CA 3,000,063 acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound. Salts: The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio. As used herein "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2"- iminobis(ethanol)), diethylamine, 2-(diethylami no)-ethano I, 2-(dimethylamino)-ethanol, 2-a minoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine (L- lysine), praline (L-proline), magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, morpholine, piperazine, potassium hydroxide, 1 -(2-hyd roxyeth yI)-pyrrol id i ne, 1 -(2-hyd roxyethyl )-pyrrol ido ne, sodium hydroxide, triethanolamine (2,2",2"-nitrilotris(ethanol), tromethamine, zinc hydroxide, acetic acid, 2,2-dichloro acetic acid, adipic acid, alginic acid, ascorbic acid (L), L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4- acetamidobenzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid (capric acid), dodecylsulfuric acid, ethane-1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D- glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2- oxoglutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid (caproic acid), hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1- hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid (caprylic acid), oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, 76 Date Recue/Date Received 2023-03-01 CA 3,000,063 succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. The salts include acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, Ca-edetates/edetates, camsylates, carbonates, camphorsulfonate, chlorides/hydrochlorides, chlorotheophyllinate, citrates, edisylates, ethane disulfonates, estolates esylates, fumarates, gluceptates, gluconates, glucuronate, glutamates, glycolates, glycollylarsnilates, hexylresorcinates, hippurate, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isethionates, isothionates, lactates, lactobionates, laurylsulfates, malates, maleates, mandelates, methanesulfonates, mesylates, methylbromides, methylnitrates, methylsulfates, mucates, naphthoate, napsylates, nitrates, octadecanoates, oleates, oxalates, pamoates, pantothenates, phenylacetates, phosphates/diphosphates, polygalacturonates, propionates, salicylates, stearates subacetates, succinates, sulfamides, sulfates, sulfosalicylates, tannates, tartrates, teoclates, toluenesulfonates, triethiodides, trifluoroacetates, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19). The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts), also comprise a part of the invention. The present invention also includes the co-crystals of any compound according to the invention, i.e. those crystalline forms composed of at least two components (one being the compound according to the invention, the other being co-crystal formers) forming a unique crystalline structure without, in contrast to the crystalline salts, proton transfer from one 77 Date Recue/Date Received 2023-03-01 CA 3,000,063 component to the other. Potential co-crystal farmers are acids and bases as listed above for salts/salt formers. In a representation such as for example x-- IA I A Xi- or or or or the letter A has the function of a ring designation in order to make it easier, for example, to indicate the attachment of the ring in question to other rings. For bivalent groups in which it is crucial to determine which adjacent groups they bind and with which valency, the corresponding binding partners are indicated in brackets where necessary for clarification purposes, as in the following representations: µµ. (RI) \--N , (A) sNN' or (R2) -C(0)NH- or (R2) -NHC(0)-; Groups or substituents are frequently selected from among a number of alternative groups/substituents with a corresponding group designation (e.g. Ra, Rb etc). If such a group is used repeatedly to define a compound according to the invention in different parts of the molecule, it is pointed out that the various uses are to be regarded as totally independent of one another. By a therapeutically effective amount for the purposes of this invention is meant a quantity of substance that is capable of obviating symptoms of illness or of preventing or alleviating these symptoms, or which prolong the survival of a treated patient. The term "about" when used to specify a temperature or a temperature range usually means the temperature given 5 C, when used to specify a pressure or a pressure range the pressure given 0.5 bar. In all other cases "about" includes the range 5% around the specific value given. 78 Date Recue/Date Received 2023-03-01 CA 3,000,063 List of abbreviations Ac acetyl acac acetylacetonate AcCN acetonitrile aq. aquatic, aqueous ATP adenosine triphosphate Bn benzyl Boc tert-butyloxycarbonyl Bu butyl concentration day(s) dba dibenzylideneacetone TLC thin layer chromatography DABCO 1 ,4-diazabicyclo[2.2.2]octan Davephos 2-dimethylamino-2'-dicyclohexylaminophosphinobiphenyl DBA dibenzylideneacetone DCM dichloromethane DEA diethylamine DEAD diethyl azodicarboxylate DIPA N,N-diisopropylamine Dl PEA N-ethyl-N,N-diisopropylamine (Hunig's base) DMAP 4-N,N-dimethylaminopyridine DME 1 ,2-dimethoxyethane DMF N,N-d imethylformamide DMSO dimethylsulphoxide DPPA diphenylphosphorylazide dppf 1 .1"-bis(diphenylphosphi no)ferrocene EDTA ethylenediaminetetraacetic acid EGTA ethyleneglycoltetraacetic acid eq equivalent(s) ESI electron spray ionization Et ethyl Et20 diethyl ether Et0Ac ethyl acetate 79 Date Recue/Date Received 2023-03-01 CA 3,000,063 Et0H ethanol hour 0-(7-azabenzotriazol-1-y1)-N,N,M,W-tetramethyl-uronium HATU hexafluorophosphate HPLC high performance liquid chromatography IBX 2-iodoxy benzoic acid iso conc. concentrated LC liquid chromatography LiHMDS lithium bis(trimethylsilyl)amide sin, solution MCH methyl cyclohexane Me methyl Me0H methanol min minutes MPLC medium pressure liquid chromatography MS mass spectrometry MTBE methyl tert-butyl ether NBS N-bromo-succinimide NIS N-iodo-succinimide NMM N-methylmorpholine NMP N-methylpyrrolidone NP normal phase n.a. not available PBS phosphate-buffered saline Ph phenyl Pr propyl Py pyridine rac racemic red. reduction Rf (Rf) retention factor RP reversed phase rt ambient temperature SFC supercritical fluid chromatography Date Recue/Date Received 2023-03-01 CA 3,000,063 SN nucleophilic substitution TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TBME tert-butylmethylether 0-(be nzotriazol-1 -yI)-N, N, 1\11,Ni-tetra methyl-uroniu m TBTU tetrafluorobo rate tBu tert-butyl TEA triethyla mine temp. temperature tett tertiary Tf triflate TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl tRet retention time (HPLC) TRIS tris(hydroxymethyl)-aminomethane Ts0H p-toluenesulphonic acid UV ultraviolet Features and advantages of the present invention will become apparent from the following detailed examples which illustrate the principles of the invention by way of example without restricting its scope: Preparation of the compounds according to the invention General Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon). The compounds according to the invention are named in accordance with CAS rules using the software Autonom (Beilstein). If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is decisive. Microwave reactions are carried out in an initiator/reactor made by Biotage or in an 81 Date Recue/Date Received 2023-03-01 CA 3,000,063 Explorer made by CEM or in Synthos 3000 or Monowave 3000 made by Anton Paar in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring. Chromatography The thin layer chromatography is carried out on ready-made silica gel 60 TLC plates on glass (with fluorescence indicator F-254) made by Merck. The preparative high pressure chromatography (RP HPLC) of the example compounds according to the invention is carried out on Agilent or Gilson systems with columns made by Waters (names: SunFireTM Prep C18, OBDTM 10 pm, 50 x 150 mm or SunFireTM Prep C18 OBDTM 5 pm, 30 x 50 mm or XBridgeTM Prep C18, OBDTM 10 pm, 50x 150 mm or XBridgeTM Prep C18, OBDTM 5 pm, 30 x 150 mm or XBridgeTm Prep C18, OBDTM 5 pm, 30 x 50 mm) and YMC (names: Actus-Triart Prep C18, 5 pm, 30 x 50 mm). Different gradients of H20/acetonitrile are used to elute the compounds, while for Agilent systems 5 % acidic modifier (20 mL HCOOH to 1 L H20/acetonitrile (1/1)) is added to the water (acidic conditions). For Gilson systems the water is added 0.1 % HCOOH. For the chromatography under basic conditions for Agilent systems H20/acetonitrile gradients are used as well, while the water is made alkaline by addition of 5 % basic modifier (50 g NH4FIC03 + 50 mL NH3 (25 % in H20) to 1 L with H20). For Gilson systems the water is made alkaline as follows: 5mL NH4FIC03 solution (158 g in 1L H20) and 2 mL NH3 (28 % in H20) are replenished to 1 L with H20. The supercritical fluid chromatography (SFC) of the intermediates and example compounds according to the invention is carried out on a JASCO SFC-system with the following colums: Chiralcel OJ (250 x 20 mm, 5 pm), Chiralpak AD (250 x 20 mm, 5 pm), Chiralpak AS (250 x 20 mm, 5 pm), Chiralpak IC (250 x 20 mm, 5 pm), Chiralpak IA (250 x 20 mm, 5 pm), Chiralcel OJ (250 x 20 mm, 5 pm), Chiralcel OD (250 x 20 mm, 5 pm), Phenomenex Lux C2 (250 x 20 mm, 5 pm). The analytical HPLC (reaction control) of intermediate and final compounds is carried out using columns made by Waters (names: XBridgeTM C18, 2.5 pm, 2.1 x 20 mm or XBridgeTm C18, 2.5 pm, 2.1 x 30 mm or Aquity UPLC BEH C18, 1.7 pm, 2.1 x 50mm) and YMC (names: Triart C18, 3.0 pm, 2.0 x 30 mm) and Phenomenex (names: Luna C18, 5.0 pm, 2.0 x 30 mm). The analytical equipment is also equipped with a mass detector in each case. HPLC-mass spectroscopy/UV-spectrometry The retention times/MS-ESI+ for characterizing the example compounds according to the 82 Date Recue/Date Received 2023-03-01 CA 3,000,063 invention are produced using an HPLC-MS apparatus (high performance liquid chromatography with mass detector). Compounds that elute at the injection peak are given the retention time tRet = 0.00. HPLC-methods: Method A HPLC Agilent 1100 Series MS Agilent LC/MSD SL column Waters, XbridgeTM 018, 2.5 pm, 2.1 x 20 mm, Part.No. 186003201 solvent A: 20 mM NH4HCO3/NH3 pH 9 B: acetonitrile (HPLC grade) detection MS: positive and negative mass range: 120 ¨900 m/z fragmentor: 120 gain EMV: 1 threshold: 150 stepsize: 0.2 UV: 315 nm bandwidth: 170 nm reference: off range: 230 - 400 nm range step: 1.00 nm peakwidth: <0.01 min slit: 1 nm injection 5 pL flow 1.00 mL/min column temperature 60 C gradient 0.00 min 10 % B 0.00 ¨ 1.50 min 10 % 4 95 % B 1.50 ¨ 2.00 min 95 % B 2.00 ¨ 2.10 min 95 % 4 10 % B Method B HPLC Agilent 1200 Series 83 Date Recue/Date Received 2023-03-01 CA 3,000,063 MS Agilent 6130 Quadropole LC/MS column Waters, XbridgeTM C18, 2.5 pm, 2.1 x 30 mm solvent A: 20 mM NH4FIC03/NH3 in water; pH 9.3 B: acetonitrile (HPLC grade) detection MS: polarity: positive ionizator: MM-ES+APCI mass range: 150 ¨ 750 m/z fragmentor values: mass fragmentor 150 70 750 110 gain EMV: 1.00 threshold: 150 stepsize: 0.2 UV: 254 nm: reference off 214 nm: reference off range: 190 ¨ 400 nm range step: 2.00 nm threshold: 1.00 mAU peakwidth: 0.0025 min (0.05 s) slit: 4 nm injection 0.5 pL flow 1.400 mUmin column temperature 45 C gradient 0.00 ¨ 1.00 min 15 % -> 95 % B 1.00 ¨ 1.30 min 95 % B Method C HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column YMC, Triart C18, 3.0 pm, 2.0 x 30 mm, 12 nm solvent A: water + 0.1 % HCOOH 84 Date Recue/Date Received 2023-03-01 CA 3,000,063 B: acetonitrile + 0.1 % HCOOH (HPLC grade) detection MS: polarity: positive mass range: 150 ¨ 750 m/z fragmentor values: mass fragmentor 150 70 750 110 gain EMV: 1.00 threshold: 150 stepsize: 0.20 UV: 254 nm: reference off 214 nm: reference off range: 190 ¨ 400 nm range step: 4.00 nm threshold: 1.00 mAU peakwidth: 0.005 min (0.1 s) slit: 4 nm injection 0.5 pL flow 1.400 mL/min column temperature 45 C gradient 0.00 ¨ 1.00 min 15% 100% B 1.00 ¨ 1.13 min 100 % B Method D HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column Waters, XbridgeTM C18, 2.5 pm, 2.1 x 30 mm solvent A: 20 mM NH4FIC03/NH3 in water; pH 9.3 B: acetonitrile (HPLC grade) detection MS: polarity: positive + negative ionization: MM-ES Date Recue/Date Received 2023-03-01 CA 3,000,063 mass range: 150 ¨ 750 m/z fragmentor values: mass fragmentor 150 70 750 110 gain EMV: 1.00 threshold: 150 stepsize: 0.2 UV: 254 nm: reference off 214 nm: reference off range: 190 ¨ 400 nm range step: 2.00 nm threshold: 1.00 mAU peakwidth: 0.0025 min (0.05 s) slit: 4 nm injection 0.5 pL flow 1.400 mL/min column temperature 45 C gradient 0.00 ¨ 1.00 min 15% 95% B 1.00 ¨ 1.30 min 95 % B Method E HPLC Agilent 1200 Series: MS Agilent 6130 Quadropole LC/MS column Waters, XbridgeTM C18, 2.5 pm, 2.1 x 30 mm Column XP; Part.No. 186006028 solvent A: 20 mM NH4FIC03/NH3 in water; pH 9.3 B: acetonitrile (HPLC grade) detection MS: polarity: positive + negative ionizator: API-ES mass range: 150 ¨ 750 m/z fragmentor values: 86 Date Recue/Date Received 2023-03-01 CA 3,000,063 mass fragmentor 150 70 750 110 gain EMV: 1.00 threshold: 150 stepsize: 0.2 UV: 254 nm: reference off 214 nm: reference off range: 190 ¨ 400 nm range step: 2.00 nm threshold: 1.00 mAU peakwidth: 0.0025 min (0.05 s) slit: 4 nm injection 0.5 pL flow 1.400 mL/min column temperature 45 C gradient 0.00 ¨ 1.00 min 15% 4 95% B 1.00 ¨ 1.30 min 95 % B Method F HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column YMC, Triart C18, 3.0 pm, 2.0 x 30 mm, 12 nm solvent A: water + 0.1 % HCOOH B: acetonitrile + 0.1 % HCOOH (HPLC grade) detection MS: polarity: positive + negative mass range: 150 ¨750 m/z fragmentor values: mass fragmentor 150 70 750 110 87 Date Recue/Date Received 2023-03-01 CA 3,000,063 gain EMV: 1.00 threshold: 150 stepsize: 0.20 UV: 254 nm: reference off 214 nm: reference off range: 190 ¨ 400 nm range step: 4.00 nm threshold: 1.00 mAU peakwidth: 0.0063 min (0.13 s) slit: 4 nm injection 0.5 pL flow 1.400 mUmin column temperature 45 C gradient 0.00 ¨ 1.00 min 15% 100% B 1.00 ¨ 1.13 min 100 % B Method G HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column YMC, Triart C18, 3.0 pm, 2.0 x 30 mm, 12 nm solvent A: water +0.1 % HCOOH B: acetonitrile + 0.1 % HCOOH (HPLC grade) detection MS: polarity: positive + negative mass range: 150 ¨ 750 m/z fragmentor values: Mass Fragmentor 150 70 750 110 gain EMV: 1.00 threshold: 150 stepsize: 0.20 UV: 88 Date Recue/Date Received 2023-03-01 CA 3,000,063 254 nm: reference off 230 nm: reference off 214 nm: reference off range: 190 ¨ 400 nm range step: 4.00 nm threshold: 1.00 mAU peakwidth: 0.005 min (0.1 s) slit: 4 nm injection 0.5 pL flow 1.400 mUmin column temperature 45 C gradient 0.00 ¨ 1.00 min 15% 100% B 1.00 ¨ 1.13 min 100 % B Method H HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column YMC, Triart 018, 3.0 pm, 2.0 x 30 mm, 12 nm solvent A: water +0.1 % HCOOH B: acetonitrile + 0.1 % HCOOH (HPLC grade) detection MS: polarity: positive + negative mass range: 200 ¨ 800 m/z fragmentor : 70 gain: 1.00 threshold: 150 stepsize: 0.20 UV: 254 nm: reference off 230 nm: reference off range: 190 ¨ 400 nm range step: 2.00 nm peakwidth: >0.01 min (0.2 s) slit: 4 nm 89 Date Recue/Date Received 2023-03-01 CA 3,000,063 injection 1.0 pL flow 1.000 mUmin column temperature 45 C gradient 0.00 ¨ 0.10 min 5% B 0.10 ¨ 1.85 min 5% B 4 95.0 % B 1.85 ¨ 1.90 min 95 % B 1.95 ¨ 1.92 min 95 % B 4 5.0 % B Method I HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MS column YMC, Triart C18, 3.0 pm, 2.0 x 30 mm, 12 nm solvent A: water +0.1 % HCOOH B: acetonitrile + 0.1 % HCOOH (HPLC grade) detection MS: polarity: positive + negative mass range: 200 ¨ 800 m/z fragmentor: 70 gain: 1.00 threshold: 150 stepsize: 0.20 UV: 254 nm: reference off 230 nm: reference off range: 190 ¨ 400 nm range step: 2.00 nm peakwidth: > 0.01 min (0.2 s) slit: 4 nm injection 1.0 pL flow 1.000 mUmin column temperature 45 C gradient 0.00 ¨ 0.10 min 15 % B 0.10 ¨ 1.55 min 15% B 4 95.0 % B 1.55 ¨ 1.90 min 95 % B Date Recue/Date Received 2023-03-01 CA 3,000,063 1.95 ¨ 1.92 min 95 % B 4 15.0 % B Method J HPLC Agilent 1260 Series MS Agilent 6130 Quadropole LC/MS column YMC, Triart C18, 3.0 pm, 2.0 x 30 mm, 12 nm solvent A: water + 0.1 % HCOOH B: acetonitrile (HPLC grade) detection MS: polarity: positive + negative mass range: 100 ¨ 800 m/z fragmentor: 70 gain: 1.00 threshold: 100 stepsize: 0.15 UV: 254 nm: reference off 230 nm: reference off range: 190 ¨ 400 nm range step: 4.00 nm peakwidth: > 0.013 min (0.25 s) slit: 4 nm injection 0.5 pL flow 1.400 mUmin column temperature 45 C gradient 0.00 ¨ 1.00 min 5% 4 100% B 1.00 ¨ 1.37 min 100%B 1.37 ¨ 1.40 min 100% 4 5 % B Method K HPLC Agilent 1260 Series MS Agilent 6130 Quadropole LC/MS column Waters, XbridgeTM C18, 2.5 pm, 2.1 x 30 mm solvent A: 5 mM NH4HCO3/19 mM NH3 in water B: acetonitrile (HPLC grade) 91 Date Regue/Date Received 2023-03-01 CA 3,000,063 detection MS: polarity: positive + negative mass range: 100 ¨ 800 m/z fragmentor: 70 gain: 1.00 threshold: 100 stepsize: 0.15 UV: 254 nm: reference off 230 nm: reference off range: 190 ¨ 400 nm range step: 4.00 nm peakwidth: > 0.013 min (0.25 s) slit: 4 nm injection 0.5 pL flow 1.400 mUmin column temperature 45 C gradient 0.00 ¨ 0.01 min 5 % B 0.01 ¨1.00 min 5 % 4 100% B 1.00 ¨ 1.37 min 100 % B 1.37 ¨ 1.40 min 100 % 4 5 % B Method L HPLC/MS Waters UPLC-micromass Triple quad column Aquity UPLC BEH 018,1.7 pM, 2.1 x50 mm solvent A: water + 0.1 % HCOOH B: acetonitrile (H PLC grade) + 0.1 % HCOOH detection MS: ES/APCI positive and negative mode mass range: 100¨ 1000 m/z capillary voltage: 3500 V cone voltage: 30 - 50 V disolvation gas: 600 Uh disolvation temp: 300 C 92 Date Recue/Date Received 2023-03-01 CA 3,000,063 UV: bandwidth: 190 nm range: 210 - 400 nm resolution: 1.20 nm sample rate: 5 injection 0.5 pL flow 0.400 mL/min column temperature 40 C gradient 0.00 - 1.80 min 0 % B 1.80 - 3.80 min 0 % --> 75 % B 3.80 - 4.50 min 75 % -> 95 % B 4.50 - 6.00 min 95 % B 6.00 - 6.01 min 95 % -> 0 % B Method M HPLC/MS Agilent 1200, 6120MS column Luna 018(2) 5pm, 30 x 2.0 mm solvent A: water + 0.037 % TFA B: acetonitrile + 0.018% TFA detection MS: positive and negative mode mass range: 100 - 1000 m/z fragmentor: 70 gain EMV: 1 threshold: 150 stepsize: 0.1 UV: 220/254 nm bandwidth: 200 nm reference: off range: 200 - 400 nm range step: 0.4 nm Peakwidth: > 0.05 min Slit: 4 nm injection 0.5 pL flow 1.0 mL/min 93 Date Recue/Date Received 2023-03-01 CA 3,000,063 column temperature 50 C gradient 0.00 ¨ 0.30 min 0 % B 0.30 ¨ 1.40 min 0 % 4 60 % B 1.40 ¨ 1.55 min 60 % B 1.55 ¨ 1.56 min 60 % 4 0 % B 1.56 ¨ 2.00 min 0 % B The compounds according to the invention are prepared by the methods of synthesis described hereinafter in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known prior art compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis. 94 Date Recue/Date Received 2023-03-01 CA 3,000,063 Compounds (la) General reaction scheme and summary of the synthesis route Scheme 1 R = e.g. alkyl 0 OH R2 R3 I's H2N ). %I 0 N OR NO2 0 0 OR , 0 B-2 etAilJ.c B-1 .1::11",1H (R7)q¨ k- V Me0H (R7)cr" V PI N \nethod B method A H S-1 B-3 OR 2 3 02 N RcR 0 OH I method D Rir.:2, 0 NO2 H2N (117).1 )-Q.... V B-2 B-5 OH N Me0H H B-4 : OH OH method C R3002 'SI V47/ NO2 121..? R21....: X;I' "" i) NH _____ ... 00 N-R1 (R7)q¨k-v?... V method E (127).1)--V.... V N H N B-6 H B-7 95 Date Recue/Date Received 2023-03-01 CA 3,000,063 Scheme 2 (R4), .._., NO R 2 R µ _ OH 0 NO IV/ t r4 24 NOis r OH or. s . L ...... 1 ....x N....R1 __ 1 14 N- !P 'n X R ,*- (R74-t- .e ifth V method F (R7) /F,it, . N:R4B)19 NO2 X IV 1,;--tvc method G 2. , i 1 ..,;(14*<;;7 'NI'y N '' H N H (R7)q-t-wIN B-7 B-8 H B-10 method H 1 _ (R4), ¨ * CO H2N = (R4)r (R4)r lep NO2 0 NI I HN , NO2 %N i % R31 2 ,c In 3 IS II R3* 2 in A ____ R - le ____ R RI % R S'= ..al method J .ey isi..õRi method I ,y 0 N-R1 X 1... ,x %. N-0- (R7),7-t-X .....; µµ" V 7 X '`. %% (N7),7t- (R 4-p- I V 3i=*., N w N W 11 H H ¨ B-13 ¨ B-12 B-11 method K\ method J (R4)r 0 N," I N i 1 optional Fe. 2 In derivatisation steps R = __________ " (in R1 to R7, re'vT - R especially R4) (R7),7--tvc V N H (la) * The location of overoxidation/N-oxid formation is not entirely clear. B-13 as depicted in scheme 2 seems to be probable. 96 Date Recue/Date Received 2023-03-01 CA 3,000,063 Scheme 3 (air no (a% (air o ---1 A A --e- -"lc _.... N \ H2N \ II 41) H Br B-14 B-15 (R4), B-16 (Rs), o A --4 A BocNe"%%%.... H2N \ = ___________ N 1/4 H s .. ___ 0 II H2N B-18 BocNH B-17 o x'YN (117),i , V N (124), H (R4), S-1 I R2 R3 (114), ....c H2N \ A NO2 H2N = A B-2 HO, H2N \ 02N,... i 0FeJR - N 3 - , p RI; H --- Vj....1 0 R2 4: ;11 NH N ).... 