Compounds and derivatives thereof as MDM2-P53 inhibitors

Abstract

The invention comprises compounds of formula (I) wherein the groups R1 to R4, R7, A, D, E, F, V, W, X, Y, n, r and q are as defined in claim 1, their use as inhibitors of MDM2-p53 interaction, pharmaceutical compositions comprising such compounds, their use as medicaments, especially as agents for the treatment and / or prophylaxis of neoplastic diseases, and synthetic intermediates. # imgabs0 #

Description

[0001] This application is a divisional application of Chinese patent application No. 202110322485.6 (application date: October 7, 2016, invention name: Compounds and derivatives thereof as MDM2-P53 inhibitors). Technical Field

[0002] The present invention relates to spiro[3H-indole-3,2′-pyrrolidine]-2(1H)-one compounds of formula (I) and derivatives thereof

[0003]

[0004] The group R 1 To R 4 , R 7 , A, D, E, F, V, W, X, Y, n, r and q have the meanings given in the claims and the description, their use as inhibitors of MDM2-p53 interaction, pharmaceutical compositions containing such compounds, their use as drugs, especially as agents for the treatment and / or prevention of neoplastic diseases, and synthetic intermediates. Background Art

[0005] The tumor suppressor protein p53 is a sequence-specific transcription factor and plays an important role in regulating several cellular processes, including cell cycle and growth arrest, apoptosis, DNA repair, senescence, angiogenesis, and innate immunity. The mouse double minute 2 (MDM2) protein (or its human homolog, also known as HDM2) serves to downregulate p53 activity in an autoregulatory manner, and under normal cellular conditions (no stress), the MDM2 protein serves to maintain p53 activity at a low level. MDM2 directly inhibits the transactivation function of p53, exports p53 from the nucleus, and promotes the proteasome-mediated degradation of p53 via its E3 ubiquitin ligase activity.

[0006] Normal cells are transformed into malignant cells by imbalance of MDM2 / p53 balance caused by overexpression of MDM2 or by mutation or loss of p53. Currently, p53 is known to play an important role in all types of human cancer in practice, and mutation or loss of the p53 gene can 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 was amplified in 7% of human cancers and that MDM2 overexpression and p53 mutation caused by amplification were largely mutually exclusive (Momand et al., Nucleic Acid Res (1998) 26: 3453-3459).

[0007] Because p53 has a powerful tumor suppressor function, reactivation of p53 has long been sought as a potential cancer treatment strategy. In tumors with wild-type p53, MDM2 is the major cellular inhibitor of p53 activity, and overexpression of MDM2 is found in many human tumors. Because MDM2 inhibits p53 via a direct protein-protein interaction, the use of small molecules to block this interaction has been pursued in several academic and industrial pharmaceutical laboratories over the past decade. A variety of non-peptide drug-like small molecules such as, for example, imidazole compounds (e.g., Nutlin or RG7112), benzodiazepine dione compounds, spiroindolinone compounds (e.g., MI-219), substituted piperidines, pyrrolidone compounds (e.g., PXN820-dl), and modifications thereof have been selected and designed to block MDM2 / p53 interactions as a means of reactivating 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 al., J Am Soc (2005) 127:10130-10131; WO2010 / 028862, U.S. Pat. No. 7,884,107, WO 2008 / 119741). The antitumor activity of several potent MDM2 / p53 inhibitors has been evaluated in animal models of human cancer (Vassilev et al., Science (2004) 303:844-848; Tovar et al., Cancer Res (2013) 73(8):2587-2597; Ding et al., Journal of Medicinal Chemistry (2013) 56(14):5979-5983; Rew et al., Journal of Medicinal Chemistry (2012) 55:4936-4954; Sun et al., Journal of Medicinal Chemistry (2014) 57(4):1454-1472).

[0008] Early evidence demonstrating high levels of antiproliferative activity of RG7112, an inhibitor of the MDM2-p53 interaction, was observed in vitro and in vivo in the NCI Pediatric Preclinical Testing Program (PPTP). Specifically, RG-7112 showed a lower median IC 200 in p53 wild-type versus p53 mutant cell lines. 50RG-7112 has shown cytotoxic activity of 50% (Carol et al., Pediatric Blood and Cancer (2013) 60(4): 633-641). In addition, RG-7112 caused tumor growth inhibition in solid tumor xenograft models and was particularly effective in acute lymphoblastic leukemia (ALL) xenograft models with mixed lineage leukemia (MLL) rearrangements (Carol et al., Pediatric Blood and Cancer (2013) 60(4): 633-641). In addition, the antiproliferative and pro-apoptotic activities of RG7112 have been observed in human acute myeloid leukemia (AML) and human prostate tumor xenograft models with p53 wild type (Tovar et al., Cancer Res (2013) 73(8): 2587-2597).

[0009] Accordingly, small molecule inhibitors of MDM2 protein interactions provide an important approach to cancer therapy as single agents or in combination with various anti-tumor therapies, and thus there is a need for additional MDM2 inhibitors that can be used to treat cancer.

[0010] The following prior art documents disclose spiroindolinone compounds as inhibitors of MDM2-p53 interaction:

[0011] 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.

[0012] It is an object of the present invention to provide compounds that are useful for preventing and / or treating diseases and / or disorders characterized by excessive or abnormal cell proliferation, particularly diseases and / or disorders in which inhibition of the interaction between MDM2 and p53 is of therapeutic benefit.

[0013] The compounds according to the invention are characterized by a strong inhibitory effect on the interaction between MDM2 and p53 and subsequently a high in vitro efficacy against tumor cells such as osteosarcoma, ALL, etc. mediated by the inhibition of the interaction between MDM2 and p53, and a prerequisite for exerting a corresponding therapeutic effect 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. In addition, they have good metabolic stability, which is an important requirement for the active pharmaceutical ingredient to reach its site of action and have a lasting therapeutic effect. Finally, and unlike many compounds known in the prior art, these compounds have good chemical stability, i.e., they are, for example, not susceptible to epimerization, a problem identified for many representative spiroindolinones known in the prior art (see, for example, 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 the construction of the skeleton of compound (I) (i.e., the skeleton of each subgroup (Ia), (Ib) and (Ic)) is unprecedented in itself and requires highly complex synthetic methods to obtain these compounds of high structural complexity. DETAILED DESCRIPTION OF THE INVENTION

[0015] It has now surprisingly been found that compounds of formula (I) (wherein the radical R 1 To R 4 , R 7 , A, D, E, F, V, W, X, Y, n, r and q have the meanings given hereinafter) act as inhibitors of specific protein-protein interactions involved in controlling cell proliferation. Therefore, the compounds according to the invention can be used, for example, to treat diseases associated with such protein-protein interactions and characterized by excessive or abnormal cell proliferation.

[0016] The present invention therefore relates to a compound of formula (I)

[0017] in

[0018] [A0]

[0019] R 1 is optionally substituted by one or more identical or different R b1 and / or R c1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0020] Each R b1 Independently selected from -OR c1 、-NR c1 R c1 , halogen, -CN, -C(O)R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O)2R c1 、-S(O)2NR c1 R c1 、-NHC(O)R c1 、-N(C 1-4 alkyl)C(O)R c1 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[0021] Each R c1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d1 and / or R e1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0022] Each R d1 Independently selected from -OR e1 、-NR e1 R e1 , halogen, -CN, -C(O)R e1 、-C(O)OR e1 、-C(O)NR e1 R e1 、-S(O)2R e1 、-S(O)2NR e1 R e1 、-NHC(O)R e1 、-N(C 1-4 alkyl)C(O)R e1 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[0023] Each R e1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f1and / or R g1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0024] Each R f1 Independently selected from -OR g1 、-NR g1 R g1 , halogen, -CN, -C(O)R g1 、-C(O)OR g1 、-C(O)NR g1 R g1 、-S(O)2R g1 、-S(O)2NR g1 R g1 、-NHC(O)R g1 、-N(C 1-4 alkyl)C(O)R g1 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[0025] Each R g1 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group;

[0026] [B0]

[0027] R 2 With R 3 are each independently selected from hydrogen, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, wherein the C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups are optionally substituted with one or more identical or different R b2 and / or R c2 replace;

[0028] Each R b2 Independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)Rc2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-S(O)2R c2 、-S(O)2NR c2 R c2 、-NHC(O)R c2 、-N(C 1-4 alkyl)C(O)R c2 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[0029] Each R c2 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d2 and / or R e2 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0030] Each R d2 Independently selected from -OR e2 、-NR e2 R e2 , halogen, -CN, -C(O)R e2 、-C(O)OR e2 、-C(O)NR e2 R e2 、-S(O)2R e2 、-S(O)2NR e2 R e2 、-NHC(O)R e2 、-N(C 1-4 alkyl)C(O)R e2 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[0031] Each R e2 independently represent hydrogen or selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0032] [C0]

[0033] If F is carbon, then A is selected from phenyl and 5- to 6-membered heteroaryl, or

[0034] If F is nitrogen, then A is a 5- to 6-membered nitrogen-containing heteroaryl group;

[0035] Each R 4 Independently selected from R a4 and R b4 ;

[0036] Each R a4 are independently selected from one or more identical or different R b4 and / or R c4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0037] Each R b4 Independently selected from -OR c4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-C(O)NR g4 OR c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHSO2R c4 、-N(C 1-4 Alkyl)SO2R c4 、-NHC(O)R c4 、-N(C 1-4 alkyl)C(O)R c4 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[0038] Each R c4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d4 and / or R e4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0039] Each R d4 Independently selected from -OR e4 、-NR e4 R e4 , halogen, -CN, -C(O)R e4 、-C(O)OR e4 、-C(O)NR e4 R e4 、-C(O)NR g4 OR e4 、-S(O)2R e4 、-S(O)2NR e4 R e4 、-NHC(O)R e4 、-N(C 1-4 alkyl)C(O)R e4 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[0040] Each R e4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f4 and / or R g4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0041] Each R f4 Independently selected from -OR g4 、-NR g4 R g4 , halogen, -CN, -C(O)R g4 、-C(O)OR g4 、-C(O)NR g4 R g4 、-C(O)NR g4 OR g4 、-S(O)2R g4 、-S(O)2NR g4 R g4 、-NHC(O)R g4 、-N(C 1-4 alkyl)C(O)R g4and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[0042] Each R g4 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group;