7',...NH X;ry (Rig __ (127)q _____ iic "al vc N H N ("q B-20 H 1 B-21 B-19 (rac --> optional chiral separation) (R4), (Rir (R4)r olio Ili H2N = N/ I N/ I µN µ14 HN 12 ,yi.....R3.- .c' 0)ni - R. : )n RT. , R *1 R I' R2 -....v 00 NH X Y (Rig --41- I V (R74-tinr V (127)q--t w N N ii N H H H (la) B-23 B-22 n = 1 n = 1 Novel compounds of structure (la) can be prepared stepwise starting with a synthesis route depicted in scheme 1 from isatin derivatives S-1 via a decarboxylative 1,3 dipolar cycloaddition with an amino acid B-1 (method A) or B-5 (method D) and a nitro ethene B-2 to build up spiro systems B-3 and B-6 as a racemic mixture potentially along with other 97 Date Recue/Date Received 2023-03-01 CA 3,000,063 regio- and/or diastereoisomers of B-3 and B-6. The enantiomers of B-3 and B-6 can be separated at this stage by chiral SFC or alternatively the racemic mixture can be separated at any later stage of the synthesis. Also all other means known for separation of enantiomers can be applied here or after any later synthetic step herein described, e.g. crystallisation, chiral resolution, chiral HPLC etc. (see also Enantiomers, racemates, and resolutions, Jean Jacques, Andre Collet, Samuel H Wilen John Wiley and Sons, NY, 1981). B-3 and B-6 can be reacted with aldehydes or ketones in a reductive amination reaction to give B-4 (method B) and B-7 (method E). Alternatively, an alkylation, addition, acylation or sulfonylation reaction can be performed with B-3 and B-6 to obtain intermediates B-4 and B-7. Intermediate B-4 can be reduced with DIBAL or another reducing reagent and will then also yield intermediates B-7 (method C). The hydoxy group of intermediate B-7 is oxidized, e.g. with DESS-MARTIN periodinan, IBX or an alternative oxidizing reagent, to the corresponding carbonyl compound B- 8 (method F, scheme 2) which can be further reacted with nucleophiles, especially organometallic reagents like GRIGNARD or organo-zinc reagents (obtainable from B-9 via a metal-halogen exchange reaction) to intermediate B-10 as a mixture of two diastereomers (method G). The diastereoisomers of intermediates B-10 are not separated and used as mixtures for further reactions. Intermediates B-10 can be oxidized to the ketone intermediates B-11 by using DESS-MARTIN periodinan, IBX or other oxidation methods (method H). Reduction of both nitro groups of intermediates B-11 and subsequent reductive cyclization is triggered by treatment of intermediates B-11 with hydrogen under RANEY-NiTM catalysis, or with alternative reducing agents, and gives intermediates B-12 as a mixture of two diastereoisomers (method l). The diastereomers of intermediates B-12 are not separated and used as the mixture for further reactions. An oxidative cyclization of intermediates 6-12 by treatment with OXONE (potassium peroxymonosulfate) in a mixture of water and DCM, or by treatment with alternative oxidizing agents gives compounds (la) according to the invention (method J). If overoxidation occurs when treated with OXONE a subsequent reduction of the crude mixture containing overoxidation product B-13 with bis(pinacolato)diborone or other reducing can be performed to yield compounds (la). 98 Date Recue/Date Received 2023-03-01 CA 3,000,063 Compounds (la) which are initially obtained from B-12 or B-13 can be derivatized in optional derivatization steps not explicitly depicted in the schemes in all residues, especially in R4, if they carry functional groups, that can be further modified such as e.g. halogen atoms, amino and hydroxy groups (including cyclic amines), carboxylic acid or ester functions, nitrils etc. to further compounds (la) by well-established organic chemical transformations such as metal-catalyzed cross coupling reactions, acylation, amidation, addition, reduction or (reductive) alkylation or cleavage of protecting groups. These additional steps are not depicted in the general schemes. Likewise, it is also possible to include these additional steps in the synthetic routes depicted in the general schemes, i.e. to carry out derivatization reactions with intermediate compounds. In addition, it may also be possible that building blocks bearing protecting groups are used, i.e. further steps for deprotection are necessary. Alternatively, compounds (la) can also be prepared with the following reaction sequence: Starting from anilines or amino heteroaryls B-14 the amino function can be acetylated with acetic anhydride or other standard acetylation methods to give intermediates B- 15. Intermediates B-15 are brominated with NBS, Ts0H and Pd(OAc)2 to yield bromo intermediates B-16. SONOGASHIRA coupling with Boc-prop-2-ynyl-amine under Pd and Cu catalysis gives intermediates B-17 which can by hydratized in acidic conditions under Pd(OAc)2 catalysis followed by global deprotection under acidic conditions (HCI) to yield amines B-18. Modifications of intermediates thus obtained, e.g. esterification of free carboxyl groups (if one of R4 = COOH) with SOCl2 and Me0H or a alternative esterification method, gives additional intermediates B-18. Imine formation of intermediates B-18 with isatins S-1 gives imine intermediates B-19 which can then react in a 1,3 dipolar cycloaddition with nitro ethenes B-2 to yield racemic intermediates B-20 along with other regio- and stereoisomers. The enantiomers of B-20 can be separated at this stage by chiral SFC or alternatively the racemic mixture can be separated at any later stage of the synthesis, e.g. when intermediate B-22 is reached. Also all other means known for separation of enantiomers can be applied here or after any later synthetic step herein described, e.g. crystallisation, chiral resolution, chiral HPLC etc. (see also Enantiomers, racemates, and resolutions, Jean Jacques, Andre Collet, Samuel H Wilen John Wiley and Sons, NY, 1981). Reduction and cyclisation of intermediate B-20 with H2 under Pt/C catalysis gives intermediates B-21 which can be reduced subsequently by addition of VO(acac)2 to the reaction mixture and continued stirring under H2 pressure to yield intermediates B-22. An oxidative cyclization of intermediates B-22 with Na2W04 dihydrate 99 Date Recue/Date Received 2023-03-01 CA 3,000,063 and H202, or by treatment with alternative oxidizing agents gives intermediates B-23 that can be converted to compounds (la) by reactions with aldehydes or ketones in a reductive amination reaction. Alternatively, an alkylation, addition, acylation or sulfonylation reaction can be performed with B-23 to obtain additional compounds (la). Compounds (la) have been tested for their activity to affect MDM2-p53 interaction in their racemic form or alternatively as the enantiopure form (in particular (le)). Each of the two enantiomers of a racemic mixture may have activity against MDM2 although with a different binding mode. Enantiopure compounds are marked with the label "Chiral". Compounds listed in any table below that are labeled "Chiral" (both intermediates as well as compounds (lb) according to the invention) can be separated by chiral SFC chromatography from their enantiomer or are synthesized from enantiopure starting material which is separated by chiral SFC. Example: OH OH OH 0 0 0 Chiral Chiral 1LN" / \ 44NN. ss - CI F CI CI F 0 CI CI CI A Structure A defines the racemic mixture of compounds with structure B and C, Le. structure A encompasses two structures (compounds B and C), whereas structures B and C, respectively, are enantiopure and only define one specific compound. Thus, formulae (la) and (1a*) (R4),. (R% A A 14,1 I Chiral N I 3 - ) R n µN R. 3 Y N R X (127)q ___________________________ V (I27)q¨t V V1r w a) (le) 100 Date Recue/Date Received 2023-03-01 CA 3,000,063 with a set of specific definitions for groups R1 to R4, R7, V, W, X, Y, n, rand q represent the racemic mixture of two enantiomers ( (la); structure A above is one specific example of such a racemic mixture) or a single enantiomer ( (la*); structure B above is one specific enantiomer), unless there are additional stereocenters present in one or more of the substituents. The same definition applies to synthetic intermediates. Synthesis of intermediates B-6 Experimental procedure for the synthesis of B-6a (method D) I OTDH 0 F CI H2N I F NO OH 0 OH B-5a Me0H NO2 B-2a to. NH ____________________________________________ . 0 H H S-la B-6a 6-Chloroisatin S-la (31.5 g, 174 mmol), 1-(3-chloro-2-fluoro-phenyl)-2- nitroethene B-2a (35 g, 174 mmol) and L-homoserine B-5a (20.7 g, 174 mmol) are refluxed in Me0H for 4 h. The reaction mixture is concentrated in vacuo and purified by crystallization or chromatography if necessary. The following intermediates B-6 (table 1) are available in an analogous manner starting from different annulated 1H-pyrrole-2,3-diones S-1, amino acids B-5 and nitroethenes B-2. 101 Date Regue/Date Received 2023-03-01 CA 3,000,063 Table 1 structure tret [min] [M+H] HPLC method Cl F OHt102.0__/ B-6a 1.21 440 A NH 0 Cl CI F/ O1024Hr B-6b 1.21 440 A NH 0 CI 11 Chiral Cl NL,FNO OH I a 214¨/ B-6c NH 1.09 441 A "I 0 Cl CI NI,F NO H Ia 204¨/ B-6d 1.09 441 A NH 0 CI N Chiral Cl OH 411 F tiOir B-6e 1.13 441 A NH I Cl N# N 102 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method CI F110OH2r B-6f 1.13 441 A NH o CI NN Chiral CI OH 621i Fi B-6g t17 422 A NH 101 o CI N CI OH *OA. 40,õ/ B-6h 1.17 422 A NH "v CI N Chiral CI OH F 1102Fi B-6i 1.25 458 A NH 101"µ 0 Cl CI F1 O1020H, B-6j 1.25 458 A NH Or" CI N Chiral 103 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates B-7 Experimental procedure for the synthesis of B-7a (method E) CI Cl Ft102NO OH 0 OH / - 2 = NH 110 0%, tio 0 AcOH 0 CI CI B-6a B-7a To a solution of cyclopropanecarbaldehyde (1.7 mL, 22.7 mmol) in AcOH (19.5 mL) is added intermediate B-6a (1.609, 3.8 mmol) and the reaction mixture is stirred for 15 min. Sodium triacetoxyborohydride (1.34 g, 6.3 mmol) is added and the reaction mixture is stirred overnight. Water is added to the reaction mixture and it is extracted with Et0Ac. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo and the crude product B-7a is purified by chromatography if necessary. The following intermediates B-7 (table 2) are available in an analogous manner starting from different intermediates B-6 and aldehydes. Table 2 structure tret [min] [M+H] HPLC method Cl OH FN0/ B-7a 1.37 494 A 0 Cl N CI OH NO = B-7b 1.37 494 A Nel 0 CI N Chiral 104 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method CI F OH B-7c ' N,.L7 1.44 508 A " 0 CI N Chiral CI OH F/j02ri B-7d NJ 1.43 496 A o CI Chiral CI OH Ft10204.__/ B-7e 1.47 510 A Or" CI 1-1 Chiral CI F OHt102 B-7f 1.37 482 A Chiral CI OH 011 FVO2ri B-7g 1.32 468 A or CI N Chiral CI OH B-7h 1.28 498 A N¨ CI U H Chiral 105 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [WM+ HPLC method CI F1 OH= B-7i N 1.47 574 A 0 0 ci N Isµ CI OH Olt Ft1024.4._i B-7j N 1.45 574 A 110 CI H Chiral C CI NI F NO H B-7k 495 t29 A N 0 CI N CI IµV F NOv2H I B-7I 495 t29 A CI H Chiral CI OH F N. _1 020 B-7m 1.29 495 A I "" 0 CI Isc N Chiral _2H CI .21 45 B-7n 1.37 476 A µ0 0 CI 106 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [WM+ HPLC method CI OH 0211, B-70 1.37 476 A N CI Chiral CI F 0 OH B-7p F 1.38 512 A CItt'IN o CI OH Olt F 02.1.0__/ B-7q F N .46 1.38 512 A ' 0 CI HN Chiral CI OH * FV02õ.../ B-7r N * 0.80 575 I 0 0 CI lµr N CI OH F 0 B-7s N 4 0.80 575 0 0 1%. CI N N Chiral 107 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates B-3 Experimental procedure for the synthesis of B-3a (method A) 0 OH H2N 0 01 CI 0 F NO2 0 NO2 B-la B-2a NH 1101 0 1101 N Me0H CI CI S-la B-3a 6-Chloroisatin S-la (5 g, 27,0 mmol), 1-(3-chloro-2-fluoro-phenyl)-2- nitroethene B-2a (5.5 g, 27.0 mmol) and amino acid B-la (4.4 g, 27.0 mmol) are refluxed in Me0H for 4 h. The reaction mixture is concentrated in vacuo and purified by crystallization or chromatography if necessary. The following intermediates B-3 (table 3) are available in an analogous manner starting from different annulated 1H-pyrrole-2,3-diones S-1, amino acids B-1 and nitroethenes B-2. Table 3 structure tree [min] [M+Hr HPLC method Cl 0 F tio24)-0 B-3a 1.42 482 A NH 0 Cl F B-3b 1.42 482 A NH 0 Cl H Chiral 108 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates B-4 Experimental procedure for the synthesis of B-4a (method B) 0 CI 0 F NO2 .,Y CI 0 0 F NO-? NH so 0 so CIN MeCN, AcOH 0 CI B-3a B-4a To a solution of cyclopropanecarbaldehyde (0.64 g, 8.9 mmol) in AcOH (0.5 mL) is added intermediate B-3a (2.68 g, 4.4 mmol) and the reaction mixture is stirred for 15 min. Sodium triacetoxyborohydride (2.8 g, 13.3 mmol) is added and the reaction mixture is stirred overnight. Water is added to the reaction mixture and it is extracted with Et0Ac. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo and the crude product B-4a is purified by chromatography if necessary. The following intermediates B-4 (table 4) are available in an analogous manner starting from different intermediates B-3 and different aldehydes. Table 4 structure tret [min] [M+H] HPLC method Cl 0 F tio2e)-0µ B-4a 1.52 536 A 110 Cl 0 CI 0 FN020)¨ \ B-4b 1.52 536 A 0 Chiral CI 109 Date Recue/Date Received 2023-03-01 CA 3,000,063 Synthesis of additional intermediates B-7 Experimental procedure for the synthesis of B-7t (method C) o/ CI CI F NO2,__/-0H F No2 _)=0 4 * = DIBAL CI B B-4a -7t To a solution of B-4a (2.38 g, 4.0 mmol) in DCM is added DIBAL (18.0 mL, 18 mmol, 1.0 M in DCM) slowly at 0 C and the reaction mixture is stirred for 1 h. To the reaction mixture is added water and saturated aqueous potassium sodium tartrate solution and the mixture is stirred overnight at rt. The phases are separated and the aqueous phase is extracted with DCM. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo and the crude product B-7t is purified by chromatography if necessary. The following intermediates B-7 (table 5) are available in an analogous manner starting from different intermediates B-4. Table 5 structure tret [min] [M+111+ HPLC method CI F tio24,2-0H B-7t 1.52 508 A 0 Cl CI F j--OH NO; B-7u 1.52 508 A 4000 0 Cl H Chiral 110 Date Recue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates B-8 Experimental procedure for the synthesis of B-8b (method F) CI CI OH t102 NO2 ko z 44--, 7. ss Dess-Martin io tio 40) 0 MeCN 0 CI CI H Chiral H Chiral B-7b B-8b To a solution of intermediate B-7b (1 g, 2.02 mmol) in ACN (20 mL) is added NaHCO3 (0.34 g, 4.05 mmol) and stirred for 5 min before DESS-MARTIN periodinan (1.72 g, 4.05 mmol) is added portionwise to the mixture. The reaction mixture is stirred for additional 30 min before it is diluted with H20, saturated NaHCO3 and Et0Ac. The reaction mixture is extracted with Et0Ac. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo and the crude product B-8b is purified by chromatography if necessary. The following intermediates B-8 (table 6) are available in an analogous manner starting from different intermediates B-7. Table 6 structure tret [min] [M+H] HPLC method Cl ork F NO201/o B-8a 1.45 492 A "µ 0 Cl CI FO B-8b A 1.46 492 A o 0 Cl H Chiral 111 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+11+ HPLC method CI F t1,02e_i0 B-8c N .L7 1.48 506 A o CI Chiral ci F 0 204, B-8d 1.50 494 A o CI N H Chiral ci Fij 02.4_3 B-8e 1.55 506 A 110"" O'Y CI H Chiral Cl 011 F tIO24r B-8f 1.46 480 A so"' n ci H Chiral Cl Ft10204,1/ B-8g 1.39 464 A Or' N0?( CI H Chiral ci F B-8h 1.35 494 A N. Cl H Chiral 112 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+11+ , HPLC method CI 0 Frj 0 //o B-8i N * 0.91 572 B 0 H CI 0 FV02401/o B-8j N * 1.53 572 A I. 0 ? CI N H Chiral Cl N' F NO ,O 1 , 241. B-8k 1.37 493 A Noo'6, CI [1 N 0 H CI N." FNO2.rs 1 . ..õ,. ' B-8I 1.37 493 A to N..sA` *0 CI N H Chiral ci 0 FV020_ So B-8m 1.34 493 A N.%.A Itlt% o CI N HN Chiral CI 4 FN020__/= B-8n 1.42 506 A 0 , Is1/4..A Ottt CI N H 113 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+11+ , HPLC method CI 4 F No_ 4 f i=0 B-80 N 46i 1.42 506 A , 40 " . CI N H Chiral CI 4 N_0241,Sio B-8p N....A 1.46 474 A 10"1 0 CI N H Chiral CI 4 F111024rso B-8q F 0.84 510 B N.I6i 110 CI 0 HN Chiral CI 4 F .11102F2 B-8r N * 0 n.a. n.a. n.a. I s 0 CI isr N Chiral c H 114 Date Recue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates B-10 Experimental procedure for the synthesis of B-10a (method G) 0 CI F 111; 0 0 02N NO - 2 02N CI B-9a MgCI F NO2 *0 THF OH Cl N Chiral 1.1% B-8b CI H Chiral B-10a A solution of 4-iodo-3-nitro-benzoic acid methyl ester B-9a (2.60 g, 8.48 mmol) in THF (17 mL) is cooled to ¨ 50 C and phenylmagnesium chloride (4.05 mL, 8.09 mmol, 2 M) is added dropwise and the reaction mixture is stirred for additional 30 min at ¨50 C. A solution of intermediate B-8b (1.90 g, 3.85 mmol) in THF (7.7 mL) is added to the reaction mixture dropwise at ¨ 50 C and the reaction mixture is stirred for additional 15 min at the same temperature. The reaction mixture is slowly warmed to rt and stirred for additional 2 h before saturated aqueous KHSO4 solution and Et0Ac is added. The reaction mixture is extracted with Et0Ac. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo and the crude product B-10a is purified by chromatography. B-10a is obtained as a mixture of two diastereomers which is used for the next step without separation. The following intermediates B-10 (table 7) are available in an analogous manner starting from different intermediates B-8 and different iodides B-9. 115 Date Recue/Date Received 2023-03-01 CA 3,000,063 Table 7 structure tret [min] [M+H1+ HPLC method o/ 0 02N B-10a tI020 1.58 673 A OH Cl Chiral 0 0 Cl 02N 111 B-lob Isj 1.63 687 A OH Cl H Chiral o/ 0 02N B-10c F VO. 1.61 675 A OH 110 N.")--"" 0 CI H Chiral 0 0 02N * B-10d F VO. 1.62 687 A OH 0 01" 0 CI Chiral Fl 116 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 CI 02N 411 B-10e * t1020 1.57 659 A OH 01" 0 CI H Chiral o/ 0 CI 02N B-lot = V020 1.53 647 A OH 0 CI HN Chiral 0 0 CI 02N * B-10g = FNO 1.49 675 A 41. OH N-N--0 Or 0 % CI H Chiral o/ 0 CI 02N F NO B-10h 1.63 753 A OH CI W 0 Chiral 117 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 CI 02N 411 B-101 * t10 1.61 687 A OH CI H Chiral o/ 0 CI 02N B-10j = t1020 1.62 687 A OH o CI Chiral 0 0 CI 02N * 0 = B-10k F t10 1.52 703 A OH --Nfi7 N CI Chiral ,0 0 0 02N = B-101 VO 1.58 709 A OH CI 118 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method ,0 0 0 CI 02N 411 B-10m * t1020 1.58 709 A OH 1011 CI H Chiral CI 02N = O¨ F 0 V024... B-10n OH 1.54 673 A Cl N Chiral o/ 0 Cl 02N B-10o t10 1.66 698 A OH E0 CI Chiral 0 0 CI 02N= B-10p V0.4 OH 1.62 767 A "4 0 CI 41 ON_ Chiral 119 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 CI 02N 411 B-10q itV F NO a 2# 1.51 674 A I"\ XOH 1011 CI o/ 0 CI 02N * B-10r N F NO I a 2# 1.51 674 A \ OH "" Isroc7, CI H Chiral 0 0 CI F 02N * B-10sNO 1.48 674 A 41. OH I NO7e CI N r Chiral 02 HO 0- F/ 10# 0 B-10t n.a n.a. so to N\ii7 CI 120 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 02 HO O¨ F VO. 0 B-10u n.a. n.a. SO 07' CI Chiral Synthesis of intermediates B-9 Experimental procedure for the synthesis of B-9b 0 0 NaNO2, HCl, 0 0 KI 110 * NO2 NO2 N H2 B-9b To a solution of 4-amino-2-methyl-3-nitro-benzoic acid methyl ester (2.4 g, 11.0 mmol) in HCI (25 mL) at 0 C is slowly added sodium nitrite and the mixture is stirred for 30 min at the same temperature. Potassiom iodide (5.7 g, 34.0 mmol) is added portionwise at 0 C and the mixture is stirred at rt for 1 h. To the reaction mixture is added water and Et20. The phases are separated and the aqueous phase is extracted with Et20. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo and the crude product B-9b is purified by chromatography if necessary. Experimental procedure for the synthesis of B-9c 00 0 = 0 Mel, K2CO3 * OH _I.. OMe NO2 NO2 B-9c To a solution of 2-hydroxy-4-iodo-3-nitro-benzoic acid methyl ester (1.0 g, 3.1 mmol) is added potassium carbonate (1.3 g, 9.3 mmol) and methyl iodide (0.4 mL, 6.2 mmol) at rt. The reaction mixture is stirred at rt for 4 h. Water is added to the mixture and the formed 121 Date Recue/Date Received 2023-03-01 CA 3,000,063 solid is filtered and dried to yield intermediate B-9c. Table 8 structure It [min] [m+H] HPLC method 0 r( B-9b 1.25 n.a. A NO2 0 r( B-9c OMe 1.19 338 A NO2 Synthesis of intermediates B-11 Experimental procedure for the synthesis of B-11a 0 0 0 Cl 0 02N 02N CI , r NO2 FNO2 OH Dess-Martin ____ * o MeCN .1"" 0c7. CI CI H Chiral H Chiral B-10a B-1 la To a solution of intermediate B-10a (1 g, 1.49 mmol) in THF (10 mL) is added NaHCO3 (0.34 g, 1.49 mmol) and stirred for 5 min before DESS-MARTIN periodinan (1.26 g, 2.97 mmol) is added portionwise to the mixture. The reaction mixture is stirred for additional 2 h at rt before it is diluted with H20, saturated NaHCO3 and Et0Ac. The reaction mixture is extracted with Et0Ac. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo and the crude product B-1 1a is purified by chromatography if necessary. The following intermediates B-11 (table 9) are available in an analogous manner starting from different intermediates B-10. 122 Date Recue/Date Received 2023-03-01 CA 3,000,063 Table 9 structure tret [min] [M+Fi] HPLC method o/ 0 02N B-11a NO; t57 671 A S 0 Cl H Chiral 0 0 Cl 02N 4111 B-11b isjOi. t66 685 A 0 = " 0)=1 Cl H Chiral o/ 0 02N = B-11c NO t64 673 A = 0 Cl H Chiral 0 0 02N * B-11d VO t65 687 A 0 00 0 Cl N Chiral 123 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method / 0 0 CI 02N 411 B-11e F 4 t1C:1 t60 659 A 0 0 N"-N...... 01 1 CI N 0Chiral H o/ 0 CI 02N e B-11f = Ft102, t56 645 A . 0 r..... CI LW N Chiral H / 0 0 CI 02N * B-1 F1g . VO t50 675 A 0 011 0 N"-N.,..0 0 = CI N Chiral H o/ 0 CI ON = B-11h I. F1110 - # 1.63 751 A 0 N CI N W.. 0 H \_ Chiral 124 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 CI 02N B-11i VO 1.63 685 A 0 ...N1c7 o CI H Chiral o/ 0 CI 02N B-11j t10 1.62 685 A 0 CI Chiral 0 0 CI FO022:0 B-11k V 1.57 701 A * 0 0\c7 CI H Chiral 0 ¨0 0 CI 02N B-111 F 1.54 701 A 0 N CI 125 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 ¨0 0 CI 02N 411 B-urn NO t54 701 A 0 --Nfc7 o CI H Chiral 0¨ CI 02N = 0 NO B-11n 0 1.56 671 A CI N Chiral o/ 0 CI 02N B-11 NO 1.70 687 A 0 CI H Chiral 0 0 CI 02N B-lip VO 1.65 765 A 0 Or" iz) CI m 0 Chiral 126 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 I ON F 411 B-11q N' yo,_ - 1.55 672 A 0 101"" NO\fc7 CI o/ 0 CI 02N * B-11r NFNO 1.55 672 A I 0 o CI N õ H uhiral 0 0 02N B-us F 0.89 672 * 0 Chiral I tsi CI N' N 02N 0 O¨ F VO 0 . B-11 t 0.98 699 "" NO\V CI 127 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 02 0 0- 4 = F Ir. 0 B-11u 0.98 699 Cl H Chiral Synthesis of intermediates B-12 Experimental procedure for the synthesis of B-12a (method I) 0 0 0 0 CI 02N 41 H2N = F NO Raney-Ni, H 2 C I s 0 Me0H, DCM HN " 0 Cl H Chiral Cl B-11a H Chiral B-12a To a solution of intermediate B-11a (1.10 g, 1.60 mmol) in Me0H (6 mL) and DCM (9 mL) in an autoclave is added a catalytic amount of RANEY nickel and the reaction mixture is stirred for 24 h under an atmosphere of hydrogen (8 bar). Additional RANEY nickel is added and the reaction mixture is stirred for additional 24 h under an atmosphere of hydrogen (8 bar). The reaction mixture is filtered (Celite ) and the solvents are removed in vacuo. The residue is dissolved in Et0Ac and saturated aqueous NaHCO3 solution is added. The reaction mixture is extracted with Et0Ac. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo and the crude product B-12a is purified by chromatography if necessary. Intermediate B-12a is obtained as a mixture of two diastereomers which is used for the next step without further separation. The following intermediates B-12 (table 10) are available in an analogous manner starting from different intermediates B-11. 128 Date Recue/Date Received 2023-03-01 CA 3,000,063 Table 10 structure tret [min] [M+11]* HPLC method O0 = CI = NH2 B-12a HN 1.52 595 A Cl ii Chiral O0 Cl* NH2 B-12b Hy 1.59 609 A Cl H Chiral O0 Cl* NH2 B-12c NV 1.58 597 A Ny 1101"" Cl H Chiral 00 NH2 B-12d Htl 1.62 611 A 0 N H Chiral 129 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method 00 \ ci * F NH2 B-12e 4 Hy 0 1.53 583 A 0 N.-N..... 01 t% CI 0 N Chiral H 00 = CI 41# F NH2 B-12f 4 Hy 1.48 568 A N\ 0 0 CI HN Chiral 00 µ CI /* F NH2 B-12g 4 HV # 1.40 599 A 0 ' o 1410 0 = CI HN Chiral 0 0 = CI f* F NH2 B-12h 100) HN, 1.56 675 A - 1 N 0 µ..--- CI N H Chiral 130 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method O0 CI B-12i NH2 Hy * 1.55 609 A ="" CI H Chiral O0 = CI 11* B-12j NH2 1.58 609 A CI H Chiral O0 --0 CI B-12k NH2 Hy * 1.42 625 A CI H Chiral 00 = 0 = B-12I NH2 1.55 625 A CI 131 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 00 CI * B-12m NH2 FIly 1.55 625 A "' Oc/' CI H Chiral 0' B-12n NH2 Hy 1.50 595 A Ns CI H Chiral 00 CI B-120 Hy NH2 * 1.63 611 A "" 07 CI H Chiral 00 HN B-12p NH2 1.61 689 A - 0 CI Chiral 132 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method O0 CI FHN B-12q NH I 1.48 596 A to (10 o - N O 0 CI 41# N./ FHN B-12r NH2 1.48 596 A I CI H Chiral O0 CI B-12s NH2 * 1.44 596 A I "" CI N N H Chiral 0 0 110 NH2 F B-12t CI HN 1.61 623 A [00 o V CI 133 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure Let [min] [M+H] HPLC method 0 1110 NH2 B-12u CI FHN 1.61 623 A 01" 0 VIP Cl H Chiral Synthesis of compounds (la) according to the invention Experimental procedure for the synthesis of la-1 (method J) k 00 00 H2N * CI Oxone Cl N' HN sl%1 DCM, H20 = I01"" 0c7P CI ci 101 N H Chiral H Chiral B-12a la-1 To a solution of intermediate B-12a (329 mg, 0.65 mmol) in DCM (7 mL) is added a solution of Oxone (793 mg, 1.29 mmol) in H20 (7 mL) at 0 C dropwise. The biphasic reaction mixture is stirred vigorously for 20 min at 0 C and for additional 2 h at rt. The reaction mixture is diluted with H20 and is extracted with DCM. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo and the crude product is purified by 1() chromatography which gives compound la-1. The following compounds (la) (table 11) are available in an analogous manner starting from different intermediates B-12. 134 Date Recue/Date Received 2023-03-01 CA 3,000,063 Table 11 structure tret [min] [WM+ HPLC method 0 0Cl = N la-1 F N 1.60 591 A NSS 4 z Cl H Chiral 0 111 CI ,N r I la-2 1.67 605 A 1101"" 0 Cl hi Chiral 0 0. Cl ,N- I F la-3 1.64 593 A N. Cl H Chiral 0 0 0111 Cl N" I la-4 F N 1.59 579 A 4 - 0 Cl N H Chiral 135 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+Fi] HPLC method 0 0' # CI N la-5 F 'hi 1.54 565 A N-N 0 CI N H Chiral 0-.0 0 ci ,N" I la-6 r 'isi 1.49 595 A = dik - SO' = N\,..0 0 = CI 1-1 N 1 Chiral 0,. 0 ci N;.1 / 'N la-7 di )'X F 1.59 671 A 0 1"" N N o CI H Chiral 0 CL- . CI N.J I la-8 F )4 1.64 605 A 4 2 N CI N Fl Chiral 136 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [WM+ H PLC method 0 la-9 CI FNN 1.63 605 A 4-? ..**Nv CI hi Chiral 0 0 CI IC I la-10 F 1.50 621 A 4 CI H Chiral 0 0 la-11 CI FN "N 1.58 621 A = lar - 0\c7 CI 0 0 N I la-12 CI F 19 1.58 621 A 4 - CI H Chiral 137 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [WM+ HPLC method 0 0 411 CI _14. N la r -13 t59 591 A 4=. ci H Chiral o CI N I la-14 F 'N 1.69 685 A 411 (10 I 0 Olk 0 N.00- CI H Chiral 0 CI la-15 F 1.67 607 A - CI H Chiral 0 CI _N la-16 r 1.66 607 A õ 101% 0 CI H Chiral 138 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 CI ,N r la-17 1.48 592 A , o N CI 0 0 CI NI' I la-18 1.48 592 A N CI H Chiral 0 4111 CI N la-19 F N 1.48 592 A = CI 1.417 0)7 N N H Chiral 139 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of additional compounds (la) according to the invention Experimental procedure for the synthesis of la-20 (method J + method K) / ¨ ¨ . o I 1 o o o o o H2N b = Bis(pinacolato)- 01 CI HN p Oxone CI N/ CI I diboron ____ N/ I ' .14 - * 4 = , DCM, H20 = sly MeCN = N * N---\c? CI r N N H CI CI Chiral ¨ H Chiral r, Chiral ¨ B-12j B-13a la-20 * The location of overoxidation/N-oxid formation is not entirely clear. B-13a as depicted seems to be probable. To a solution of intermediate B-12) (417 mg, 0.68 mmol) in DCM (10 mL) is added a solution of Oxone (841 mg, 1.37 mmol) in H20 (7 mL) at 0 C dropwise. The biphasic reaction mixture is stirred vigorously for 20 min at 0 C and for additional 6 h at rt. The reaction mixture is diluted with H20 and extracted with DCM. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo which gives a crude mixture of la-20 and an oxidized form B-13a (M+H = 621). This mixture is dissolved in MeCN (4.2 mL) and bis(pinacolato)diborone (326 mg, 1.28 mmol) is added. The reaction mixture is heated under microwave irradiation to 100 C for 30 min. The reaction mixture is diluted with H20 and extracted with DCM. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo and the crude product is purified by chromatography which gives compound la-20. The following overoxidized compounds B-13 (table 12) are available in an analogous manner starting from different intermediates B-12 and can be reduced to additional compounds (la) (table 13). 140 Date Regue/Date Received 2023-03-01 CA 3,000,063 Table 12 structure tret [min] [WM+ HPLC method 0 0%., Cl FN. B-13a 4111 N.. 0.96 621 - N, - Or 0 CI H Chiral 0 0 Cl N B-13b F..1 0.89 565 4+1 N, - 0 Cl Chiral 0 0" Cl B-13c F N 0.94 611 = * /¨d + N. - 01" 8 Cl Chiral 0 = 0 Cl F N.,N B-13d 0.95 635 4 + 0" 0 Cl 141 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+Ei] HPLC method 0 1 0 ClN B-13e F 0.95 635 ; ) ssY- N V% CI H Chiral Table 13 structure tret [min] [M+H] HPLC method 0 0%. N Cl i la-20 F 1.66 605 A N CI H Chiral 0 "%. Cl N" I la-21 F 1.54 565 A 4 = Kr\ 0 Cl H Chiral 142 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [Min] [m+Fi]' HPLC method 0 0 1111 CI ,N r la-22 1.46 595 A * No..0 IP 0 ci 1.1 Chiral 0 0 CI F N.N la-23 1.01 619 - V 101 N CI 0 Chiral 0 F ci la-24 1.01 619 - " 0 7 CI 143 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of further compounds (la) via ester saponification Experimental procedure for the synthesis of la-25 0 HO 0 CI F Ns NaOH CI F N N * = **c; CI H Chiral H chiral la-1 la-25 la-1 (405 mg, 0.69 mmol) is dissolved in THF (30 mL) and aq. NaOH solution (2 mL, 8 M) is added. The reaction mixture is stirred at 70 C for 8 h. After acidification with 2 M aq. HCI and extraction with Et0Ac the organic phase is dried with MgSO4. Purification with reversed phase HPLC leads to pure la-25. The following compounds (la) (table 14) are available in an analogous manner starting from initially obtained compounds (la). Table 14 structure tret [min] .. [M+Hr HPLC method 0 OH CI la-25 F .14 1.04 577 A 411 z 1101 N CI H Chiral 144 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method OH 0 4 ci N la-26 F 'hi 1.10 591 A 4 2 4, N CI N 11 Chiral 0 OH 0 ci N" I la-27 F 14 = 1.09 579 A 4= N )"- CI N H Chiral 0 OH ill GI N la-28 F "N 1.14 593 A 4 z N CI 101µ 0 N Chiral H OH 0 4111 CI N., I la-29 F 19 1.06 565 A 4 - 41. N-N..... 0 0 a ri Chiral 145 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method 0 OH di a N la-30 F "hi 1.00 551 A 4 - NS'N 0 4 0 CI N H Chiral 0 OH 0 CI N. I la-31 F )4 0.95 581 A 4= 11101 " 0 \ CI N H Chiral OH ci ON?: / FN la-32 4 3 %, 1.11 657 A N CI N H Chiral 0OH 4 ci N la-33 F )4 1.07 591 A 4 2 N 0 C-N7 CI N H Chiral 146 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] HPLC method 0 OH 411 ci N la-34 F 1.03 591 A 4 4.= CI H Chiral 0 OH ci N" I la-35 F N 1.04 607 A z 101"" CI H Chiral 0 OH 0 CI N la-36 F 1.04 607 A 411 = Or" 07)7' CI 0 OH 04 CI ,N r la-37 1.04 607 A 4 CI H Chiral 147 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] HPLC method 0 OH 111 CI N la-38 F 1.01 577 A - V N CI H Chiral 0 OH = ci N I la-39 F N 1.09 593 A z % N-"Nr 101 N CI H Chiral OH CI N la-40 F si ) 1.13 671 A * = - 0 CI H Chiral 0 OH CI ,Nz la-41 r =1.02 578 A N ci Isr"\vo N 148 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method OH 0 1111 ci N la-42"F 1.02 578 A N LP oto CI H Chiral OH 0 ci N" I la-43 F 1.02 578 A I "" CI N HN Chiral 0 HO la-44 ci F 1.07 605 A 4 - Ott 0 7 cIii 0 HO Chiral CI F N.N la-45 1.07 605 A 4 CI 149 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of further compounds (la) via amidation Experimental procedure for the synthesis of la-46 HO 0 HN 0 CI N I HATU ____________________________________________ CI NI = = lar 0)=1 ot. CI 11 Chiral 1.1 0 Cl El Chiral la-26 la-46 la-26 (10 mg, 0.02 mmol) is dissolved in anhydrous THF (1 mL) and HATU (8 mg, 0.02 mmol) is added at rt. After addition of DIPEA (3.4 mg, 0.03 mmol) the reaction mixture is allowed to stir at rt for 15 min. 1-Amino-2-methylpropan-2-ol (2 M in THF, 1.5 mg, 0.02 mmol) is added and the reaction is allowed to stir for additional 60 min. The crude reaction mixture is submitted to reversed phase column chromatography yielding pure la- 46. The following compounds (la) (Table 15) are available in an analogous manner starting from to intitially obtained compounds (la). Table 15 structure tret [min] [M+H] HPLC method [4 0 J - OH la-46 Cl ,h1' r"N 1.43 662 A z % Cl Chiral 150 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] HPLC method 0 "V ci N" la-47 F N 1.49 630 A 4 2 0"" D CI H Chiral 0 0 4111 CI ,N r la-48 )si 1.51 692 A 2 NcT): CI HN Chiral 0 la-49 CI FNN 1.46 692 A 0 AI CI H Chiral 0 ci N. I la-50 F 11 1.22 594 A 4 _ o ci ri Chiral 151 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] HPLC method o µ¨N F ci ,N/ la-51 1.35 621 A 4 2 N\ 0 CI N H Chiral 0 la-52 CI N 1.50 618 A F - 14--\ 01"" 0 CI H Chiral Hsto0 ci Nz la-53 F N 1.33 620 A 4 2 fkrN 0 CI N Chiral 152 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] HPLC method O'M 0 LeN Ci Frski la-54 1.52 740 A = = Or 0 * ()µ CI Chiral LI 0 HN la-55 ci N. I 1.51 728 A FN = c, H Chiral 0 HN ci I la-56 r N 1.49 684 A = Or 0 C) CI H Chiral 153 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [m+Fi]' HPLC method 0 Cl FN II N'/ la-57 1.54 698 A 2 01 0 * CI H Chiral Synthesis of starting material S-1 Experimental procedure for the synthesis of S-1 b Br Br 0 0 AgNO3 I I 0 CI N N S-1 b 3,3-Dibromo-6-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (7.6 g, 23.3 mmol) is suspended in acetonitrile (500 mL) and water (25 mL). AgNO3 (8.9 g, 52.7 mmol) is added and the reaction mixture is stirred at rt for 1 h. Acetonitrile is removed under reduced pressure and Et0Ac is added. The phases are separated and the organic layer is dried with MgSO4. Removal of the solvents gives pure 6-chloro-1H-pyrrolo[2,3-b]pyridine- 2,3-dione 5- lb. Synthesis of intermediates B-15 Experimental procedure for the synthesis of B-1 5a CO2Me Ac 20 CO2Me AcOH H2N HN "AO B-14a B-15a To a solution of B-14a (1 eq.) in toluene is added Ac20 (1.05 eq.) dropwise at reflux and 154 Date Recue/Date Received 2023-03-01 CA 3,000,063 the mixture is stirred at reflux for several minutes. The product B-15a can be crystallized out of the mixture by cooling down and further dilution. The following intermediates B-15 (table 15-1) are available in an analogous manner starting from different anilines B-14. Table 15-1 structure [M+H] CO2Me B-15a 194 HN CO2Me B-15b 208 110 CO2Me 0 B-15c 224 HN CO2Me 0 B-15d 224 HN CO2Me B-15e HN 194 CO2Me B-15f 208 HN Synthesis of intermediates B-16 155 Date Regue/Date Received 2023-03-01 CA 3,000,063 Experimental procedure for the synthesis of B-1 6a NBS Pd(OAc)2 CO2Me CO2Me Ts0H 1.1 AcOH HN HN 0 Br B B-15a -16a To a solution of B-15a (1 eq.) in AcOH are added Ts0H monohydrate (0.5 eq.) and Pd(OAc)2 (0.03 eq.). The mixture is heated up to 75-80 C and NBS (1.1 eq.) is added in portions. After stirring at 75-80 C for a few minutes, the solution is cooled down and water is added. The product B-16a can be isolated by filtration. The following intermediates B-16 (table 15-2) are available in an analogous manner starting from different acetamides B-15. Table 15-2 structure [M+H] CO2Me B-16a 273 HN Br 0 CO2Me B-16b 10 287 HN Br 0 CO2Me 0 B-16c 1101 303 HN L.43 Br 156 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure [M+H] CO2Me 0 B-16d 303 HN ..c= Br CO2Me B-16e HN 273 ,A Br 0 CO2Me B-16f 101 287 HN Br Synthesis of intermediates B-17 Experimental procedure for the synthesis of B-17a 0 CO2Me OAN CO2Me 101 1.1 HN Pd2(dba)3 HN Br [(t-Bu)3P1-1]Bp4 I I 0 Cul, DIPA, DMSO 0 B-16a 40AN B-17a To a suspension of B-16a (1 eq.) in DMSO are added Boc-prop-2-ynyl-amine (1.3 eq.), Cul (0.02 eq.), Pd2(dba)3 (0.01 eq.), [(tBu)31:]BE4 (0.04 eq.) and DIPA (5 eq.). The mixture is stirred at room temperature for 3 days. After cooling down the suspension and adding water the product B-17a can be isolated by filtration. The following intermediates B-17 (table 15-3) are available in an analogous manner starting from different bromo acetamides B-16. 157 Date Regue/Date Received 2023-03-01 CA 3,000,063 Table 15-3 structure [M+H] CO2Me 101 HN B-17a 1347 I I 40AN CO2Me HN B-17b 1 361 I I 40AN CO2Me 0 HN = B-17c 377 A I I 0 OAN CO2Me 0 HN B-17d 377 CO2Me HN B-17e LoD I I 347 ==10)(N 158 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure [M+H]- CO2Me 1.1 HN B-17f 361 Lco ,o II OAN Synthesis of intermediates B-18 Experimental procedure for the synthesis of B-1 8a CO2Me CO2H a) Pd(OAc)2 1101 AcOH b) HCI HN H2N I I HCI 0 40 0AN H2N HCI B-17a B-18a To a solution of B-17a (1 eq.) in AcOH is added Pd(OAc)2 (0.02 eq.) and the mixture is stirred at room temperature until complete consumption of B-17a. Subsequently, water and conc. HCI are added. After the cleavage of the Boc group (decreasing CO2 formation), the mixture is heated up to 70 C and stirred at this temperature for 3 days. The product B-18a can be crystallized from the reaction mixture by cooling down. The following intermediates B-18 (table 15-4) are available in an analogous manner starting from different phenyl alkynyls B-17. 159 Date Regue/Date Received 2023-03-01 CA 3,000,063 Table 15-4 # structure [M+H] CO2H 1.1 H2N B-18a 209 HCI 0 H2N NCI CO2H Olt H2N B-18b 223 NCI 0 H2N NCI 02H 0 41 ...... H2N B-18c 239 HCI 0 H2N HCI _ CO2H 0 ...., lit H2N B-18d 239 HCI 0 H2N HCI 160 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure [M+Hr = COOH H2N B-18e HCI 209 0 H2N HCI CO2H H2N B-18f 223 HCI 0 H2N HCI Experimental procedure for the synthesis of B-18g CO2H CO2Me SOCl2 Me0H H2N HCI H2N __________________________________________ 11 HCI 0 0 H2N H2N HCI HCI B-18a B-18g To a suspension of B-18a (1 eq.) in Me0H is added SOCl2 (3 eq.) dropwise at 60 C and the mixture is stirred overnight at this temperature. After cooling down to room temperature the mixture is filtrated over an activated carbon filter and the solvents are afterwards removed under reduced pressure. The product B-18g can be purified by crystallization. The following benzoic acid ester intermediates B-18 (table 15-5) are available in an analogous manner starting from different benzoic acids B-18 initially obtained. I0 161 Date Regue/Date Received 2023-03-01 CA 3,000,063 Table 15-5 structure [M+11]+ CO2Me = 223 H2N B-18g HCI 0 H2N HCI CO2Me H2N B-18h 237 HCI 0 H2N HCI CO2Me 0 H2N = B-181 253 HCI 0 H2N HCI CO2Me 0 = H2N B-18j 253 HCI 0 H2N HCI CO2Me H2N B-18k HCI 223 0 H2N HCI 162 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure [M+Hr CO2Me H2N 411 B-18I 237 HCI 0 H2N HCI Synthesis of intermediates 8-19 Experimental procedure for the synthesis of B-19a 0 CO2Me CO2Me 0 * N * H2N S-la H2N HCI Cl 0 0 Et3N, AcOH, Me0H H2N HCI /N 0 B-18g CI N B-19a To a suspension of B-18g (1 eq.) in Me0H is added 6-chloroisatin S-1 a (1.1 eq.), AcOH (2.4 eq.) and TEA (2 eq.). After 3 days of stirring at room temperature the product B-19a can be filtrated. The following imine intermediates B-19 (table 15-6) are available in an analogous manner starting from different benzoic acid esters B-18. 163 Date Recue/Date Received 2023-03-01 CA 3,000,063 Table 15-6 structure [M+Hr CO2Me H2N * B-19a 0 387 110 N Cl CO2Me H2N * B-19b 0 400 N Cl 0 CO2Me H2N * 0 , B-19c 0 416 * N Cl 0 164 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure [M+Hr CO2 Me H2N * B-19d 0 416 /N 1101 N 0 CI 4it CO2Me H2N B-19e 0 387 iN N CI CO2Me H2N * B-19f 0 400 N 0 CI 165 Date Recue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates B-20 Experimental procedure for the synthesis of B-20a CO2Me Cl H2N CO2Me CI 2N 2 F tp, No2H 0 NO 0 õ NH 0 00 N 0 CI N CI B-19a B-20a 1-Chloro-2-fluoro-3-(E)-2-nitro-vinyl)-benzene (1.1 eq.) is suspended in toluene and water and heated up. Subsequently, the imine B-19a (1 eq.) and 1-methylpyrrolidine (4 eq.) are added. The mixture is stirred under reflux. The reaction is quenched at 0 C by the addition of AcOH. The organic phase is washed with water and saline and is then added dropwise to nHep. The product B-20a can be purified by crystallization. If a chiral separation of the enantiomers of the race mic mixture of intermediate B-20a is to desired then a crystallization with chiral acids like e.g. (S,S)-(+)-2,3- dibenzoyl-D-tartaric acid, (S,S)-(+)-2,3-p-toluyl-D-tartaric acid, (1S)-(+)camphor-10-sulfonic acid, (1R)- (-)camphor-10-sulfonic acid, (R)-(-)-mandelic acid, L-pyroglutamic acid or (S,S)-D-(-)- tartaric acid can be considered. The use of (1R)-(-)camphor-10-sulfonic acid is preferred. The following intermediates B-20 (table 15-7) are available in an analogous manner starting from different imines B-19. Table 15-7 structure [M+H] CO2Me CI H2N * F NO2 .s B-20a 587 0 N ow 0 Cl H 166 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure [M+H]1 CO2Me H2N * CI F NO2 B-20b * F.. s , O 601 NH AO 00 0 CI N H CO2Me C H2N I * F NO20 B-20c * 3 , s, O µ 617 NH 4010" 0 CI N H 0 CO2Me H2N * CI F NO2 B-20d it 1: , %, O 617 NH 40 µ 0 0` CI N H H2N * CI F NO2 CO2Me B-20e 4 E: . % 0 587 NH *WI 0 CI N H CO2Me H2N * CI F NO2B-20f * 3 s, O 601 NH (100 " 0 CI N H 167 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure [M+H]1 CO2Me H2N * CI F NO2B-20g 4 s = O 587 NH *ow 43 chiral CI N H _ CO2Me CI H2N * F NO2 B-20h 4 FS ,, O 601 NH loow 0 CI N chiral H CO2Me H2N * CI F NO20 B-20i * 3 , µ O µ 617 NH *ow 0 CI N chiral H ---0 CO2Me H2N * CI F NO2 B-201 4 F. s , O 617 NH *ow 0 CI N chiral H H2N * CI F NO2 CO2Me B-20k 4 z µ , o 587 NH *ow 0 CI N chiral H 168 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure [M+H] CO2Me CI H2N * F NO24 sõ. B-201 0 601 NH 40/00. 0 CI chiral Synthesis of intermediates 8-22 Experimental procedure for the synthesis of B-22a CO2Me CO2Me H2N H2N 1110 CI HO CI Pt/C, H2 F F NO2 MeTHF F.: s 411 % 0 NH OW 00 NH CI H chiral CI chiral B-20g B-21a VO(acac)2 1 H2 CO2Me H2N * CI F HN ow, NH 0 CI H chiral B-22a 5 To a solution of B-20g (1 eq.) in MeTHF is added water and Pt/C (15 wt%). The mixture is hydrogenated for 3 days at 30 C under 70 bar H2 pressure. After complete conversion to B-21a, VO(acac)2 (0.11 eq.) is added and the mixture is further hydrogenated at 30 C at 169 Date Regue/Date Received 2023-03-01 CA 3,000,063 70 bar for 2 days. The catalysts are filtered out and the solvent is removed under reduced pressure. The product B-22a is dissolved in toluene and by adding 2 M H2SO4 (1.11 eq.) the sulfate of B-22a can be precipitated. The reaction sequence B-20 B-21 B-22 is also possible with racemic B-20 (if there is no chiral separation of B-20). In this case chiral separation can also be performed on the stage of B-22 by a crystallization with chiral acids like e.g. (S,S)-(+)-2,3- dibenzoyl-D-tartaric acid, (S,S)-(+)-2,3-p-toluyl-D-tartaric acid, (1S)-(+)camphor-10-sulfonic acid, (R)-(-)- mandelic acid, L-pyroglutamic acid, (S,S)-D )-tartaric acid, (S)-(-)-L-malic acid or L-(+)- lactic acid ((S,S)-(+)-2,3-p-toluyl-D-tartaric acid is preferred). The following intermediates B-21 and B-22 (table 15-8) are available in an analogous manner starting from different intermediates B-20. Table 15-8 structure [M+Hr CO2Me H2N Cl HO F 'N B-21a 557 * NH /pool 0 Cl chiral CO2Me H2N * CI HO F 'N B-21b c 571 NH ' 0 Cl N chiral 170 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure [M+H] CO2Me H2N * 0 CI HO F B-21c E s, 587 NH 0" CI N chiral ¨0 CO2Me H2N * CI HO F 'N B-21d s, 587 NH 00 C I N chiral H2N * CO2Me CI HO F B-21e * 557 NH *oo 0 CI chiral CO2Me H2N CI HO F 'N B-21f E s, 571 NH 401.4. 0 CI N chiral 171 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure [M+H] CO2Me HN * CI F HN B-22a * E s, 541 NH to' 0 CI chiral CO2Me HN * CI F HN B-22b * E s, 555 NH [Or0 CI chiral CO2Me HN * 0 CI F HN B-22c * s, 571 NH 0 C I µWN chiral ¨0 CO2Me H2N * CI F HN B-22d E s, 571 NH 1101 0 CI N chiral 172 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure [M+Fi] H2N * CO2Me CI F HN E s B-22e * 541 NH 0 CI chiral CO2Me HN CI F HN B-22f s, 555 NH 101 CI chiral Synthesis of intermediates 8-23 Experimental procedure for the synthesis of B-23a CO2Me CO2Me H2N Na2W04*2H20 fsk/ CI H202 Cl F HN F N CH2Cl2/H20 NH * NH 0 0" 0 Cl CI B-22a B-23a To a suspension of B-22a (1 eq.) in CH20I2 and water (4:1) is added Na2W04 dihydrate (0.01 eq.) and H202 solution (30 % in water, 2.5 eq.) and the mixture is stirred under reflux for 2 h. Then a solution of K2CO3 (2 eq.) in water is added and the CH2Cl2 is removed under reduced pressure. The solid product B-23a can be purified by slurrying in an appropriate solvent. The following intermediates B-23 (table 15-10) are available in an analogous manner 173 Date Recue/Date Received 2023-03-01 CA 3,000,063 starting from different intermediates B-22. Table 15-9 structure [WM+ CO2Me CI N"! 537 B-23a F * NH 110011 0 Cl N chiral CO2Me CI NI F 'N' B-23b * % 551 , NH 0 CI N chiral CO2Me Cl NI1111% I F N B-23c 567 NH 0 CI N chiral 174 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure [M+H] CO2Me 0 CI N I B-23d 567 NH IOW 0 CI N chiral CI CO2Me NI F N B-23e = 537 NH *ow 0 CI N chiral CO2Me /4111 CI N F 'N' B-23f 551 NH *ow 0 CI N chiral 175 Date Recue/Date Received 2023-03-01 CA 3,000,063 Compounds (lb) General reaction scheme and summary of the synthesis route Scheme 3 R2 R3 COOtBu COOH COOtBu I( BocHN llµLti ) H2N l'"Lti L A-2 COOH TFA BocHN'L) ti ___________________________ - HN 0 .....? _õ.. HN 0 method A 3 method B R3 NH2 Ry Y A-1 R2 R2 A-3 A-4 BocHN-M) )r, NH 0 A-6 e R R3 ( vtfl--1(V method C 2 127)q¨t N Me0H H 1 A.2 I COOH S-1 method D 0 NHBoc X;YXI( 0 H NH2 (R7) 141) ) q--11- V ...-N n LI1 )n '''''Ar II H R3. E On HN 0 S-1 HN 0 _______________________________________________________ ,y NH _.. "=.--- _ (127)qX .7.: v R3 method E ¨th R3y NMP .iAr N R2 2 H R A-7 A-5 ¨ ¨ A-8 (R4)r (124)r method F (R4)r A 0 A 0 H CI 21,1 \ 0 -.., 2N .--rkl N 0 Br R3,, On $,..-N .-N R3,, l' On -.. le A-10 R21... ... method H R/1 method G y N.-R1 )r (R7)q_=.... V (R7)q--11- V (R7)q_ V w N ( H '`Ihr N N H H A-9 (lb) A-11 Novel compounds of structure (lb) can be prepared stepwise by a synthesis route starting from protected amino acids A-1 (scheme 3). First, an acylation reaction using acrylic acid derivatives A-2 yields compounds of structure A-3 (method A). Acrylic acids which are not 176 Date Recue/Date Received 2023-03-01 CA 3,000,063 directly available can be obtained e.g. by WITrIG reaction (D-1, D-2, not depicted in scheme 3). Treatment of intermediates A-3 under acidic conditions, preferentially with trifluoro acetic acid, forms free unsaturated amino acid derivatives A-4 (method B). A decarboxylative 1,3- dipolar cycloaddition of A-4 and isatin derivatives S-1 yields cycloadducts A- 5 as a mixture of diastereo isomers and builds up the Spiro system (method C). The diastereomers can be separated, e.g. by HPLC or SFC. The obtainable racemic mixture can be resolved by chiral SFC separation or at any later stage in the synthesis. Also all other means known for separation of enantiomers can be applied here or after any later synthetic step herein described, e.g. crystallisation, chiral resolution, chiral HPLC etc. (see also Enantiomers, racemates, and resolutions, Jean Jacques, Andre Collet, Samuel H Wilen John Wiley and Sons, NY, 1981). Alternatively cycloadduct A-5 can be prepared by a 1,3-dipolar cycloaddition of amine A-8 and isatin derivatives S-1 as a mixture of diastereo isomers (method E). Intermediates A-8 can be prepared in one pot from amines A-6 by an acylation reaction using acrylic acid derivatives A-2 and subsequent cleavage of the Boc-protecting group by addition of HCI (method D). Intermediates A-5 can be reacted with aldehydes or ketones in a reductive amination reaction to give intermediates A-9 (introduction of R1, method F). Alternatively, an alkylation, addition, acylation or sulfonylation reaction can be performed with A-5 to additional intermediates of formula A-9. Subjecting intermediates A-9 to metal-catalyzed cross coupling reactions (e.g. BUCHWALD amidation) with substituted nitro (hetero)aryl halides A- 10 gives intermediates A-11 (method G). A reductive cyclization of intermediates A-11 by treatment with iron powder in acetic acid, or alternative reducing agents gives compounds (lb). Compounds (lb) which are initially obtained can be derivatized in optional derivatization steps not explicitly depicted in the schemes in all residues, especially in R4, if they carry functional groups, that can be further modified such as e.g. halogen atoms, amino and hydroxy groups (including cyclic amines), carboxylic acid or ester functions, nitrils etc. to further compounds (la) by well-established organic chemical transformations such as metal- catalyzed cross coupling reactions, acylation, amidation, addition, reduction or (reductive) alkylation or cleavage of protecting groups. These additional steps are not depicted in the general schemes. Likewise, it is also possible to include these additional steps in the synthetic routes depicted in the general schemes, i.e. to carry out derivatization reactions 177 Date Recue/Date Received 2023-03-01 CA 3,000,063 with intermediate compounds. In addition, it may also be possible that building blocks bearing protecting groups are used, i.e. further steps for deprotection are necessary. Scheme 4 (R4)r (R4)r 0 H 1 A A %N 02N \ 3, On R% 2 On ON R Br 0%N RiliZt A-10 method I x)I' 00 N'=i- method ; (127)g¨cv v (R7)g¨l.h _ V ,), N.- .. N ily- N X "i' H H (R7)g¨cov A-5 A-12 ' v N H A-13 method H 1 (R4), (R4)r (R4)r A A A N NI.,N NN lee 2 On R ' s method K R ',. ' method J Rie.:2 (R7)g¨ method L y NH - ..... ift..4 V X µ0" X ow (Rig [cc V N H iiir N ' N H H (lb) A-15 A-14 Alternatively, novel compounds of structure (lb) can be prepared stepwise by a synthesis route starting from intermediates A-5 (scheme 4). Intermediates A-5 are treated with acetic anhydride in formic acid to generate intermediates A-12 (method I). Subjecting intermediates A-12 to metal-catalyzed cross coupling reactions (e.g. BUCHWALD amidation) with substituted nitro (hetero)aryl halides A-10 gives intermediates A-13 (method G). A reductive cyclization of intermediates A-13 by treatment with iron powder in acetic acid, or alternative reducing agents, gives intermediates A-14. Deformylation mediated by hydrochloric acid in Me0H gives intermediates A-15 (method J). Intermediates A- 15 can be reacted with aldehydes or ketones in a reductive amination reaction to give compounds (lb) (introduction of R1, methods K and L). Alternatively, an alkylation, addition, acylation or 178 Date Recue/Date Received 2023-03-01 CA 3,000,063 sulfonylation reaction can be performed with A-15 to additional compounds of formula (lb). Scheme 5 (R4),. (1:14), R2(R3 COOH A 0 _ method M R3 N NH2 method N (R4 01 , H2N NH2 ¨ H H R2/ A-16 R2 A-17 A-18 o HNA0tBu method 0 ? LI Br A-19 (Ri)r o , r "It'ilµ A (Rig_tvir N v 01 Nt...-N H 4111 14.\>R3 S-1 N")¨N3 3 ) _______ 12,, - ..= ^ (R4 (114 r ____________________ H2 method Q ( ),, method P ( n .,y NH NH2 X ,µ"µ. A-21 tBuO-INH A-20 (R7)q¨t V 0 Wi N H method K A-15 or method L (R4)r A N R:õ 5 y ,n optional ,Ry ' N....RI derivatisation X ".= .... V iii. _______________________________________________________ =- steesppse(ciniaRli; to R5, (127)q¨th 'w N H (lb) Alternatively, novel compounds of structure (lb) can be prepared stepwise by a synthesis route starting from diamino (hetero)aryls A-16 (scheme 5). First, an acylation reaction using acrylic acid derivatives A-2 yields compounds of structure A-17 (method M). Acrylic acids which are not directly available can be obtained e.g. by WITTIG reaction (D-1, D-2, not depicted in scheme 5). Treatment of intermediates A-17 with hydrochloric acid gives condensed imidazole (e.g. benzimidazole) intermediates A-18 (method N). Alkylation of intermediate A-18 with bromides A-19, or alternative alkylating agents, gives intermediates A-20 (method 0). Treatment of intermediates A-20 under acidic conditions, preferentially with trifluoro acetic acid, forms free unsaturated amine derivatives A-21 (method P). A 1,3- 179 Date Recue/Date Received 2023-03-01 CA 3,000,063 dipolar cycloaddition of A-21 and isatin derivatives S-1 yields cycloadducts A- 15 as a mixture of diastereo isomers and builds up the Spiro system (method Q). Intermediates A- 15, as described above, can be reacted with aldehydes or ketones in a reductive amination reaction to give compounds (lb) (introduction of R1, methods K and L). Alternatively, an alkylation, addition, acylation or sulfonylation reaction can be performed with A-15 to additional compounds of formula (lb). Compounds (lb) have been tested for their activity to affect MDM2-p53 interaction in their racemic form or alternatively as the enantiopure form. Each of the two enantiomers of a racemic mixture may have activity against MDM2 although with a different binding mode. Enantiopure compounds are marked with the label "Chiral". Compounds listed in any table below that are labeled "Chiral" (both intermediates as well as compounds (lb) according to the invention) can be separated by chiral SFC chromatography from their enantiomer or are synthesized from enantiopure starting material which is separated by chiral SFC. Example: OH OH OH 0 0 0 Chiral Chiral N s 4 ) CI I WF Cl C CI CI A Structure A defines the racemic mixture of compounds with structure B and C, Le. structure A encompasses two structures (compounds B and C), whereas structures B and C, respectively, are enantiopure and only define one specific compound. Thus, formulae (lb) and (lb*) 180 Date Recue/Date Received 2023-03-01 CA 3,000,063 (R4), (I24), A A Chiral N 11211 R211.:2 R1 N (127)q--11-- V (117)q ______ V N (lb) (1b*) with a set of specific definitions for groups R1 to R4, R7, V, W, X, Y, n, rand q represent the racemic mixture of two enantiomers (lb); structure A above is one specific example of such a racemic mixture) or a single enantiomer (lb*); structure B above is one specific enantiomer), unless there are additional stereocenters present in one or more of the substituents. The same definition applies to synthetic intermediates. Synthesis of intermediates A-2 Experimental procedure for the synthesis of A-2a oI 0 0 0 1101 411P N21F NaOH OH MTBE NI NI CI D-la Cl Cl D-2a A-2a to 2-Chloro-3-fluoro-pyridine-4-carbaldehyde D-la (1 g, 6.3 mmol) is dissolved in anhydrous MTBE (10 mL) under an argon atmosphere. Methyl (triphenylphosphoranylidene)acetate (2.1 g, 6.3 mmol) is added in one portion and the reaction mixture is stirred at rt for 1 h. Water and Et0Ac is added and the phases are separated. The organic phase is dried with MgSO4, filtered and the solvent is removed under reduced pressure. The residue is purified by reversed phase column chromatography giving pure (E)-3-(2-chloro-3-fluoro- pyridin-4- y1)-acrylic acid methyl ester D-2a. D-2a (780 mg, 3.6 mmol) is dissolved in THF (3 mL) and 2 M NaOH is added (3.6 mL, 7.2 mmol). The reaction mixture is stirred at 60 C for 1 h before it is quenched by the 181 Date Recue/Date Received 2023-03-01 CA 3,000,063 addition of 2 M HCI. Extraction with Et0Ac and subsequent drying of the organic phase using MgSO4 yields crude A-2a upon removal of the solvents under reduced pressure. Reversed phase column chromatography gives pure (E)-3-(2-chloro-3-fluoro- pyridin-4-yI)- acrylic acid A-2a. Further building blocks A-2 are available in an analogous manner starting from different carbaldehydes D-1. Table 16 structure tret [min] [M+H] HPLC method 0 OH A-2a NrLF 0.0 202 A Cl Synthesis of intermediates A-3 (method A) Experimental procedure for the synthesis of A-3a CI 140 F Chiral Chiral I OH ON HN0 A-2h 0 HN 0 H2 N'' HATU CI x HCI A-3a A-la 3-Chloro-2-fluoro cinnamic acid A-2b (10.3 g, 50.67 mmol) is suspended in anhydrous DMF (300 mL) at 0 C and DIPEA (19.5 mL, 120.65 mmol) and HATU (20.39 g, 53.09 mmol) are added to the reaction mixture. The reaction mixture is stirred at 0 C for 30 min. A solution of (S)-4-amino-2-tert-butoxycarbonylamino-butyric acid tert-butyl ester hydrochloride A-1a (15.0 g, 48.26 mmol) in DMF (100 mL) is added dropwise over a period of 15 min. The reaction mixture is stirred for additional 60 min and sat. aq. NH4C1 solution is added. Deionized water is added and the mixture is extracted with a 1:1 mixture of Et0Ac and cyclohexane. The layers are separated and the organic phase is washed with deionized water and dried with MgSO4. The solvents are removed under reduced pressure and (S)-2- tert-butoxycarbonylamino-4-[(E)-3-(3-ch loro-2-fluoro-phenyl)acryloylamino]- butyric acid 182 Date Recue/Date Received 2023-03-01 CA 3,000,063 fert-butyl ester A-3a is used without further purification. The following intermediates A-3 (table 17) are available in an analogous manner starting from different acrylic acids A-2 and protected amino acids A-1. Table 17 # structure tret [min] [WM+ H PLC method 1:?IN 0 HI41"-µ0 [M+H-Boc] A-3a 1.56 A 357 F y.) Cl Chiral $:?IN 0 HN--µ0 [M+H-Boc] A-3b 1.56 A . N Cr 357 H F y:20 CI O 0 * r.,)(0 A-3c F HN,.0 I 0.82 443 G Cl )e...? O 0 Fr 0 A-3d * iF HNO r 0.82 443 G Cl Chiral ),õ? O 0 * r.,04 A-3e F HNO r n.a. n.a. Br 183 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+Ei] H PLC method O 0 * Fri NIA:)4 A-3f F Hisl0 i n.a. n.a. Br Chiral Ny? O 0 1 N' Nt::1 A-3g N F H HNy0 1.44 466 A CI O 0 N I NMAO A-3h F H HNy0 1.44 466 A CI y) Chiral 0 A-3i n.a. n.a. 1 NCr N H F Nr..13 CI 6>IN. 0 Hikrµo A-3j n.a. n.a. 1 Nr N H F y) CI Chiral 184 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates A-4 (method B) Experimental procedure for the synthesis of A-4a Chiral C--;>I 0 NH2 0 HN.0 TFA E N H N F OH H Chiral Cl A-3a A-4a (S)-2-tert-Butoxycarbonylamino-4-[(E)-3-(3-chloro-2-fluoro-phenyl)- acryloylaminoi-butyric acid tett-butyl ester A-3a (22.4 g, 48.9 mmol) is dissolved in DCM (150 mL). TFA (35 mL) is added at 0 C and the reaction mixture is slowly warmed to rt. The reaction mixture is heated to reflux for 24 h. Before it is concentrated in vacuo, aq. NaOH (4 M) is added at 0 C until a pH of 12 is reached. Addition of aq. HCI (2 M) results in the formation of a precipitate at pH 6-7 which is filtered off. The solid residue (S)-2-amino-4- [(E)-3-(3-chloro- 2-fluoro-phenyl)-acryloylaminoFbutyric acid hydrochloride A-4a is washed with water and acetonitrile and dried at 50 C under reduced pressure. The following intermediates A-4 (table 18) are available in an analogous manner starting from different intermediates A-3. Table 18 # structure tret [min] [M+11]* HPLC method 0 NH2 0 NrCi A-4a H 0.91 301 A F OH Cl Chiral 0 NH2 0 .... ir...../cr0 A-4b 0.91 301 A F OH CI 0 0 ils ........ 1.11....y.. OH A-4c 0.63 287 A NH2 F CI 185 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+Hr HPLC method O 0 A-4d 0 trY LOH 0.63 287 A NH2 F CI Chiral O 0 1 NTh)OH A-4e N H 0.21 288 A NH2 F CI O 0 A-4f N H OH 0.21 288 A F CI Chiral NH2 O NH I NA=r A-4g N H 1.40 302 M F OH CI O NH2 I Nr A-4h N H 1A0 302 M F OH CI Chiral Synthesis of intermediate A-5 (method C) Experimental procedure for the synthesis of A-5a and A-5c 0 0 \--OH H2N..... 40 0 H N 0 H N Cl N (:),/. ---1 1 I NH S-la H . CI 0 + CI 0 FiN õ NH / For, NH Me0H 0 Chiral F Cl WI N Cl N H H 110. CI A-5a A-5c A-4a (S)-2-Amino-4-[(E)-3-(3-chloro-2-fluoro-phenyl)-acryloylaminoFbutyric acid A- 4a (0.34 g, 1.13 mmol), 6-chloro-1H-indole-2,3-dione S-la (2.1 g, 1.13 mmol) and ground, activated 4 A molecular sieves are suspended in anhydrous Me0H (15 mL) in a microwave vial. The 186 Date Recue/Date Received 2023-03-01 CA 3,000,063 reaction vessel is sealed with Teflon caps and irradiated for 30 min at a final temperature of 100 C. After cooling to rt, the crude mixture is filtered over a pad of Celite and solvents are removed under reduced pressure. The crude reaction mixture is purified by reversed phase HPLC which gives diastereomers A-5a and A-5c. The following intermediates A-5 (Table 19) are available in an analogous manner starting from different intermediates A-4 and S-1. Table 19 structure tret [min] [M+H] HPLC method tot Oer4L1 ss.4 A-5a Cl 0.49 420 F , NH 100 0 Cl 01%1 141111 A-5b Cl Chiral 0.49 420 F NH 0 Cl 0 A-5c Cl 0.45 420 Witt, F ki)%1F1 0 Cl A-5d Cl 0.53 512 F NH 0 187 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method H 0,A A-5e CI Chiral 0.53 512 G Fir6 NH 0% 0 I N H 0.114) A-5f CI 0.93 421 A F ....... õ, NH 0 C1I N N H H 0/111) - ss.= A-5g CI NH Chiral 0.93 421 A 0 CI N-- N H H 0. NI % 1 0., A-5h CI NH 0.89 421 A F CI N N H 0 H A-5i CI 0.99 406 A Fiorõ NH 0 CI N H H 101 at_ N, A-5j CI r 0 NH Chiral 0.99 406 A = 1/10 t 0 CI N H 188 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 A-5k 0.99 406 A NH i=0 CI H Chiral 0 - - A-5I CI 0.93 421 A NH I CI N N ..-111 O Chiral Azm CI 0.93 421 A NH I CI N N A-5n Br Flow NH 0.50 451 0 CI o Azo Br 0.50 451 For NH Chiral CI N I .== A-5p NH 0.91 421 A F CI 100'"N 0 189 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+Hr HPLC method H A-5q CI I 0% 1 Nssiiµ Chiral 0 0.91 421 A a 1101 N H Synthesis of intermediates A-8 (method D) Experimental procedure for the synthesis of A-8a CI ¨S I OH A-2c 0 o HN0 iriNH2 1. HATU H2N,.) 2. HCI Cl A-8a A-6a (E)-3-(4-Chloro-thiophen-2-yI)-acrylic acid A-2c (554 mg, 2.94 mmol) is suspended in anhydrous DMF (5 mL) at 0 C and DIPEA (1.14 g, 129.3 mmol) and HATU (1.34 g, 3.52 mmol) are added to the reaction mixture. The mixture is stirred at 0 C for 30 min. A solution of (2-amino-ethyl)carbamic acid tert-butyl ester A-6a (470 mg, 2.94 mmol) in DMF (1 mL) is added dropwise over a period of 15 min. The reaction mixture is stirred for additional 30 min. Concentrated HCI (2.89 g, 29.37 mmol) is added and the mixture is heated to 90 C and stirred for 90 min. Sodium hydroxide (8 N in H20) is added until a pH of 12 is reached and the mixture is extracted with Et0Ac. The layers are separated and the organic phase is washed with deionized water and dried with MgSO4. The solvents are removed under reduced preasure and the crude reaction mixture is purified by reversed phase HPLC if necessary to obtain intermediate A-8a. The following intermediates A-8 (table 20) are available in an analogous manner starting from different acrylic acids A-2 and amines A-6. 190 Date Regue/Date Received 2023-03-01 CA 3,000,063 Table 20 # structure tret [min] [M+H] HPLC method 0 A-8a c 1 \\s \ .....CrAHNNH2 0.28 231 G 0 ,N N.N.NH2 A-8b \ S H 0.29 231 G CI 0 0 N/".N.,...N12 A-8c H 0.86 243 A F Cl 0 110 NNH A-8d H 2 0.86 257 A F Cl Synthesis of additional intermediates A-5 (method E) Experimental procedure for the synthesis of A-5r and A-5t NH 0 r) 2 40 0 01 0 H ci 0 H N 0 NH CI N 1 1 y N h H S-la S + S CI1,,,,. NMP 0 N CI N ¨ H H CI A-5r A-5t A-8a (E)-N-(2-Amino-ethyl)-3-(4-chloro-thiophen-2-yl)acrylamide A-8a (0.37 g, 1.60 mmol), 6-chloro-1H-indole-2,3-dione S-la (306 mg, 1.60 mmol) and triethylamine (162 mg, 1.60 mmol) are suspended in anhydrous NMP (12 mL) in a microwave vial. The reaction vessel is sealed with a Teflon cap and irradiated for 30 min at a final temperature of 110 C. After cooling to rt the solvents are removed under reduced pressure. The product is used crude for the next step or purified by reversed phase HPLC which gives diastereomers A- 5r and A-5t. 191 Date Recue/Date Received 2023-03-01 CA 3,000,063 The following intermediates A-5 (table 21) are available in an analogous manner starting from different intermediates S-1 and A-8. Table 21 # structure tret [min] [M+H] HPLC method CI1 0 H 1 yN A-5r S NH 0.47 394 G 101 00 0 Cl N H Cl 0 H Chiral 1 1 1,--N S A-5s NH 0.47 394 G 101 to. 0 Cl N H Cl 0 Ill S 44 NH A-5t 0.47 394 G 110/ 00 0 Cl N H Cl 0 Isli Chiral h'S 4H A-5u 0.47 394 G 110 00 0 Cl N H 0--HN CI S A-5v 40 . NH 0.39 394 A ... 0 Cl N H 192 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method Chiral 0 H ..,...111 A-5w S 039 394 A NH lio 0%. 0 CI N H O 1E41 CI_...Ã1 S '", A-5x NH 039 394 A 410 to. 0 CI N H Chiral 0 lisil CI-0. S 4', A-5y 039 394 A NH lail 00 0 CI N H _ O H A-5z CI I.1 ..,--N, = : õ 0.99 406 A For NH 0 CI N H 0 H . 1.....N>. A-5as CI F NH Chiral 0.99 406 A /Or 0 CI N H O H N A-5ab CI Pio NH 0.80 406 K 0 CI N H 193 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method 0 t\'11 Chiral 141111õ A-5ac CI 0.80 406 K Flo NH 0 CI 11 N f., lkil ..,.e = 1 ) A-5ad CI 049 420 G F NH 0 CI N H rl - so, A-5ae CI Chiral 0.49 420 G NH 0 CI 111" N H H alit 0 N A-5af CI 111W k? 0.45 420 G F, NH 0 CI LW N H Synthesis of intermediates A-9 (method F) Experimental procedure for the synthesis of A-9a H H 0/NI N CI 0....j,õ,õ CI 0 CI NaBH(OAc)3 0 N CI N H H A-5a A-9a A-5a (120 mg, 0.29 mmol) and isobutyraldehyde (62 mL, 0.86 mmol) are dissolved in AcOH (5 mL), and sodium triacetoxyborohydride (0.30 g, 1.43 mmol) is added. The reaction 194 Date Recue/Date Received 2023-03-01 CA 3,000,063 mixture is stirred at rt for 30 min and another portion of sodium triacetoxyborohydride (0.30 g, 1.43 mmol) is added and stirring is conitued for additional 30 min before deionized water is added. Et0Ac is added and the phases are separated. After washing with water, the organic phase is dried with MgSO4 and the solvents are removed under reduced pressure. If needed the product is purified using reversed phase HPLC resulting in purified A-9a. The following intermediates A-9 (table 22) are available in an analogous manner starting from different intermediates A-5. Table 22 structure tret [mini [M-FH]+ HPLC method Orsi) - A-9a CI 0.74 476 tW' N 0 CI 02/141 ,e4 A-9b CI Chiral 0.74 476 0 CI ON) A-9c CI N/A 1.29 474 A 0 CI N ) A-9d CI F 1.29 474 A 0 N Chiral 195 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [WM+ HPLC method N 1 A-9e CI)c1K,,,.A 0/3 566 0 N Chiral esi A-9f CI n.a. n.a. 0 N A-9g CI 1.38 554 A ..... N 0 0 CI 1 0) A-9h CI = 1.38 554 A N F ....... 0 0 CI H Chiral A.-9i CI 1.19 475 A 0 Chiral A-9j Cl 1.19 475 A A 0 CI N 196 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0.eN NI A-9k CI 1.28 555 A 0 CI N N Chiral s A-9I CIF 40 1.28 555 A N 0 0 ci !sr- N n - es A-9m 1.20 475 A Fi&o. IsINA 0 CI 11411-1 1 N N 11:1:11) Chiral I A-9n CI 1.20 475 A 0 CI N ,1s1 A-90 CI F 1.24 460 A 000 0 CI N 0 A-9p CI F 14¨P' 1.23 460 A Chiral CI 197 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [WM+ HPLC method 111 1 ) A-9q CI F., N--/ 0.62 434 G 0 CI N H Chiral kil 1 ) A-9r Ci 0.62 434 G 0 CI H 0--.NIE1 A-9s Br F N 1.21 504 A 401µ.... 0 CI N H ) N A-9f Br F N--Y¨ 1.21 504 A 0 ow" 0 CI N H Chiral 0,,,,N11 1 > , . 0 A-9u CI For, N \..._. 1.47 540 A 0 CI N H 0.--NFI A-9v CI 0 F00,.. N v...... 1.47 540 A 0 CI N Chiral H 198 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method CI (3...1,1 I E ) A-9w '-.S.-- N 1.19 448 A ir CI -0)). N H CI H h0,,,,.N Chiral 1 s ) A-9x S N 1.19 448 A CI N H CI H 0 ikl S 1" A-9y 1.14 448 A * "(;)). CI N H h CI H Chiral 0 N S % N A-9z 1.14 448 A WIN > CI H 0,..-NH CI S A-9aa N 1.19 448 A CI N ) H ONFI Chiral S A-9ab N 1.19 448 A CI N V H 199 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [WM+ HPLC method H 0 N CIM A-9ac N V 1.14 448 A CI N H H 0 N Chiral CI-41 -S--4", A-9ad N 'L14 448 A 101"" "C)). CI N H 0 H ---N 0> 4 A-9ae CI)cIIL 0 \,... 1.25 541 A CI N N H 0 H ,.._.-N 1 > e . 0 A-9af Cl 1 irs F1 0...N. No v......_ 1.25 541 A c Chiral H 200 Date Recue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates A-11 (method G) Experimental procedure for the synthesis of A-11a 0 0 * NO2 Br * NO2 A-10a CI 0, 0 CI CI F A-9a 0 CI A-1 1a Intermediate A-9a (400 mg, 0.84 mmol), 4-bromo-3-nitro-benzoic acid methyl ester (A-10a, 5 334 mg, 0.1.26 mol), cesium carbonate (410 mg, 1.26 mmol), Xantphos (97.2 mg, 0.17 mmol), and palladium trifluoroacetate (Pd(TFA)2; 28 mg, 0.08 mmol) are suspended in 1,4- dioxane (8 mL) in a microwave vial. The reaction is sealed and stirred at 130 C for 5 h. After consumption of the starting material, the reaction is diluted with acetonitrile and filtered through a plug of silica. The solvents are removed under reduced pressure yielding crude 10 A-11a which is purified by reversed phase column chromatography if necessary. The following intermediates A-11 (table 23) are available in an analogous manner starting from different intermediates A-9 and A-10. Table 23 structure tret [min] [M+1-1]+ HPLC method \ 0 0 IP NO2 A-11a ""A 1.00 655 Cl F 0)¨ CI 201 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [Whi]+ HPLC method Chiral 1 0 0 IP NO2 A-11b 0.93 655 Cl CI 0\ * NO2 A-11c 0./. "-A 0.88 653 CI F * so. CI Chiral 0 0 11110 NO2 A-11d 0.90 653 CI =0 202 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H]+ HPLC method Chiral 0 0 11110 NO2 A-11e 0 0.90 653 CI CI 0 110 NO2 0 .,!N A-11f s, 1 0.91 733 ..s. CI F ri 0 CI N r0 Chiral \ 0 0 IP NO2 A-11g 0.91 733 CI c 0 N r0 203 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [Whi]+ HPLC method Chiral 0 0 NO2 0 A-11h 0.91 733 CI CI i*r0411 0 IP NO2 A-11i 0.80 644 1 CI F ., 40,. N > !sr". Chiral 0 10 NO2 A-11j s (DIN) 0.80 644 CI VI 0 N 204 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [Whi]+ .. HPLC method 0 0 * 2 NO A-11k ) 1.53 653 A CI F 0 Cl z Chiral 0 0 1110 2 NO A-11I 1.53 653 A CI N CI 14 Chiral 0 2 NO 0 N A-11m 0.95 667 CI N CI Chiral k 0 O 40 2 NO A-11n 0.85 683 CI CI 205 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [mini [M+H]+ HPLC method Chiral ( 0 0 F)<CFI NO2 A-110 0.97 751 - CI CI Chiral ( 0 1110 NO2 A-11p 0.97 681 CI Ncs:;)>. CI Chiral ( 0 0 * NO2 A-11q 0.90 667 CI F õ.. CI 206 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [Whi]+ HPLC method Chiral k 0 1110 NO2 A-1 1r N") 0.91 681 CI 0 CI Chiral k 0 AO NO2 A-11s N") 0.96 695 CI CI Chiral ( 0 0 F 2 NO A-lit 0.96 685 0../ CI F CI N 207 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [Whi]+ HPLC method Chiral k 0 F F 410 2 NO A-11u N") 0.92 721 CI 0 CI NO2 A-11v 0.89 693 CI F * N CI Chiral NO2 A-11w NM 0.89 693 CI F CI 208 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [mini [M+H]+ HPLC method 0 NO2 A-11x 0.91 695 CI ')> 0 CI Chiral 0-- 0 NO2 A-11y 0.91 695 CI F CI 0 1110 NO2 A-11z s") 0.85 667 CI F *0. ci N 209 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H]+ HPLC method Chiral 0 *NO2 A-11aa 0.85 667 CI = ) . 0 CI 0 0 110 NO2 A-11ab 0.55 640 CI CI N I -0)). N Chiral 0 0 104 NO2 A-11ac 0.55 640 CI N I CI N 210 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [Whi]+ HPLC method k 0 0 * NO2 A-had N's) 0.89 734 CI N 0 CI N N 410. 0 H Chiral 0 0 410 NO2 A-11ae 010,N-1 0.89 734 CI F N I CI N N =0 H 01 IP NO2 A-11af N NV 0.86 668 I CI F 0 CI 1> 211 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [Whi]+ HPLC method 0 Chiral 0 111 NO2 A-hag I4V 113, 0.86 668 = CI = -1> 0 CI 0 0 = A-llah NO2 0.87 639 CI 400. CI Chiral 0 0 = A-1 NO21ai E 0.88 639 CI F 40,.µ. CI Chiral 0 0 = 0 N A-11aj NO2 0.88 639 CI CI 212 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [mini [M+H]+ HPLC method 0 0 0 II I NO2 0.89 639 A-11ak CI ci 1W- N 0 Chiral = 0 I. NO2 A-fial - 0.89 639 CI N CI Chiral 00 ===-=N NO2 A-11am 0.93 677 sõ CI F VIC CI 0 0 = A-Ilan NO2 0.89 653 e. CI CI 213 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [Whi]+ HPLC method Chiral 00 = A-11ao o NO2 0.89 653 CI C)>. CI 0 0 = NO2 A-11ap 0.87 627 CI F õ.. 0 CI o Chiral 0 0 NO2 A-11aq 0.87 627 CI F 0\ ci 0 0 CF3 NO2 A-11ar 0.92 707 E CI CI 214 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [Whi]+ HPLC method Chiral 00 * CF3 NO2 A-11as 0.92 707 E CI CI 0 0 F3C = NO2 A-11 at 0.92 707 CI F N -0) . CI 0 Chiral 0 F3C = NO2 A-11 au 0.92 707 CI F CI 0 Chiral 0 F3C0 = NO2 A-11av 0.96 737 CI CI 215 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [mini [M+H]+ HPLC method 0 0 NO2 A N, 0.89 683 -11aw Br õ,. 0 CI 0 Chiral 0 = NO2 A 0.89 683 -11ax Br CI 0 0 = CI A-11ay / ) NO2 0.87 627 1101"µµ CI 0 Chiral 0 = CI A-11az NO2 0.87 627 N CI 216 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [mini [111+11]+ HPLC method 0 0 NO2 A-11ba / 0.88 627 CI 7 ) 110"sµ 0) CI Chiral 00 = 0 NO2 A-11bb / 0.88 627 CI ) CI 1110 NO2 A-11bc 0.80 673 CI F . CI Chiral 110 NO2 A-11bd 0.81 673 1 CI Sr0 1,10,. CI 217 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H]+ HPLC method 02N * NO2 A-11 be 1.50 640 A CI F *00 CI Chiral 02N 110 NO2 A-11bf 1.50 640 A - CI CI Chiral 0 0 110 NO2 A-11bg 0.91 667 _ CI F 0., Chiral 0 0 * NO2 A-11bh 0.93 667 CI F N 218 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H]+ HPLC method Chiral 0 0 * NO2 A-11bi 0.92 667 CI F 401 N;):>. CI Synthesis of compounds (lb) according to the invention (method H) Experimental procedure for the synthesis of lb-1 \ 0 0- 0 0 NO2 Fe, AcOH N N 0/N CI 0 Fio Fs õõ 0 CI CI A-11a lb-1 A-11a (533 mg, 0.8 mmol) is dissolved in acetic acid (10 mL) and iron powder (469 mg, 8.4 mmol) is added. The suspension is heated to 130 C overnight. After addition of Et0Ac and saturated aqueous Na2CO3 solution, the phases are separated and the organic phase is dried by the addition of MgSO4. Removal of the solvents yields crude lb-1, which is of sufficient purity for the further derivatisation or purified by reversed phase column chromatography. The following compounds (lb) according to the invention (table 24) are available in an analogous manner starting from different intermediates A-11. 219 Date Recue/Date Received 2023-03-01 CA 3,000,063 Table 24 structure tret [min] [M+H] HPLC method 0¨ lb-1 0.86 607 Cl F Cl 0 Chiral 0 N N lb-2 0.92 607 oss Cl F CI 0 ¨ 0 N N lb-3 1.52 605 A Cl 0 CISN ¨ Chiral 0 lb-4 ) 1.52 605 A CI F CI 0,... -0) . 220 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 Chiral 0 lb-5 ahh N 1.52 605 A CI CI 0¨ = N.,.seN-.1 0 0.54 685 lb-6 CI 011 F õµ= N 0 CI \() Chiral 0 lb-7 NN 0 .,õ1 0.54 685 CI ciF 0 0¨ Chiral 0 = aihNN. N lb-8 0.54 685 CI , N CI 221 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method \c) 0 = lb-9 0.74 596 sõ) CI N 0- 0 Chiral it lb-10 N*N-A 0.74 596 - C F N 0 / 0 N N lb-11 ---A 0.81 605 CI F CI 0 Chiral 0 lb-12 N 0.81 605 CI 0 CI 222 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method Chiral 0 0 N N lb-13 0.97 619 CI ci N Chiral 0-0¨ N) lb-14 0.73 635 CI F CI Chiral 0 0 04-F = lb-15 N N 0.97 703 CI F Iwo NI-0; CI 223 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 Chiral = lb-16 N N.-- 0.87 633 1 , CI =0 0 Chiral = lb-17 0.85 619 _ CI F 0 ci IW;N 0¨ Chiral 0 N lb-18 ***1 0.83 633 CI iF õ.. c 1111111" N 224 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 Chiral 0 lb-19 hisyN-1 0.89 647 CI F CI oJ 0 F Chiral lb-20 N N 0.96 685 CI S. 01w. 0 CI 0¨ F F 0 411 Chiral Ns, N lb-21 ***1 0.92 673 S. CI F õ,. CI 225 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 lb-22 N,(1%1Th 0.81 645 CI F 00.= CI 0 Chiral 0 lb-23 N N 1.1 0.81 645 CI F 000 0 0 1 lb-24 N N 0.80 647 CI =, CI 226 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 Chiral 0 lb-25 0.80 647 CI F 0õ.= CI 0 0 lb-26 N N =s../ --1 7-. 0.73 619 CI F 000 Chiral 0 0 lb-27 N N 0/3 619 CI F CI 227 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 = lb-28 NN n.a. n.a. n.a. CI F 1, 00 0 CI N 0-/ 0 Chiral lb-29 N N n.a. n.a. n.a. .z.õ( CI F os4 0 CI N N 0 lb-30 N4,41(N-1 0 n.a. n.a. n.a. CI = F 0 CI N 228 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0¨ Chiral N.,(N-1 0 lb-31 n.a. n.a. n.a. CI N I 0 CI N N 0- 0 N lb-32 l'sV 0.84 620 CI IF N--\ 0 0¨ Chiral = lb-33 N 0.84 620 CI I N-, Or 0 \> C 0 -- 4 - lb-34 NtN : 0.84 591 CI CI F N- 229 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 Chiral lb-35 z 0.84 591 CI F tw:" 0 CI 0 0 Chiral µ lb-36 N N 0.84 591 CI CI 0 0 * Nt-N lb-37 - 0.89 591 Cl CI Chiral 0 0 * lb-38 - , 0.89 591 CI iF 400. c N 230 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 Chiral lb-39 0.90 619 CI -)>0 CI 0 0 Nt-N lb-40 - 0.87 605 CI = F NI-(;)> CI 0 Chiral N lb-41 0.87 605 CI F CI 0 0 N lb-42 0.83 579 E CI F N- CI 231 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 1 Chiral 0 0 lb-43 0.83 579 CI F 0 CI 0 0 F F lb-44 rii NN s ) 0.92 659 CI F 000 cl 0 0 Chiral F F * N lb-45 0.92 659 Cl CI 0 F F lb-46 0.90 659 E e.. Cl F 14*-0.)> CI 232 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method Chiral 0 FF * F lb-47 N 0.90 659 = = CI sõ "kw 010.. CI 0 0,/ OCF3 Chiral lb-48 0.97 689 - CI = CI 0 0 011 lb-49 1.60 671 A CI CIF N c( 0 0, Chiral lb-50 t60 671 A i NN = CI No CI 411 0 233 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 N't-N lb-51 E 0.87 637 Br F CILw 14.6, o0 Chiral lb-52 0.87 637 Br F 0 0.0 "- CI Nt¨N lb-53 0.84 579 / ) IllW" 0 CI 0 0 Chiral CI Nt.-111 lb-54 / ) 0.84 579 =140 CI N C)> 234 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 lb-55 0.85 579 CI / 0)> CI 0 ¨ Chiral Nt.-N lb-56 0.85 579 / CI spo. CI \ ,0 .S" = lb-57 1.40 625 A CI F CI0,1' 0 =,10õ \. .S" Chiral lb-58 1.40 625 A A CI F Iwo Nc¨:1) CiN > 235 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method \O HN lb-59 1.33 604 A CI F )> CI Chiral \O HN lb-60 N--syN) 1.33 604 A CI F CI 0 0 lb-61 N*. Chiral 0.90 619 CI )>0 CI 236 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 lb-62 N?N Chiral 0.93 619 CI CIis0 0 0 1b-63 N*.N) Chiral 0.92 619 CI 0 CI Synthesis of intermediates A-12 (method I) Experimental procedure for the synthesis of A-12a 01/141) 1 oss Ac20, HCO2H CI CI Fo NH Fio%,.. 0 0 CI CI A-5a A-12a Intermediate A-5a (2.0 g, 4.8 mmol) is dissolved in formic acid (10 mL) and acetic anhydride is added (3.5 mL, 38.1 mmol). The reaction mixture is stirred at 50 C for 16 h and subsequently quenched by the addition of water. Purification by reversed phase column chromatography yields intermediate A-1 2a. The following intermediates A-12 (Table 25) are available in an analogous manner starting from different intermediates A-5. 237 Date Regue/Date Received 2023-03-01 CA 3,000,063 Table 25 tret structure [M+H] HPLC method [min] o N) A-12a CI N 0.99 448 A F 0 ci Chiral o- A.-12b ci 0.99 448 A F tgir "" "0 CI A-12c CI N = 0.49 434 F CI Chiral ojj A-12d CI 0 0.49 434 F 401 0 CI 238 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates A-13 (method G) Synthesis of A-13a \ 0 0 I 0 H 10 NO2 0/N Br 110 NO2 .=== A-1 0a 0 CI N CI H Fdli, N .0 A-12a 0 CI 1-11 N H A-13a Intermediate A-13 can be synthesized from intermediate A-12 in analogy to the synthesis of intermediate A-11 from intermediate A-9 (method G, see above). Table 26 # structure tret [min] [M+H] HPLC method 0 CL- IP NO2 N A-13a 0... ) 0.70 627 G CI F Cl N H Chiral 0 O. NO2 A-13b 0,N- 0.70 627 G Cl F 0 ,... N:o Cl N H 239 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method 0 0 = A-13c NO2 - 010 613 CI F 40 õµ. Cl Chiral 00 A-13d NO2 0.70 613 CI F CI Synthesis of intermediate A-14 (method H) Synthesis of A-14a I 0 0¨ 0 0 # NO2 = Fe, AcOH Nrn.. N CI CI F NO F N 0 "µ 0 CI N CI A-13a A-14a Intermediate A-14 can be synthesized from intermediate A-13 in analogy to the synthesis of compounds (lb) according to the invention from intermediate A-11 (method H, see above). 240 Date Recue/Date Received 2023-03-01 CA 3,000,063 Table 27 structure tret [min] [M+H] HPLC method 0¨ = N N 0.65 579 A-1 4a Cl F N 0 16, Cl ke-PN 0¨ Chiral 0 N N 0.65 579 A-14b CI , 0 F 40%," CI 0 CI¨ * A-14c 0.66 565 E Cl / 0 F "-= 0 Cl Chiral 0 It:s A-14d 0.66 565 Cl F N = 0 ci IW:"N 241 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates A-15 (method J) Experimental procedure for the synthesis of A-15a o¨ o¨ o = HCI, Me0H CI CI F F NH 00 0 0 CI CI A-14a A-15a A-14a (840 mg, 1.45 mmol) is dissolved in Me0H (2 mL) and conc. HCI (37 %, 500 pL) is added. The reaction mixture is heated to 100 C for 30 min. The reaction is quenched by the addition of sat. aq. NaHCO3 and subsequently extracted with Et0Ac. Phases are separated and the organic phase is dried with MgSO4. The solvents are removed under reduced pressure. Reverses phase column chromatography gives pure A-15a. The following compounds A-15 (table 28) are available in an analogous manner starting from different compounds A-14. Table 28 structure tret [min] [M+H] HPLC method 0¨ = N A-15a .") 0.67 551 CI ciF NH 0 242 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [mm] [M+Hr H PLC method 0¨ Chiral A-15b N N 0.67 551 CI F ow, NH 0 CI 0 O. 411 N A-15c 0.68 537 CI 0 CI 0 0'- Chiral A-15d I NN 0.68 537 .õ CI NH 0 CIF al N 243 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates A-17 (method M) Experimental procedure for the synthesis of A-17a CI = F OH CI H2 N A-2b 0 F H2N 0 0 H2N HATU 0 H A-16a A-17a 3-Chloro-2-fluoro cinnamic acid A-2b (3.0 g, 14.81 mmol) is suspended in anhydrous DMF (25 mL) at 0 C and DIPEA (3.6 mL, 22.21 mmol) and HATU (5.6 g, 14.73 mmol) are added to the reaction mixture. The reaction mixture is stirred at 0 C for 30 min. A solution of 3,4- diamino-benzoic acid methyl ester A-16a (2.95 g, 17.77 mmol) in DMF (5 mL) is added dropwise over a period of 15 min. The reaction mixture is stirred for additional 3 h and aq. K2CO3 solution (8 mL, 2 N) is added. Deionized water is added and the mixture is extracted to with DCM. The layers are separated and the organic phase is washed with deionized water and dried with MgSO4. The solvents are removed under reduced pressure and the mixture is used without further purification or is purified by reversed phase column chromatography to yield A-17a. The following intermediates A-17 (table 29) are available in an analogous manner starting from different intermediates A-2 and A-16. Table 29 structure tret [min] [M+H]* HPLC method Cl 11 H2N =A-17a F 0 1.16 349 A 0 H 244 Date Recue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediate A-18 (method N) Experimental procedure for the synthesis of A-18a ilk 0 HCI 0 H2N N= N / F _ 0 N / F 0 H CI A-18a A-17a Intermedate A-17a (839 mg, 2.4 mmol) is dissolved in dioxane (5 mL) and conc. HCI (1.76 g) and Me0H (24 mL) is added. The resulting mixture is stirred for 15 h at 70 C. The mixture is diluted with Et0Ac and aq. NaOH (4 N) is added until pH = 10 is reached. Conc. HCI is added and the resulting solid is collected by filtration. Intermediate A-18a is used without further purification for the next step. The following intermediates A-18 (table 30) are available in an analogous manner starting to from different intermediates A-17. Table 30 # structure tret [min] [M+H] HPLC method HN li 0 /0 A-18a 1.22 331 A F CI 245 Date Recue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediate A-20 (method 0) Experimental procedure for the synthesis of A-20a and A-20b _)--0 11 0 N >LO 0 0 NH HN CI A-20a Br A-19a 0 _________________________________________ 40 -N K2CO3 Cl A-18a 0 11 0 ZN CI A-20b Intermediate A-1 8a (100 mg, 0.30 mmol) is dissolved in NMP (3 mL) and NaH (38 mg, 1.51 5 mmol) is added at rt. The resulting mixture is stirred for 5 min and A- 19a is added. The reaction mixture is stirred at 70 C for 15 h. Deionized water is added and the mixture is extracted with Et0Ac. The layers are separated and the organic phase is washed with deionized water and dried with MgSO4. The solvents are removed under reduced pressure and the mixture is purified by reversed phase column chromatography to yield A- 20a and 10 A-20b. The following intermediates A-20 (table 31) are available in an analogous manner starting from different intermediates A-18 and/or A-19. Table 31 structure tret [min] [M+H] HPLC method )r- 0 z0 A-20a N 1.38 474 A /0 CI 246 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 z0 A-20b N 1.38 474 A CI Synthesis of intermediate A-21 (method P) Experimental procedure for the synthesis of A-21a H2 0 N 0 TFA 0 101 Cl A-20a CI A-21a Intermediate A-20a (50 mg, 0.05 mmol) is dissolved in DCM (1 mL). TFA (40 pL) is added at 0 C and the reaction mixture is slowly warmed to rt. The reaction mixture is heated to reflux for 24 h and concentrated in vacuo.The residue is dissolved in Et0Ac and water and aq. NaOH (4 M) is added until a pH of 12 is reached. The layers are separated and the aqueous phase is extracted with Et0Ac. The combined organic layers are dried with MgSO4. The solvents are removed under reduced pressure and the mixture is purified by reversed phase column chromatography to yield A-21a. The following intermediates A-21 (Table 32) are available in an analogous manner starting from different intermediates A-20. Table 32 structure tret [min] [M+H] HPLC method H2N zN A-21a /0 1.14 374 A CI 247 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+Hr HPLC method H 02N z N A-21b L14 374 A CI Synthesis of additional intermediates A-15 (method Q) Experimental procedure for the synthesis of A-15c (alternative synthesis, see also method 0 CI H2N-"Nõ...N S-1a NMP = CI NH 0 CI CI N A-21a A-15c Intermediate A-21a (20 mg, 0.027 mmol), 6-chloro-1H-indole-2,3-dione S-la (5 mg, 0.027 mmol) and triethylamine (17 pL, 0.13 mmol) are suspended in anhydrous NMP (500 pL) in a microwave vial. The reaction vessel is sealed with a Teflon cap and irradiated for 45 min at a final temperature of 100 C. After cooling to rt the solvents are removed under reduced pressure. The product is purified by reversed phase HPLC which gives intermediate A-15c. The following intermediates A-15 (table 33) are available in an analogous manner starting from different intermediates A-21 and/or S-1. 248 Date Recue/Date Received 2023-03-01 CA 3,000,063 Table 33 structure tret [min] [WM+ HPLC method 0 0 4 A-15c Cl NN t26 537 A Olt NH 0 Cl 0 Chiral 0 4 A-15d Cl NN 1.26 537 A F NH 401 0 Cl 0 0 I A-15e Cl N ) 1.26 537 A NH 0 Cl 249 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+Hr HPLC method 0 0 chiral I Nt¨N A-15f 1.26 537 A CI F* %I. NH 0 CI Synthesis of further compounds (Ih) according to the invention (method K) a¨ o¨ o = on,- = N N NaBH(OAc),, CI AcOH CI F NH F N 0 CI CI A-15a lb-64 A-15a (0.030 g, 0.054 mmol) and 3-methyl-butyraldehyde (0.14 mg, 0.163 mmol) are dissolved in acetic acid (1 mL) and sodium triacetoxyborohydride (0.06 g, 0.272 mmol) is added. The reaction mixture is allowed to stir at ambient temperature for 1 h before it is quenched by the careful addition of sat. aq. NaHCO3 solution at 0 C. Deionized water and Et0Ac are added and the phases are separated. After washing with sat. aq. NaHCO3 and water, the organic phase is dried with MgSO4 and the solvent is removed under reduced pressure. Reversed phase column chromatography gives pure lb-64. The following compounds (lb) (table 34) are available in an analogous manner starting from different intermediates A-15. 250 Date Regue/Date Received 2023-03-01 CA 3,000,063 Table 34 structure tret [min] [M+H] HPLC method 0- 4111 N N lb-64 0.90 621 CI <Cl 0¨ Chiral 0 N N lb-65 0.90 621 Cl F.... N CI N 0- 0 = N N lb-66 t55 619 A r: 0,` Cl F CI 0¨ o Chiral N N lb-67 1.55 619 A sõ1 CI F VI" CI 251 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 = lb-68 N N 0.78 579 CI F CI Chiral 0 0¨ 4fr N N lb-69 0.78 579 - CI F so 0õ N-0\ CI 0¨ N N lb-70 .--1 0.83 593 CI N 0 Chiral 0 lb-71NN-- 0.83 593 Cl F os. Cl Isl 252 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0¨ N N lb-72 0.87 607 r ss CI F CI 0 0¨ Chiral fit N N lb-73 0.87 607 CI *1" F CI N 0¨ N N lb-74 0.90 621 CI CIF 0¨ Chiral 0 41i lb-75 N*, 0.90 621 CI osµ CIF = N 253 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 0 = lb-76 0.88 619 CI o CI 0- Chiral 0 41i N N lb-77 0.88 619 CI ci N b \0 0 lb-78 NM n.a n.a. n.a. 0,* CI -P4.:401 CI 0- Chiral lb-79 N N n.a. n.a. n.a. CI 0 \-0 CI w'N 254 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H]1 HPLC method 0 0 lb-80 N N 0.81 637 CI F 0 \---0 ci N 0 Chiral 0 lb-81 r=k.ersi) 0.81 637 CI F 0 \---0 Cl N 0- 0 N N lb-82 0.88 651 CI 0 \---0 F CI = N A- 255 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0¨ Chiral 0 N N lb-83 0.88 651 CI N--\ 0 \---0 CIF N 0- 0 = N lb-84 0.67 671 CI F CI N 07-S,17 0¨ o Chiral = lb-85 0.67 671 s 0.% CI F gir CI b 0- 0 111 lb-86 N NTh 0.93 633 CI 'CbCI 256 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0 Chiral 0 lb-87 0.93 633 CI F NcbCI 0- 0 4410 N N lb-88 0.95 647 CI F NobCI N 0 0¨ Chiral 111 N N lb-89 0.95 647 oss CI F 401,0. N-ti) CI 0 0 lb-90 N N 0.81 647 F F CI 0 CIF = N 257 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method 0¨ Chiral 0 N N lb-91 0.81 647 keS ***11 F_F CI F 0,0 0 CI 0- 0 0 N lb-92 0.88 685 CI 0 CI Chiral 0- 0 0 lb-93 0.88 685 õ1 N's * CI F 0 CI N 0¨ N N lb-94 = 0.87 685 0 CI F 0 CI W% N 258 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H]1 HPLC method 0¨ Chiral 0 lb-95 N ...--is,N ---i =o 0.87 685 G I C I No 40 CI N H O 0-- 41 N...-N lb-96 E .) 1.11 671 K CI F s,,,, N \ N 41 CI H 0 0. Chiral * ,..N lb-97 N- E 1.11 671 K CI CI 0 0 N 410. H 0 0 ' * N\..-N lb-98 1.13 671 K E ) CI O- F N lar0 " =CI N H 259 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H]1 HPLC method Chiral 0 0-- 4 Nt-N lb-99 1.13 671 CI O¨ F N 0 CI Synthesis of further compounds (lb) according to the invention (method L) o¨ o¨ o 41, HoLIF = CI H 2. NaBH(OAc), N j- F 0 0 CI CI A-15a lb-100 (3,3-difluorocyclobutyl)methanol (100 mg, 0.819 mmol) is dissolved in acetic acid (500 pL) and IBX (298 mg, 1.065 mmol) is added. The reaction mixture is stirred at 40 C for 3 h before it is filtered through a plug of Celite . To the filtrate, a solution of A-15a (30 mg, 0.054 mmol) in acetic acid (500 pL) is added at rt. Sodium triacetoxyborohydride (58 mg, 0.272 mmol) is added in one portion to the reaction mixture and the reaction is allowed to stir at rt for 30 min before it is quenched by the careful addition of sat. aq. NaHCO3 solution at 0 C. to Deionized water and Et0Ac are added and the phases are separated. After washing with sat. aq. NaHCO3 and water, the organic phase is dried with MgSO4 and the solvent is removed under reduced pressure. Reversed phase column chromatography gives pure lb- 100. The following compounds (lb) (table 35) are available in an analogous manner starting from different intermediates A-15 and/or different alcohols. 260 Date Recue/Date Received 2023-03-01 CA 3,000,063 Table 35 structure tivt [min] [M+H] HPLC method 0 0 lb-1 N00 N 0.82 655 oss Cl F is ci 0¨ Chiral 0 N lb-101 0.82 655 Cl F H F 0- 0 N N 4õ,õ( --AfiAN lb-102 0.78 656 CI F 0 CI 261 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H]1 HPLC method 0¨ N N lb-103 --)fizs 0.78 656 CI F 0 CI N Chiral 0 ¨ 0 lb-104 N N 0.96 621 CI ;19-- F sow. 0 CI Chiral 0- 0 lb-105 N N 0.96 621 CI F 401,0, 0 CI 262 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of further compounds (lb) by ester saponification Experimental procedure for the synthesis of lb-106 co¨ OH 0 0 4fr NaOH CI CI F 0 0 CI tWIµN CI lb-3 lb-106 lb-3 (484 mg, 0.8 mmol) is dissolved in Me0H (10 mL) and aq. NaOH solution (2 mL, 4 M) is added. The reaction mixture is heated to reflux for 1 h. After acidification with 2 M aq. HCI and extraction with Et0Ac the organic phase is dried with MgSO4. Purification with reversed phase HPLC leads to pure lb-106. The following compounds (lb) (Table 36) are available in an analogous manner starting from initially obtained compounds (lb). Table 36 structure Let [min] [M+Hr HPLC method OH 0 lb-106 N ,(N) 1.21 591 A Cl F õ.. N 0 CI 263 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method OH Chiral 0 N lb-107 1.03 591 A - 0.= CI 0 CiSN OH Chiral 0 = N lb-108 1.03 591 A CI OH 0 lb-109 1.12 593 A s) CI F O CI OH Chiral 0 N N lb-110 1.08 593 A CI CI IV 264 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+Ei]1 HPLC method OH 0 = lb-111 N 1.01 565 A - CI F N""\ 0 CI Chiral OH 0 = N N lb-112 1.01 565 A - CI Ors, F CI OH 0 lb-113 a 1.09 579 A - ss..= Cl ciF ri Chiral OH 0 lb-114 N"x"' 1.09 579 A CI F...= Cl N 265 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method OH 0 N N lb-115 1.11 593 A - CI F CI OH Chiral 0 = N N lb-116 1.11 593 A CI F N N CI OH 0 = lb-117 1.14 607 A - so% CI F No N OH 0 Chiral N lb-118 1.14 607 A CI F CI 266 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+111- HPLC method OH 0 lb-119 14;syN) 1.13 607 A CI CI OH Chiral 0 = N N lb-120 1.13 607 A CI CI OH 0 = lb-121 1.10 605 A s - sõs 40,0. 0 ¨ CI OH Chiral 0 lb-122 1.10 605 A - CI F ior. N CI N 267 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+Fi]' HPLC method OH 0 lb-123 N N 1.11 605 A CI 40 ' -017 CI OH Chiral 0 = lb-124 N N 1.11 605 A .,õ CI F 0,... CI OH 0 N N lb-125 1j1i1.06 641 A = CI H F OH Chiral 0 = lb-126 1.06 641 A CI F glr CI 268 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method OH 0 = N N lb-127 ) 0.95 595 A CI F ci õ.. 0 \---0 OH 0 Chiral 411 N N lb-128 --A 0.95 595 A CI F %%%%% 0 \---0 CI Si N OH 0 lb-129 1.05 623 A CI F 0 0 CI ""N OH 0 Chiral N N lb-130 --A 1.05 623 A CI F õµ. CI 269 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method OH 0 = N lb-131 1.09 637 A CI F CI [ow. 0 \---0 OH Chiral 0 N N lb-132 1.09 637 A CI F CI OH 0 4111 N N lb-133 0.86 657 A CI C I 0 sS- OH 0 Chiral = N N lb-134 0.86 657 A CI F CI 270 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method OH 0 N N lb-135 ) 1.14 619 A CI F 400.. ci N N-Ob OH Chiral 0 = N N lb-136 1.14 619 A CI F CI *Es" OH 0 = lb-137 1.19 633 A CI F N-ct CI OH Chiral 0 N N lb-138 1.19 633 A z CI F 0õõ. CI 271 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+111- HPLC method OH 0 = 14,z,,N-1 lb-139 1.09 671 A CI 411 F ors. N 0 CI OH Chiral 0 4110 NsyN-1 lb-140 1.09 671 A CI * F N 0 CI OH Chiral 0 lb-141 41!N 1.09 671 A CI F r&sõõ, C) -" CI IW N OH 0 = 0 N N )lb-142 1.08 671 A CI F 0 CI N 272 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method OH Chiral 0 0 N N lb-143 ossl 1.08 671 A CI F 0 CI OH 0 = lb-144 \o 1.12 671 A CI F N 0 CI OH Chiral 0 lb-145 1.12 671 A ) CI N 110 0 CI OH 0 N;vN--1 lb-146 1.09 633 A F F CI F 0 273 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+111- HPLC method OH Chiral 0 lb-147 ..,;(N-1 1.09 633 A F F CI 0 CIF I*1 N OH 0 = Ny,N--157AN lb-148 1.03 642 A .0=4 CI 0 CI OH 0 N,µ,Ny õN lb-149 1.03 642 A CI F N 0 CI N Chiral OH 0 N lb-150 , \,1 'L15 607 A CI F rah 0 ci 111111":"'N 274 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method OH Chiral 0 lb-151 1.15 607 A CI ciF 0 OH 0 = N N lb-152 0.97 582 A CI F 0õ.. 14 Chiral OH 0 lb-153 0.97 582 A CI N 0 OH N N lb-154 1.03 591 A CI IOr" Ci> C 275 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method 0 Chiral OH = = N lb-155 Y. 1.05 591 A CI F Chiral OH 41 0 N N lb-156 0.97 591 A CI F 0õ.. CI Chiral OH O 0¨ lb-157 NN 1.09 621 A CI F *I" CI OH F Chiral O 0¨eF = N N lb-158 1.16 675 A ) CI F *I 0 CI 276 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+111- HPLC method OH Chiral 0 N lb-159 1.08 605 A CI OH Chiral 0 N N lb-160 1.05 605 A .%4 CI F S õ.. CI OH Chiral 0 = lb-161 N N ^-1 1.08 619 A CI lerw 0 CI OH Chiral 0 lb-162 1.14 633 A õss Cl F If" 0 1)111. CI 277 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method OH F Chiral 0 = lb-163 1 1.05 609 A CI 0 CI oFiF 0 = Chiral N lb-164 1.12 659 A CI CI 0 OH lb-165 N N 1.11 631 A CI F CIsõ.. N 0 H Chiral O lb-166 N N 1.11 631 A CI F WC" 0 110., CI 278 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method 0 OH lb-167 1.11 633 A CI = 0 Chiral OH lb-168 N N ) 1.11 633 A CI F *0" 0 OH lb-169 N N 1.05 605 A CI -0)>. CI 279 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+1- 1]+ HPLC method 0 Chiral OH = lb-170 1.05 605 A CI F* Nc---))> CI OH 0 lb-171 **`\ õ 1\4 1.02 592 A CI I 0 CI N OH Chiral 0 = lb-172 1.02 592 A /\I CI F 1, 00 0 CI N N OH 0 NN-1 0 lb-173 1.08 672 A CI F õs. No CI N N 280 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method OH Chiral 0 fik N lb-174 1.08 672 A CI F No CI N N 0 OH #111 lb-175 1.08 577 A _ CI F caõ, 0 CI Chiral 0 OH lb-176 1.01 577 A s. CI F VI".. 0 CI Chiral 0 OH N\ lb-177 N 1.01 577 A CI CI 281 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+1-1]+ HPLC method 0 OH lb-178 0.99 577 A CI F ci= 0 Chiral * OH Nt-N lb-179 - , 0.99 577 A CI N 0 CI 0 Chiral OH N\ lb-180 N 0.99 577 A CI 0 OH * Nt-N lb-181 1.13 657 A CI s F CI 282 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure fret [min] [M+Fi]' HPLC method Chiral OH 0 0 0 N....-N lb-182 1.13 657 A E > Ci '. 411 N ci N 0 H O OH 01 ...,N lb-183 14- 1.05 657 A CI I N F sr. C H O OH Chiral 4 Nt-N lb-184 1.05 657 A CI CI H O OH Chiral * N\ N lb-185 1.05 657 A F N \ CI -0 N 441 H 0 283 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method 0 OH N lb-186 1.08 657 A CI O¨ F 0 Or" CI 0 OH Chiral N lb-187 1.08 657 A CI O¨ F 0 SI" CI Chiral o OH lb-188 1.05 591 A CI "" 0 . CI 0 OH lb-189 N N 1.01 591 A E CI F CI 284 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method Chiral 0 OH Nt-N lb-190 1.02 591 A CI F 0õ, CI 0 OH N lb-191 E ) 0.99 565 A CI F N-4;\ CI N Chiral o OH lb-192 E 0.99 565 A CI F CI 0 OH F F lb-193 NtN 1.03 645 A Cl F "r" CI 285 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+Fi]' HPLC method F 0 OH Chiral F F N' lb-194 1.03 645 A µõ CI F lir" 0 Cl OH F 0 1µ..N lb-195 1.08 645 A E CI F CI N o\1> 0 Chiral OH F * F lb-196 E 1.08 645 A CI F õ.= N CI Chiral ri ¨ OH OCF3 NN lb-197 1.10 661 A CI F WY" 010,. CI 286 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method 0 OH Ntõ-N - 1.06 621 A lb-198 Br 0)> CI Chiral 0 OH 41, Nt--N lb-199 - 1 1.06 621 A Br F ioõõ CI 0 OH CI Nt-N lb-200 1.01 565 A / CI N 0 OH Chiral CI Nt-N lb-201 / E ) 1.01 565 A CI N 287 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+1- 1]+ HPLC method 0 OH N lb-202 ci ) 1.03 565 A 140 N CI Chiral 0 OH lb-203 / 1.03 565 A CI CI HO 0 lb-204 Ihi*,(1-1 Chiral 1.01 605 A CIF 0 HO 0 4,1 lb-205 N N") Chiral 1.02 605 A CI 0 CI µµ"111 288 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+11]+ HPLC method HO 0 = lb-206 N'keN") Chiral 1.01 605 A CI F ow. ci N N OH 0 NõN lb-207 NV I 1.03 606 A CI F 0 CI OH Chiral 0 N ib-208 N-"' 1.03 606 A CI F%.. 0 ci N 289 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of further compounds (lb) by amidation Experimental procedure for the synthesis of lb-209 OH N¨ O Chiral = 41, Chiral N N NH Me HATU N N DIPEA, DMF _ CI N CI õ./A 0 0 CI CI ".1s1 lb-107 lb-209 lb-107 (52 mg, 0.09 mmol) is dissolved in anhydrous DMF (1 mL) and HATU (40 mg, 0.11 mmol) is added at rt. After addition of DIPEA (44.7 pL, 0.26 mmol) the reaction mixture is allowed to stir at rt for 15 min. Methyl amine (2 M in THF, 52.6 pL, 0.11 mmol) is added and the reaction is allowed to stir for additional 30 min. The crude reaction mixture is submitted to reversed phase column chromatography yielding pure lb-209. The following compounds (lb) (table 37) are available in an analogous manner starting from intitially obtained compounds (lb). Table 37 structure tret [min] [M+H]1 HPLC method NH 0 Chiral lb-209 N N ) 1.34 604 A Cl F õ=. CI 290 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [11,1+H] HPLC method NH2 0 Chiral = lb-210 1.29 590 A CI CI N¨ O Chiral lb-211 711 1 1.39 618 A - CI 14-4 CI Chiral it lb-212 N N ) 1.36 630 A CI 291 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method HDLOH 0 Chiral = lb-213 N N 1.32 662 A CI CI H_OH c 0 OH Chiral lb-214 N N 1.22 664 A CI F Iwo 0 CI OH 0 Chiral = lb-215 N N 1.25 634 A CI CI 292 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [11,1+Fi] HPLC method H N--\ 0 Chiral 41, lb-216 NeN---x 1.34 648 A CI CI N H H_CO\ N 0 Chiral = lb-217 N,,õ,N--1 1.38 692 A CI CI N H OH N 0 .--..-OH Chiral it lb-218 N, N- Y. -) 1.23 694 A CI CI N H 293 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [11,1+Fi] HPLC method 0 \¨\ 0- Chiral = lb-219 N 1.37 692 A ssõ CI F ow. CI 0 Chiral = lb-220 N 1.35 660 A CI CI (-14 0 Chiral I lb-221 1.34 673 A N) sss, CI CI 294 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [11,1+Fi] HPLC method N¨\--NH2 0 Chiral 41k lb-222 1.35 633 A CI F CI N / \¨N 0 Chiral = lb-223 N 1.37 661 A CI F twf". 0 CI H 0 o Chiral = 0 lb-224 N "`-µ 1.29 596 A CI CI 295 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method -ACO 0 Chiral = lb-225 N N 1.34 660 A CI IF 14-\ C H 0 Chiral lb-226 1.34 674 A N N CI F *,... 0 CI OH Chiral c....õS 0 lb-227 1.26 646 A N N CI F 0 CI 296 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [11,1+Fi] HPLC method HN- 0 Chiral = lb-228 N N 1.33 659 A CI 0 cl HO HNZ\O 0 Chiral = lb-229 1.27 676 A N N CI F NI(s;)>. CI HO, N- O Chiral lb-230 N N 1.34 620 A CI F [ow 0 CI 297 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [11,1+Fi] HPLC method HO NH 0 Chiral lb-231 N N 1.28 606 A CI F CI NH2 0 Chiral lb-232 N N 1.32 592 A - CI F õ.. CI N¨ O Chiral lb-233 N N 1.36 606 A CI ooss 0 CI NH 0 20-- Chiral lb-234 1.34 620 A CI CI 298 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [1111+H] HPLC method NH 0 0¨ Chiral = lb-235 N N 1.38 634 A CI CI N¨ O ¨ Chiral = lb-236 N N 1.40 648 A CI F N NH 0 Chiral 410 lb-237 N ) 1.34 618 A Cl F 1110' CI 0 NH2 Chiral N N lb-238 1.27 590 A CI F 0 CI IP; 299 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method 0 NH2 Chiral 4 Nt--N lb-239 s 1.25 576 A CI CI N H H 0 N Chiral 411 Nt¨N lb-240 1.29 590 A s> Ci F CI N H 0 NH2 * Nt¨N 0 lb-241 E ) * 1.36 656 A CI F is õ,. N 0 CI N H 0 NH2 Chiral 4 lb-242 1.36 656 A Nt--N 0 \ F N 0 CI LIV "'IV H 300 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [11,1+H] HPLC method 0 NH2 Chiral N\ N 0 lb-243 1.36 656 A 11111,õõ CI N CI N- 0 OH Chiral lb-244 N.,0 1.33 672 A CI µss 4111 F sµ= 0 Cl II N Synthesis of further compounds (lb) by ester reduction Experimental procedure for the synthesis of lb-245 0¨ OH 0 Red-Al N N ,s3 - c CI F , F 0 CI CI lb-3 lb-245 lb-3 (30 mg, 0.05 mmol) is dissolved in anhydrous toluene (1 mL) and a solution of Red-Al (60 % in toluene, 48 pL) is added. The reaction mixture is heated to 90 C for 16 h. After that period of time, additional Red-Al (24 pL) is added and heating is continued for 1 h. The reaction is quenched by the addition of water and extracted with Et0Ac. The organic layer is dried with MgSO4 and solvents are removed under reduced pressure. Reversed 301 Date Recue/Date Received 2023-03-01 CA 3,000,063 phase column chromatography gives pure lb-245. The following compounds (lb) (table 38) are available in an analogous manner starting from initially obtained compounds (lb). Table 38 structure tret [min] [M+H] HPLC method OH = ib-245 N zNThz 1.38 577 A Cl N CI OH Chiral lb-246 N 1.38 577 A Cl 0 CI Synthesis of further compounds (lb) by deacylation Experimental procedure for the synthesis of lb-247 0 )-- H2N HN = HCI, Me0H N) - CI õ 0 0 CI ci N lb-59 lb-247 302 Date Recue/Date Received 2023-03-01 CA 3,000,063 lb-59 (55 mg, 0.09 mmol) is dissolved in Me0H (500 pL) and conc. aq. HCI (37 %, 40 pL) is added. The reaction mixture is heated to 65 C for 3 h. The reaction is quenched by the addition of 4 M NaOH and Et0Ac. The phases are separated and the organic phase is dried with MgSO4. After removal of the solvents under reduced pressure, reversed phase column chromatography gives lb-247. The following compounds (lb) (table 39) are available in an analogous manner starting from initially obtained compounds (lb). Table 39 structure tret [min] [M+H] HPLC method H2N = 1-247 I ri 1.35 562 A - CI CI H2N Chiral 41k 1-248 I t35 562 A S. = CI N):). 0 CI 1.0 303 Date Recue/Date Received 2023-03-01 CA 3,000,063 Synthesis of further compounds (lb) by reductive amination Experimental procedure for the synthesis of lb-249 H2N (J= r) NaBH(OAc)3 N N - CI "õ CI 0 CI N 0 CI lb-247 lb-249 Glutyraldehyde (25 % in water, 20 pL, 0.055 mmol) is dissolved in DMF (600 pL) and lb-247 ( 10 mg, 0.018 mmol) is added as a solution in DMF (400 pL). The reaction mixture is treated with AcOH (5.1 pL, 0.05 mmol) and stirred at rt for 15 min. After that period of time, sodium triacetoxyborohydride (11.3 mg, 0.05 mmol) is added in one portion and the reaction mixture is allowed to stir at ambient temperature for 2 h. The reaction is quenched by the addition of water, filtered through syringe filter and purified by reversed phase column to chromatography to give lb-249. The following compounds (lb) (Table 40) are available in an analogous manner starting from different compounds (Ib). Table 40 structure tret [min] [M+H] HPLC method lb-249 N N 1.64 630 A Cl 0 CI 304 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+H] HPLC method Chiral Q1 lb-250 1.64 630 A -71 CI F 0.= CI ¨N N N lb-251 1.35 562 A CI CI10 ¨N N N lb-252 1.35 562 A CI F N-(;): CI 305 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of further compounds (lb) by amine cleavage Experimental procedure for the synthesis of lb-253 H2N = CI CI F 40 ..... 0 CI CI l lb-247 b-253 lb-247 (12 mg, 0.021 mmol) is added to a mixture of hypophosphorous acid (50 % in water, 300 pL, 2.7 mmol), sulfuric acid (15 pL, 0.26 mmol), and copper(I1)sulfate (3.75 mg, 0.023 mmol). The reaction mixture is stirred at rt for 5 min before sodium nitrite (6 mg, 0.085 mmol) and a couple of drops of water are added. The reaction is allowed to stir for 5 min. After quenching by the addition of diluted NaOH and extraction with Et0Ac, phases are separated and the organic phase is dried with MgSO4. Solvents are removed under reduced pressure and reversed phase column chromatography yields pure lb-253. The following compounds (lb) (table 41) are available in an analogous manner starting from initially obtained compounds (lb). Table 41 structure tret [min] [M+H] HPLC method lb-253 1.51 547 A Cl F 0 CI 306 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method Chiral . N N lb-254 .,,s1 1.51 547 A CI F N CI N H Compounds (lc) General reaction scheme and summary of the synthesis route Scheme 6 ,......_-....õ I) L R2 ,.....(1R3 (R4)r (R.. 4) (R4)r N(Boc)2 C-3 1 \--A-) µ--A-) C-2 N ' N TFA N' N N.-D __________________________________________________________ 110R3 _.). j_c_f\_ R ¨ method A method B )n H2N )11 R2 N(B002 R2 NH2 C-1 C-4 C-5 0 eT'l (127)q-il- V method C N H S-1 (R4)r (RI), 1C-D IT N N optional \-.....:J\ \,......- .1.4\ derivatisation steps Rt i (.= )11 R.1 j-= )11 method D (in RI to N....R1 ,y NH X T especially R4) ,R7, twx. v "q . N w N H H (lc) C-6 Novel compounds of structure (lc) can be prepared stepwise with a synthesis route depicted in scheme 6 starting from (hetero)aryl amines C-1 via a copper-catalyzed three- component coupling reaction with protected alkynylamines C-2 (e.g. bis- or mono-Boc protected) and 307 Date Regue/Date Received 2023-03-01 CA 3,000,063 an 0,13-unsaturated aldehyde C-3 to build up imidazo ring systems (e.g. imidazopyrimidyl) C-4 (Angew. Chem. mt. Ed. 2010, 49, 2743). The protecting group(s) on C-4 can be removed by an appropriate method. In case of mono- or di-Boc protection acidic conditions, like TFA in dioxane, can be used to generate intermediate C-5. Intermediates C- 6 can be obtained from intermediates C-5 and isatin derivatives S-1 via a 1,3-dipolar cycloaddition to build up spiro systems as a racemic mixture potentially along with other regio- and/or diastereoisomers of C-6. The enantiomers of C-6 can be separated at this stage by chiral SFC or alternatively the racemic mixture can be separated at any later stage of the synthesis. Also all other means known for separation of enantiomers can be applied here or after any later synthetic step herein described, e.g. crystallisation, chiral resolution, chiral HPLC etc. (see also Enantiomers, racemates, and resolutions, Jean Jacques, Andre Collet, Samuel H Wilen John Wiley and Sons, NY, 1981). C-6 can be reacted with aldehydes or ketones in a reductive amination reaction to yield compounds (lc). Alternatively, an alkylation, addition, acylation or sulfonylation reaction can be performed with C-6 to obtain additional compounds (lc). Compounds (lc) which are initially obtained from C-6 can be derivatized in optional derivatization steps not explicitly depicted in the schemes in all residues, especially in R4, if they carry functional groups, that can be further modified such as e.g. halogen atoms, amino and hydroxy groups (including cyclic amines), carboxylic acid or ester functions, nitrils etc. to further compounds (lc) by well-established organic chemical transformations such as metal-catalyzed cross coupling reactions, acylation, amidation, addition, reduction or (reductive) alkylation or cleavage of protecting groups. These additional steps are not depicted in the general schemes. Likewise, it is also possible to include these additional steps in the synthetic routes depicted in the general schemes, i.e. to carry out derivatization reactions with intermediate compounds. In addition, it may also be possible that building blocks bearing protecting groups are used, i.e. further steps for deprotection are necessary. Compounds (lc) have been tested for their activity to affect MDM2-p53 interaction in their racemic form or alternatively as the enantiopure form. Each of the two enantiomers of a racemic mixture may have activity against MDM2 although with a different binding mode. Enantiopure compounds are marked with the label "Chiral". Compounds listed in any table below that are labeled "Chiral" (both intermediates as well as compounds (lc) according to the invention) can be separated by chiral SFC chromatography from their enantiomer or are synthesized from enantiopure starting material which is separated by chiral SFC. 308 Date Recue/Date Received 2023-03-01 CA 3,000,063 Example: OH OH OH 0.... 0.... Od... Chiral Chiral N .?==-i Ikkre N/ = 01 1:-. so CI CI ci 4111,õ,, I F F rõ,. Ns-\ F . N C IW/. " -(.3; H H H A B C Structure A defines the racemic mixture of compounds with structure B and C, i.e. structure A encompasses two structures (compounds B and C), whereas structures B and C, respectively, are enantiopure and only define one specific compound. Thus, formulae (lc) and (lc*) (R.% (FM N-p-) A N Chiral N/ :..- \e.--,...1\ R3. 3 On (117)q lc _ V (117)g ll V N ifir N H H (lc) (le) with a set of specific definitions for groups R1 to R7, A, V, W, X, Y, n, r and q represent the racemic mixture of two enantiomers (4 (lc); structure A above is one specific example of such a racemic mixture) or a single enantiomer (4 (IC*); structure B above is one specific enantiomer), unless there are additional stereocenters present in one or more of the substituents. The same definition applies to synthetic intermediates. 309 Date Recue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates C-3 Experimental procedure for the synthesis of C-3a . ry 0 ,0 cc 0 F DMF CI N C14I I N D-la C-3a 2-Chloro-3-fluoro-pyridine-4-carbaldehyde D-la (1.00 g, 6.27 mmol) and (triphenylphos- phoranylidene)acetaldehyde (1.91 g, 6.27 mmol) are dissolved in DMF and stirred at rt for 16 h. The mixture is poured into ice-water and the precipitate is filtered. The crude product is purified by chromatography to deliver intermediate C-3a. The following intermediates C-3a (table 42) are available in an analogous manner starting from different aldehydes D-1. Table 42 # structure tret [min] [M+Fi] HPLC method 0 / C-3a F I ....rS 0.45 185 C Cl N 310 Date Recue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates C-4 Experimental procedure for the synthesis of C-4a (method A) CI F BocN14.1 C-2a I "b = N toluene H2N N F ¨ C-la NHBoc C-4a 2-Amino-isonicotinic acid methyl ester C-la (1.00 g, 6.572 mmol), N-Boc prop-2- ynylamine C-2a (1.12 g, 7.230 mmol), E-3-(3-chloro-2-fluorophenyl) propenal C-3b (1.34g, 7.23 mmol), Cu(0Tf)2(0.24 g, 0.66 mmol) and CuCI (0.06 g, 0.07 mmol) are dissolved in toluene under argon and stirred at 100 C for 20 h. The solvent is removed under vacuum and the crude product is purified by chromatography to deliver intermediate C-4a. The following intermediates C-4 (table 43) are available in an analogous manner starting from different intermediates C-1, C-2 and C-3. Table 43 structure It [min] [M+H] HPLC method olke C-4a N 1.41 474 A F ¨ CI NHBoc 311 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+H] HPLC method kelD C-4b / N 1.52 488 A F - CI II NIABoc I Or( C-4c LNj 0.87 589 C F - CI 41 NHBcoc C-4d = N 0.89 575 C F - CI \ / ...e N(Boc)2 I dq:r1 CI-Fd- N(Boc)2 \ i 312 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates C-5 Experimental procedure for the synthesis of C-5a (method B) (Leo N N TFA, 1,4-dioxane F F ¨ NHBoc NH2 C-4a C-5a Intermediate C-4a (1.00 g, 1.372 mmol) is dissolved in 1,4-dioxane and stirred at rt for 3 h.The solvent is removed under vacuum and the crude product is purified by chromatography if necessary to deliver intermediate C-5a. The following intermediates C-5 (table 44) are available in an analogous manner starting from different intermediates C-4. Table 44 structure tret [min] [M+Fi] HPLC method = C-5a N 1.16 374 A F ¨ Cl = NH2 C-5b N 1.29 388 A F ¨ CI = NH2 313 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure tret [min] [M+11]+ HPLC method (!) C-5c N 0.46 388 F - CI II NH2 (!) C-5d N 1.01 375 A F - CI NH2 \ (!kr0 C-5e _Rs)/ t12 389 A F CI NH2 \ (!) C-5f 1.06 389 A NH2 314 Date Regue/Date Received 2023-03-01 CA 3,000,063 Synthesis of intermediates C-6 Experimental procedure for the synthesis of C-6a (method C) = 1; jr13 CI * S-la _____________________________________________ CI N = Me0H = F ¨ NH I* 00 CI NH2 0 CI C-5a C-6a A solution of intermediate C-5a (735 mg, 1.792 mmol), 6-chloroisatin S-1 a (813 mg, 4.479 mmol) and N-methylpyrrolidine (763 mg. 8.958 mmol) in Me0H (30 mL) is heated under microwave irradiation at 120 C for 20 min. The reaction mixture is diluted with DCM and extracted with a saturated aqueous NaHCO3 solution. The organic layer is separated and the solvents are removed under vacuum and the resulting crude product is purified by chromatography and reversed phase HPLC to deliver intermediate C-6a. The following intermediates C-6 (table 45) are available in an analogous manner starting from different intermediates C-5 and S-1. Table 45 tret HPLC structure [M+Hr [min] method o )/ Ni'N Cl C-6a I 0.677 537 N 00 0 Cl H 315 Date Recue/Date Received 2023-03-01 CA 3,000,063 tret HPLC 11+ [min] method o,0- Chiral / 1 1 N CI 14, a C-6b F e \ 0.677 537 C 4 ' NH 140 o 0 CI N H 7f,1 0-.. .1 143 CI FN C-6c n.a. n.a. - 4 i ...., NH 0 00 0 CI N H co, Chiral 01:03. Id/ 1 ci FN\.... C-6d n.a. n.a. - 4 g ? NH VI 0 CI N H 316 Date Regue/Date Received 2023-03-01 CA 3,000,063 tret HPLC structure [M+11+ [min] method N`rkl) CI C-6e F Vr," n.a. n.a. = N oo H 0 CI 0, Chiral ci C-6f FN&n.a. n.a. NH 0 CI 071. Ci FN C-6g 1.17 538 A N' = NH 00 0 CI 0 0,- Chiral N CI Frkivo.. C-6h 1.17 538 A NH " 0 CI 317 Date Recue/Date Received 2023-03-01 CA 3,000,063 tret HPLC structure [min] Ln.....j+ method 14) CI C-61 1.23 552 A N NH calo0 CI Chiral ci C-6j 1.23 552 A N' 41' NH ts 0 CI " io- CI FN C-6k 1.23 552 A N \ s% NH 0 CI 318 Date Recue/Date Received 2023-03-01 CA 3,000,063 tret HPLC structure [M+Hr [min] method Chiral Cl FNve_r. C-61 1.23 552 A N'\ NH to 0 CI Synthesis of compounds (lc) according to the invention Experimental procedure for the synthesis of lc-1 (method D) 0 I 0 0/Th / N C F CI F * 2 AcOH * NH , ow. lOr 0 0 CI N CI C-6a To a solution of cyclopropanecarbaldehyde (2.7 mg, 0.039 mmol) in AcOH (1 mL) is added intermediate C-6a (18 mg, 0.033 mmol) and the reaction mixture is stirred for 15 min. Sodium triacetoxyborohydride (14.2 g, 0.065 mmol) is added and the reaction mixture is stirred overnight. Water is added to the reaction mixture and it is extracted with Et0Ac. The combined organic layer is dried (MgSO4), filtered, concentrated in vacuo and the crude product is purified by chromatography to give compound lc-1. The following compounds (lc) (table 46) are available in an analogous manner starting from different intermediates C-6 and different aldehydes. 319 Date Recue/Date Received 2023-03-01 CA 3,000,063 Table 46 # structure tret [M+H] HPLC [min] method _ 0... 0).1 Cl F file lc-1 1.50 1.50 A 4 -1 ' soõõ IcA 0 CI N H 0 1:) Chiral / 1 ....) / N CI IsINee. F -- lc-2 1.50 1.50 A 4 z e ...., NA Cl 0 N H ,-. 0... ::)...1 /N 3 Cl F.-rdN- lc-3 n.a. n.a. - . I .. , N,%.....A 40/ 0 0 CI N H 320 Date Recue/Date Received 2023-03-01 CA 3,000,063 tret HPLC # structure [M+Hr [min] method _ _01..0.: Chiral --Q CI N lc-4 F n.a. n.a. - 4 i , Nel Out 0 CI N H 00.... 7.....( 3 CI 141,... F=-- lc-5 n.a. n.a. - 4 - .!* N4e:\ [00 CI 0 N H OI....z Chiral NO CI F 1-, lc-6 n.a. n.a. - *I ot 0 CI N H ...i r., 0.... ..1 I-14) mift lc-7 CI r \ 1.44. 592 A N ' \ " Ne6t 0 CI [*I N H 321 Date Recue/Date Received 2023-03-01 CA 3,000,063 tret HPLC # structure [M+H] [min] method _ 01...../01--.. Chiral 1"-N3 C! FN õ lc-8 1.44. 592 A N \ /,I4Oi 0 CI N 0 H -IN) CI FIsIver\ lc-9 1.44 592 A Ik e \ 1 .% (00 0 0 CI N H cs Chiral .71.1 --%) CI N Ic-10 1.44 592 A N5 - 11016 µ..,,... IklµA 0 CI N H /-1413 Cij:1% ic-i I ma. n.a. - 0 o 0 CI N H 322 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [M+11] HPLC [min] method _ %. 00 Chiral / 1 1 N CFr= Ic-12 n.a. n.a. - N6# \ I e , Neel 0 0 0 CI N H 0, .C!)....,. ¨..14 CI ra,õ.. Ic-13 FNv 1.57 686 A N# \ 1 * N * I 0 I( Cl N H 0, 0 IdChiral ci FN\... Ic-14 1.57 686 A N# \ 1 e , N * AK c, H Synthesis of further compounds (lc) by ester saponification Experimental procedure for the synthesis of Ic-15 (method E) 323 Date Recue/Date Received 2023-03-01 CA 3,000,063 1/ 0 HO / N CI CI Nr( \ NaOH ; *00 0 0 CI CI Ic-15 lc-1 (12 mg, 0.022 mmol) is dissolved in THF (0.5 mL) and water (1 mL) and NaOH s (25 mg, 0.45 mmol) is added. The reaction mixture is stirred at 70 C for 8 h. After acidification with 2 M aq. HCI and extraction with Et0Ac the organic phase is dried with MgSO4. Purification with reversed phase HPLC leads to pure Ic-15. The following compounds (lc) (table 47) are available in an analogous manner starting from initially obtained compounds (lc). Table 47 structure It [min] [M+Fi]' HPLC method OH CI Ni-'1413 Nr-o"\ Ic-15 F 577 1.05 A * 01 0 CI 14 324 Date Regue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+Fi]' HPLC method 13?10H Chiral N, N CI Ic-16 F \577 1.05 A 41 0 CI OH CI Ic-17 n.a. n.a. *N4A 0 CI N 0 OH Chiral =-=.b CI Ic-18 n.a. n.a. /41µ..a 0 CI N OH / N CI F\ \Ic-19 n.a. n.a. 3 0 CI 325 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [MA- Fi]1 HPLC method ..... 0?, H Chiral / 1 N lc-20 CI FN/ )...ir n.a. n.a. - 4 3 s, , isLA 110 0 0 CI N H " OH .., 7...1 il%1) CI FrsIvs 1c-21 N n.a. n.a. - / µ I s% , N.A 0 0 CI N H .....) 0, H Chiral / \ / N ci FNNA 1c-22 n.a. n.a. - N 10 Ot 0 CI N H OH Cita.FINVor 0.99 592 A 1c-23 N' \ I 4, ...., 0 o 0 CI N H 326 Date Recue/Date Received 2023-03-01 CA 3,000,063 # structure tret [min] [M+11]+ HPLC method 0 OH Chiral ---..b Cit(F.:1\ lc-24 0.99 592 A -- NJ' I " 0 ci [W N H OH 7./.....( ci Ic-25 n.a. n.a. - N - .% , N46t 0 0 0 CI N H 0 OH Chiral NNA1c-26 n.a. n.a. - N' \ F ci 1 e 0 CI N H OH C.:,:...? FNNrs. Ic-27 CI 1.06 672 A le \ 3 1 0 ?s, a W'l N H 327 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method OH Chiral 0:4N1 Ci FNV!\ lc-28 1.06 672 A N \ 0 N 0 0 CI Synthesis of further compounds (lc) by amidation Experimental procedure for the synthesis of Ic-29 (method F) 0 0 N /NH N CI F N CI \ 5 HATU N \ 0 CI 0 cl lc-23 lc-29 lc-23 (7 mg, 0.012 mmol) is dissolved in anhydrous THF (1 mL) and HATU (5 mg, 0.05 mmol) is added at rt. After addition of DIPEA (5 mg, 0.05 mmol) the reaction mixture is allowed to stir at rt for 15 min. Dimethylamine (4 mg, 0.035 mmol) is added and the reaction is allowed to stir for additional 60 min. The crude reaction mixture is submitted to reversed phase column chromatography yielding pure lc-29. The following compounds (lc) (table 48) are available in an analogous manner starting from intitially obtained compounds (IC). 328 Date Recue/Date Received 2023-03-01 CA 3,000,063 Table 48 structure tret [min] [M+Fi]4 HPLC method 7I,L lc-29 CI Fr=Ive, 1.30 619 A = 0 0 C I Chiral _001i lc-30 CI FN\.. 1.30 619 A \ " soo 0 Cl CO 0 lc-31 Cl FN 0.63 646 N?r4A Cl N 329 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+Fi]' HPLC method rip 0 NJ Chiral Ic-32 CI FNA 0.63 646 ' N,I A , 0 CI ?ID Ic-33 CI FN 0/0 644 kN IsLA 0 CI Chiral 0112,,l() hil`/%1 Ic-34 CIFits 0.70 644 N,A N 0 CI 330 Date Regue/Date Received 2023-03-01 CA 3,000,063 # structure fret [min] [M+Fi]' HPLC method 00 .,,.b m, N Ic-35 CI F¨Vs% 1.45 659 A IV/ \ I 4. õ NAel 01" 0 CI N H 0 Chiral ,b Ic-36 Ci FN 1A5 659 A N' \ i ? 0 CI N H Ic-37 CI Fislµ 1.29 661 A N \5 ; s 0 0 t..... 0 CI N H 331 Date Recue/Date Received 2023-03-01 CA 3,000,063 structure fret [min] [M+H]' HPLC method aChiral _ ==-=,/ lc-38 Ct,61 N I 1.29 661 A N3 0 CI The following Examples describe the biological activity of the compounds according to the invention, without restricting the invention to these Examples. Compounds of formulae (I), (la), (lb), (lc), (1a*), (1b*) and (lc*) are characterised by their 5 many possible applications in the therapeutic field. Particular mention should be made of those applications in which the inhibiting effect on the proliferation of cultivated human tumour cells but also on the proliferation of other cells such as endothelial cells, for example, are involved. Mdm2-p53 inhibition AlphaScreen 10 This assay is used to determine whether the compounds inhibit the p53- MDM2 interaction and thus restore p53 function. pL of compound in 20 % DMSO (serial pre-dilutions of compound are done in 100 % DMSO) is pipetted to the wells of a white OptiPlate-96 (PerkinElmer). A mix consisting of nM GST-MDM2 protein (aa 23-117) and 20 nM biotinylated p53 wt peptide 15 (encompassing aa 16-27 of wt human p53, amino acid sequence QETFSDLWKLLP- Ttds- Lys-Biotin, molecular weight 2132.56 g/mol) is prepared in assay buffer (50 mM Tris/HCI pH 7.2; 120 mM NaCI; 0.1 % bovine serum albumin (BSA); 5 mM dithiothreitol (DTT); 1 mM ethylenediaminetetraacetic acid (EDTA); 0.01 % Tween 20). 30 pL of the mix is added to the compound dilutions and incubated for 15 min at rt while gently shaking the plate at 20 300 rounds per minute (rpm). Subsequently, 15 pL of premixed AlphaLISA Glutathione Acceptor Beads and AlphaScreen Streptavidin Donor Beads from PerkinElmer (in assay buffer at a concentration of 10 pg/mL each) are added and the samples are incubated for min at rt in the dark (shaking 300 rpm). Afterwards, the signal is measured in a 332 Date Recue/Date Received 2023-03-01 CA 3,000,063 PerkinElmer Envision HTS Multilabel Reader using the AlphaScreen protocol from PerkinElmer. Each plate contains negative controls where biotinylated p53-peptide and GST- MDM2 are left out and replaced by assay buffer. Negative control values are entered as low basis value when using the software GraphPad Prism for calculations. Furthermore, a positive control (5 % DMSO instead of test compound; with protein/peptide mix) is pipetted. Determination of IC50 values are carried out using GraphPad Prism 3.03 software (or updates thereof). Table 49 shows the IC50 values of example compounds determined using the above assay. Table 49 IC50 MDM2 IC50 MDM2 # # [nhol] [nhol] la-20 23 lb-108 79 la-25 2 lb-109 8 . la-26 4 lb-110 3 la-27 2 lb-111 7 la-29 2 lb-113 4 la-30 2 lb-115 7 la-31 3 lb-117 8 la-32 2 lb-119 12 la-33 3 lb-121 11 la-34 2 lb-123 4 la-35 2 lb-125 14 la-36 5 lb-127 11 la-38 2 lb-129 10 la-39 4 lb-131 22 la-40 2 lb-133 58 la-41 3 lb-135 15 la-43 2 lb-137 34 la-46 8 lb-139 4 la-47 9 lb-140 2 la-48 10 lb-141 48 la-49 6 lb-142 3 . la-50 4 lb-144 8 la-51 7 lb-146 11 la-52 69 lb-148 21 la-53 7 lb-150 20 la-54 13 lb-152 7 la-55 6 lb-154 3 _ la-56 5 lb-155 2 la-57 13 lb-156 5 lb-49 5 lb-157 2 . lb-57 12 lb-158 3 lb-58 7 lb-159 7 - lb-59 15 lb-160 4 lb-66 166 lb-161 11 lb-106 3 lb-162 6 lb-107 2 lb-163 2 333 Date Regue/Date Received 2023-03-01 CA 3,000,063 IC50 MDM2 IC50 MDM2 # # [nM] [nM] lb-164 3 lb-217 4 lb-165 28 lb-218 6 lb-167 22 lb-219 5 lb-169 7 lb-220 10 lb-171 10 lb-221 10 lb-173 7 lb-222 9 lb-175 3 lb-223 5 lb-176 2 lb-224 4 lb-177 53 lb-225 5 lb-178 4 lb-226 5 lb-179 2 lb-227 4 lb-180 83 lb-228 5 lb-183 3 lb-229 4 lb-184 2 lb-230 10 lb-185 14 lb-231 4 lb-186 4 lb-232 3 lb-188 3 lb-233 4 lb-189 3 lb-234 2 lb-190 2 lb-235 3 lb-191 6 lb-236 5 lb-193 3 lb-237 10 lb-195 6 lb-238 6 lb-197 2 lb-239 3 lb-198 4 lb-240 3 lb-200 3 lb-241 4 lb-202 7 lb-242 2 lb-204 2 lb-243 99 lb-205 3 lb-244 3 lb-206 4 lb-245 20 lb-207 8 lb-247 27 lb-209 3 lb-249 240 lb-210 4 lb-251 68 lb-211 11 lb-253 72 lb-212 5 lc-23 6 lb-213 7 lc-27 13 lb-214 3 lc-29 10 lb-215 4 . lc-35 10 lb-216 7 lc-37 10 Cell Proliferation Assays Cell Titer Glo assay for e.g. SJSA-1, SKOV-3, RS4-11 and KG-1 cells: SJSA-1 cells (Osteosarcoma, wild-type p53, ATCC CRL-2098TM) are seeded in duplicates at day 1 in flat bottom 96 well microtiter plates (white Packard View Plate 96 well Cat. No. 6005181) in 90 pL RPMI medium, 10% fetal calf serum (FCS, from e.g. JRH Biosciences #12103-500M, Lot: 3N0207) at a density of 2500 cells/well. Any other luminescence 334 Date Recue/Date Received 2023-03-01 CA 3,000,063 compatible plate format is possible. Similarly, p53 mutant SKOV-3 cells (ovarian adenocarcinoma, ATCC HTB-77Tm) are seeded in duplicates in flat bottom 96 well microtiter plates in 90 pL McCoy medium, 10 % FCS at a density of 3000 cells/well. At day 2, 5 pL dilutions of the test compounds covering a concentration range between app. 0.6 and 50000 nM are added to the cells. Cells are incubated for three days in a humidified, CO2-controlled incubator at 37 C. wildtype p53 RS4-11 cells (acute lymphoblastic leukemia, ATCC CRL-18731m): Day 1: RS4-11 cells are seeded in flat bottom 96 well microtiter plates (white Packard View Plate 96 well Cat. No. 6005181) in 90 pL RPM' medium, 10 % fetal calf serum (FCS, from e.g. JRH Biosciences #12103-500M, Lot.: 3N0207) at a density of 5000 cells/well. Any other luminescence compatible plate format is possible. Day 2: 5 pL dilutions of the test compounds covering a concentration range between app. 0.3 and 25000 nM (alternative dilution schemes are possible) are added to the cells. Cells are incubated for three days in a humidified, CO2 controlled incubator at 37 C. The final DMSO-concentration is 0.5%. p53 mutant KG-1 cells (acute myelogenous leukemia, ATCC CCL-246): Day 1: KG-1 cells harboring a p53 mutation at the exon 6/intron 6 splice donor site are seeded in flat bottom 96 well microtiter plates (white Packard View Plate 96 well Cat. No. 6005181) in 90 pL IMDM medium, 10 % FCS (JRH Biosciences #12103-500M, Lot.: 3N0207) at a density of 10000 cells/well. Any other luminescence compatible plate format is possible. Day 2: 5 pL dilutions of the test compounds covering a concentration range between app. 0.3 and 25000 nM (alternative dilution schemes are possible) are added to the cells. Cells are incubated for three days in a humidified, CO2 controlled incubator at 37 C. The final DMSO-concentration is 0.5 %. Evaluation of all Cell Titer Glo assays is done at day 5 after seeding. At day 5, 95 pL of Cell Titer Glo reagent (Cell titer Glo Luminescent Cat. No. G7571, Promega) are added to each well and incubated for additional 10 min at rt (with agitation). Luminescence is measured on a Wallac Victor using standard luminescence read out. IC50 values are calculated using standard Levenburg Marquard algorithms (GraphPad Prism). In addition, several other cancer cell lines from diverse tissue origins are sensitive to 335 Date Recue/Date Received 2023-03-01 CA 3,000,063 compounds (1), (la), (lb), (lc), (1a*), (1b*) and (lc*). Examples include NCI- H460 (lung), Molp- 8 (myeloma) and MV4-11 (AML). On the basis of their biological properties the compounds of formula (1), (la), (lb), (lc), (1a*), (1b*) or (lc*) according to the invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of all the above-mentioned forms are suitable for treating diseases characterised by excessive or abnormal cell proliferation. Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g. psoriasis); diseases based on hyperplasia which are characterised by an increase in the number of cells (e.g. fibroblasts, hepatocytes, bones and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (e.g. endometrial hyperplasia); bone diseases and cardiovascular diseases (e.g. restenosis and hypertrophy). They are also suitable for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment. For example, the following cancers/proliferative diseases may be treated with compounds according to the invention, without being restricted thereto: brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, glioma, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as for example tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumours on the peripheral nervous system such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumours of the central nervous system such as brain and bone marrow tumours; intestinal cancer such as for example carcinoma of the rectum, colon carcinoma, colorectal carcinoma, anal carcinoma, carcinoma of the large bowel, tumours of the small intestine and duodenum; eyelid tumours such as basalioma or basal cell 336 Date Recue/Date Received 2023-03-01 CA 3,000,063 carcinoma; pancreatic cancer or carcinoma of the pancreas; bladder cancer or carcinoma of the bladder and other urothelial cancers; lung cancer (bronchial carcinoma) such as for example small-cell bronchial carcinomas (oat cell carcinomas) and non-small cell bronchial carcinomas (NSCLC) such as plate epithelial carcinomas, adenocarcinomas and large-cell bronchial carcinomas; breast cancer such as for example mammary carcinoma such as infiltrating ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma, hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), Her2 positive breast cancer, triple negative breast cancer; non-Hodgkin's lymphomas (NHL) such as for example Burkitt's lymphoma, low-malignancy non- Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer or endometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer of Unknown Primary); ovarian cancer or ovarian carcinoma such as mucinous, endometrial or serous cancer; gall bladder cancer; bile duct cancer such as for example Klatskin tumour; testicular cancer such as for example seminomas and non-seminomas; lymphoma (Iymphosarcoma) such as for example malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas (NHL) such as chronic lymphatic leukaemia, leukaemic reticuloendotheliosis, immunocytoma, plasmocytoma, multiple myeloma (MM), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as for example tumours of the vocal cords, supraglottal, glottal and subglottal laryngeal tumours; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulo- sarcoma, soft tissue sarcoma, liposarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cysts and aneurysmatic bone cysts; head and neck tumours such as for example tumours of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer such as for example liver cell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such as for example acute leukaemias such as acute lymphatic/Iymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); myelodysplastic syndromes (MDS); stomach cancer or gastric carcinoma such as for example papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small-cell carcinoma and undifferentiated carcinoma; melanomas such as for example superficially spreading, nodular, lentigo- 337 Date Recue/Date Received 2023-03-01 CA 3,000,063 maligna and acral-lentiginous melanoma; renal cancer such as for example kidney cell carcinoma or hypernephroma or Grawitz's tumour; oesophageal cancer or carcinoma of the oesophagus; penile cancer; prostate cancer (e.g. castration-resistant prostate cancer); throat cancer or carcinomas of the pharynx such as for example nasopharynx carcinomas, oropharynx carcinomas and hypopharynx carcinomas; retinoblastoma, vaginal cancer or vaginal carcinoma, mesothelioma,; plate epithelial carcinomas, adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas; thyroid carcinomas such as for example papillary, follicular and medullary thyroid carcinoma, as well as anaplastic carcinomas; spinalioma, epidormoid carcinoma and plate epithelial carcinoma of the skin; thymomas, cancer of the urethra, cervical cancer, adenoid cystic carcinoma (AdCC), adrenocortical carcinoma and cancer of the vulva. Preferably, the proliferative diseases/cancers to be treated have functional p53 and/or p53 wild-type status. Functional p53 means that p53 is able to bind to DNA and activate transcription of target genes. The new compounds may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other "state-of-the-art" compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies. The compounds of formula formula (1), (la), (lb), (lc), (1a*), (1b*) or (lc*) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances. Therapeutic agents (=cytostatic and/or cytotoxic active substances) which may be administered in combination with the compounds according to the invention, include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), inhibitors of growth factors (growth factors such as for example "platelet derived growth factor (PDGF)", "fibroblast growth factor (FGF)", "vascular endothelial growth factor (VEGF)", "epidermal growth factor (EGF)", "insuline-like growth factors (IGF)", "human epidermal growth factor (HER, e.g. HER2, 338 Date Recue/Date Received 2023-03-01 CA 3,000,063 HER3, HER4)" and "hepatocyte growth factor (HGF)"), inhibitors are for example "growth factor' antibodies, "growth factor receptor" antibodies and tyrosine kinase inhibitors, such as for example cetuximab, gefitinib, imatinib, lapatinib, bosutinib and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU), capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); antitumour antibiotics (e.g. anthracyclins such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g. tasquinimod), tubuline inhibitors; DNA synthesis inhibitors (e.g. sapacitabine), PARP inhibitors, topoisomerase inhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine/threonine kinase inhibitors (e.g. PDK 1 inhibitors,Raf inhibitors, A-Raf inhibitros, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1/2 inhibitors, PI3K inhibitors, PI3Ka inhibitors, dual mTOR/PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g. PTK2/FAK inhibitors), protein protein interaction inhibitors (e.g. IAP activator, Mcl-1, MDM2/MDMX), MEK inhibitors (e.g. pimasertib), ERK inhibitors, FLT3 inhibitors (e.g. quizartinib), BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bc1- xL inhibitors, BcI-2 inhibitors (e.g. venetoclax), Bc1-2/Bc1-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (e.g. everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors (e.g. abiraterone, TAK-700), androgen receptor inhibitors (e.g. enzalutamide, ARN- 509), immunotherapy (e.g. sipuleucel-T), DNMT inhibitors (e.g. SGI 110, temozolomide, vosaroxin), HDAC inhibitors (e.g. vorinostat, entinostat, pracinostat, panobinostat), ANG1/2 inhibitors (e.g. trebananib), CYP17 inhibitors (e.g. galeterone), radiopharmaceuticals (e.g. radium-223, alpharadin), immunotherapeutic agents (e.g. poxvirus-based vaccine, ipilimumab, immune checkpoint inhibitors) and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, rituximab, 339 Date Recue/Date Received 2023-03-01 CA 3,000,063 procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer. Other possible combination partners are 2-chlorodesoxyadenosine, 2- fluorodesoxycytidine, 2-methoxyoestradiol, 2C4, 3-alethine, 131-I-TM-601, 3CPA, 7-ethyl-10- hydroxycamptothecin, 16-aza-epothilone B, ABT-199, ABT-263/navitoclax, ABT- 737, A 105972, A 204197, aldesleukin, alisertib/MLN8237, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), AMG-232, AMG-511, AMG 2520765, AMG 2112819, ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (selumetinib), ARRY-704/ AZD-8330, ATSP-7041, AR-12, AR-42, AS-703988, AXL-1717, AZD-1480, AZD-4547, AZD-8055, AZD-5363, AZD-6244, AZD-7762, ARQ-736, ARQ 680, AS-703026 (primasertib), avastin, AZD-2014, azacitidine (5-aza), azaepothilone B, azonafide, barasertib/AZD1152, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235/dactolisib, biricodar dicitrate, birinapant, BCX-1777, BKM-120/buparlisib, bleocin, BLP- 25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW 2992/afatinib, BIBF 1120/nintedanib, BI 836845, BI 2536, BI 6727/volasertib, BI 836845, BI 847325, BI 853520, BIIB-022, bleomycinic acid, bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib, brostallicin, busulphan, BYL- 719/alpelisib, CA-4 prodrug, CA-4, cabazitaxel, cabozantinib, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCI-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 cefixime, cefiatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CGM-097, CH4987655/R0-4987655, chlorotrianisene, cilengitide, ciclosporin, CD20 antibodies, CDA-II, CDC-394, CKD-602, OKI-27, clofarabine, colchicin, combretastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CPI- 613, CTP-37, CTLA-4 monoclonal antibodies (e.g. ipilimumab), CP-461, crizotinib, CV- 247, cyanomorpholinodoxorubicin, cytarabine, D 24851, dasatinib, decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol, difiomotecan, didox, DM DC, dolastatin 10, doranidazole, DS-7423, DS-3032, E7010, E-6201, edatrexat, edotreotide, efaproxiral, eflornithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin, elesclomol, elsamitrucin, epothilone B, epratuzumab, EPZ-004777, ER-86526, erloti nib, ET-18-0CH3, ethynylcytidine, ethynyloestradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, FOLFOX, FOLFOX4, FOLFIRI, formestane, 340 Date Recue/Date Received 2023-03-01 CA 3,000,063 fostamatinib, fotemustine, galarubicin, gallium maltolate, ganetespib, gefinitib, gemtuzumab, gemtuzumab ozogamicin, gimatecan, glufosfamide, GCS-100, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GMX-1778, GPX-100, gp100-peptide vaccines, GSK-5126766, GSK- 690693, GSK-1120212 (trametinib), GSK-1995010, GSK-2118436 (dabrafenib), GSK- 2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GSK-2636771, GSK-525762A/I-BET-762, GW2016, granisetron, herceptine, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate,HDM-201, ibandronate, ibritumomab, ibrutinib/PCI-32765, idasanutl in, idatrexate, idelalisib/CAL-101, idenestrol, IDN-5109, IGF-1R inhibitors, 1MC-1C11, IMC-Al2 (cixutumumab), immunol, indisulam, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, 1NK-1117, INK-128, INSM-18, ionafarnib, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX- 2, JSF-154, JQ- 1, J-107088, conjugated oestrogens, kahalid F, ketoconazole, KW-2170, KW-2450, KU- 55933, LCL-161, lobaplatin, leflunomide, lenalidomide, lenograstim, leuprolide, leuporelin, lexidronam, LGD-1550, linezolid, lovastatin, lutetium texaphyrin, lometrexol, lonidamine, losoxantrone, LU 223651, lurbinectedin, lurtotecan, LY-S6AKT1, LY-2780301, LY- 2109761/galunisertib, mafosfamide, marimastat, masoprocol, mechloroethamine, MEK inhibitors, MEK-162, methyltestosteron, methylprednisolone, MEDI-573, MEN- 10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, MLN-0128, MLN-2480, motexafin gadolinium, MS-209, MS-275, MX6, neridronate, neratinib, Nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, NU-7441 06- benzylguanine, oblimersen, omeprazole, olaparib, oncophage, oncoVEX0m-csF, ormiplatin, ortataxel, 0X44 antibodies, OS1-027, OSI-906 (linsitinib), 4-1BB antibodies, oxantrazole, oestrogen, onapristone, palbociclib/PD-0332991, panitumumab, panobinostat, patupilone, pazopanib, pegfilgrastim, PCK-3145, pegfilgrastim, PB1-1402, PBI-05204, PD0325901, PD- 1 and PD-L1 antibodies (e.g. pembrolizumab, nivolumab, pidilizumab, MEDI- 4736/durvalumab, RG-7446/atezolizumab), PD-616, PEG-paclitaxel, albumin- stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PF-3758309, PHA- 665752, PHT-427, P-04, PKC412, P54, P1-88, pelitinib, pemetrexed, pentrix, perifosine, perillylalcohol, pertuzumab, pevonedistat, P13K inhibitors, PI3K/mTOR inhibitors, PG-TXL, PG2, PLX-4032/R0-5185426 (vemurafenib), PLX-3603/R0-5212054, PT-100, PVVT- 33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol 0, PKI166, 341 Date Recue/Date Received 2023-03-01 CA 3,000,063 plevitrexed, plicamycin, polyprenic acid, ponatinib, porfiromycin, posaconazole, prednisone, prednisolone, PRT-062607, quinamed, quinupristin, quizartinib/AC220, R115777, RAF- 265, ramosetron, ranpirnase, RDEA-119/BAY 869766, RDEA-436, rebeccamycin analogues, receptor tyrosine kinase (RTK) inhibitors, revimid, RG-7167, RG- 7112, RG- 7304, RG-7421, RG-7321, RG-7356, RG 7440, RG-7775, rhizoxin, rhu-MAb, rigosertib rinfabate, risedronate, rituximab, robatumumab, rofecoxib, romidepsin, RO- 4929097, RO- 31-7453, RO-5126766, RO-5068760, RPR 109881A, rubidazone, rubitecan, R- flurbiprofen, RX-0201, ruxolitinib, S-9788, sabarubicin, SAHA, sapacitabine, SAR-405838, sargramostim, satraplatin, SB-408075, SB-431542, Se-015/Ve-015, SU5416, SU6668, SDX-101, selinexor, semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR- 31747, SR-13668, SRL-172, sorafenib, spiroplatin, squalamine, STF-31, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAE-684, TAK-733, TAS- 103, tacedinaline, talaporfin, tanespimycin, Tarceva, tariquitar, tasisu lam, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin, thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin, tosedostat. trabectedin, TransMID-107, transretinic acid, traszutumab, tremelimumab, tretinoin, triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TXD 258, tykerb/tyverb, urocidin, valproic acid, valrubicin, vandetanib, vatalanib, vincristine, vinflunine, virulizin, vismodegib, vosaroxin, WX-UK1, WX-554, vectibix, XAV- 939, xeloda, XELOX, XL-147, XL-228, XL-281, XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZDI839, ZSTK-474, zoledronat and zosuquidar. Particularly preferred are methods of treatment and medical uses including the use of the compounds (I) of the invention in combination with immunotherapeutic agents, e.g. checkpoint inhibitors including anti-PD-1 and anti-PD-L1 agents (such as e.g. pembrolizumab, nivolumab, pidilizumab, MEDI-4736/durvalumab and RG- 7446/atezolizumab) and anti-LAG3 agents. Thus, one aspect of the invention are methods of treatment and medical uses including the use of a compound (I) of the invention in combination with an anti-PD-1 or an anti-PD-L1 agent (such as e.g. pembrolizumab, nivolumab, pidilizumab, MEDI-4736/durvalumab and RG-7446/atezolizumab). Another aspect of the invention are methods of treatment and medical uses including the use of a compound (I) of the invention in combination with an anti-LAG3 agent. A further aspect of 342 Date Recue/Date Received 2023-03-01 CA 3,000,063 the invention are methods of treatment and medical uses including the use of a compound (I) of the invention in combination with an anti-PD-1 agent and an anti-LAG3 agent. Suitable preparations include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions ¨ particularly solutions for injection (s.c., i.v., i.m.) and infusion (injectables) ¨ elixirs, syrups, sachets, emulsions, inhalatives or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc, agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate, carriers, adjuvants, surfactants. The tablets may also comprise several layers. Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets. Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates. Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials 343 Date Recue/Date Received 2023-03-01 CA 3,000,063 or ampoules or infusion bottles. Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose such as neutral fats or polyethyleneglycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). The preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may of course contain, apart from the above-mentioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above. For parenteral use, solutions of the active substances with suitable liquid carriers may be used. The dosage range of the compounds of formula (1), (la), (lb), (lc), (1a*), (1b*) or (Ic*) applicable per day is usually from 1 mg to 2000 mg, preferably from 50 to 1000 mg, more preferably from 100 to 500 mg. The dosage for intravenous use is from 1 mg to 1000 mg per hour, preferably between 5 mg and 500 mg per hour. However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the 344 Date Recue/Date Received 2023-03-01 CA 3,000,063 nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day. The formulation examples which follow illustrate the present invention without restricting its scope (active substance in all examples is a compound according to formula (1), (la), (lb), (lc), (1a*), (1b*) or (lc*)): Examples of pharmaceutical formulations A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size. B) Tablets per tablet active substance 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodiumcarboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked 345 Date Recue/Date Received 2023-03-01 CA 3,000,063 with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size. C) Tablets per tablet active substance 25 mg lactose 50 mg microcrystalline cellulose 24 mg magnesium stearate 1 mg 100 mg The active substance, lactose and cellulose are mixed together. The mixture is screened, then either moistened with water, kneaded, wet-granulated and dried or dry- granulated or directely final blend with the magnesium stearate and compressed to tablets of suitable shape and size. When wet-granulated, additional lactose or cellulose and magnesium stearate is added and the mixture is compressed to produce tablets of suitable shape and size. D) Ampoule solution active substance 50 mg sodium chloride 50 mg water for inj. 5 mL The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance. 346 Date Recue/Date Received 2023-03-01