[0043] r represents a value of 0, 1, 2, or 3;

[0044] [D0]

[0045] n represents a value of 1, 2, or 3;

[0046] [E0]

[0047] Each R 7 independently selected from halogen, C 1-4 Alkyl, -CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl and -OC 1-4 Haloalkyl;

[0048] q represents a value of 0, 1, 2, or 3;

[0049] [F0]

[0050] W, X and Y are each independently selected from -N= and -CH=

[0051] The restriction is that each hydrogen in -CH= can be replaced by a substituent R 7 (if any) permutation and at most two of W, X and Y may be -N=;

[0052] [G0]

[0053] V is oxygen or sulfur;

[0054] [H0]

[0055] D is nitrogen, E is carbon and F is carbon; or

[0056] D is carbon, E is nitrogen and F is carbon; or

[0057] D is carbon, E is carbon and F is nitrogen;

[0058] or a salt thereof.

[0059] In one aspect, the present invention relates to a compound of formula (Ia)

[0060]

[0061] or a salt thereof.

[0062] In one aspect, the present invention relates to a compound of formula (Ib)

[0063]

[0064] or a salt thereof.

[0065] In one aspect, the present invention relates to a compound of formula (Ic)

[0066] or a salt thereof.

[0067] In one aspect, the present invention relates to a compound of formula (Ia*)

[0068]

[0069] or a salt thereof.

[0070] In one aspect, the present invention relates to a compound of formula (Ib*)

[0071]

[0072] or a salt thereof.

[0073] In one aspect, the present invention relates to a compound of formula (Ic*)

[0074]

[0075] or a salt thereof.

[0076] It should be understood that each of Compounds (Ia), (Ib) and (Ic) is a subset of Compound (I) and unless otherwise stated, whenever the term "Compound (I)" is used it also includes Compounds (Ia), (Ib) and (Ic).

[0077] It should be understood that compounds (Ia*), (Ib*) and (Ic*) are each a subset of compounds (Ia), (Ib) and (Ic), respectively, and unless otherwise stated, whenever (Ia), (Ib) or (Ic) is used it also includes compounds (Ia*), (Ib*) and (Ic*), respectively.

[0078] In another aspect [A1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0079] R 1 is optionally substituted by one or more identical or different R b1 and / or R c1The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0080] Each R b1 Independently selected from -OR c1 、-NR c1 R c1 , halogen, -CN, -C(O)R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O)2R c1 、-S(O)2NR c1 R c1 、-NHC(O)R c1 and-N(C 1-4 alkyl)C(O)R c1 ;

[0081] Each R c1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d1 and / or R e1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0082] Each R d1 Independently selected from -OR e1 、-NR e1 R e1 , halogen, -CN, -C(O)R e1 、-C(O)OR e1 、-C(O)NR e1 R e1 、-S(O)2R e1 、-S(O)2NR e1 R e1 、-NHC(O)R e1 and-N(C 1-4 alkyl)C(O)R e1 ;

[0083] Each R e1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f1 and / or R g1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0084] Each R f1 Independently selected from -OR g1 、-NR g1 R g1 , halogen, -CN, -C(O)R g1 、-C(O)OR g1 、-C(O)NR g1 R g1 、-S(O)2R g1 、-S(O)2NR g1 R g1 、-NHC(O)R g1 and-N(C 1-4 alkyl)C(O)R g1 ;

[0085] Each R g1 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group;

[0086] or a salt thereof.

[0087] In another aspect [A2], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0088] R 1 is optionally substituted by one or more identical or different R b1 and / or R c1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl and C 3-7 Cycloalkyl groups;

[0089] Each R b1 Independently selected from -OR c1 、-NR c1 R c1 , halogen, -CN, -C(O)R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O)2R c1 、-S(O)2NR c1 R c1 、-NHC(O)R c1 and-N(C 1-4 alkyl)C(O)R c1 ;

[0090] Each R c1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d1 and / or R e1 The substituted 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0091] Each R d1 Independently selected from -OR e1 、-NR e1 R e1 , halogen, -CN, -C(O)R e1 、-C(O)OR e1 、-C(O)NR e1 R e1 、-S(O)2R e1 、-S(O)2NR e1 R e1 、-NHC(O)R e1 and-N(C 1-4 alkyl)C(O)R e1 ;

[0092] Each R e1 independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group;

[0093] or a salt thereof.

[0094] In another aspect [A3], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0095] R 1 is optionally substituted by one or more identical or different R b1 and / or R c1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl and C 3-7 Cycloalkyl groups;

[0096] Each R b1 Independently selected from -OR c1 , halogen and -S(O)2R c1 ;

[0097] Each R c1 are independently of each other and are optionally substituted by one or more identical or different R d1 and / or R e1 The substituted 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aryl and 3- to 10-membered heterocyclic groups;

[0098] Each R d1 Independently selected from -OR e1 , -CN and halogen;

[0099] Each R e1 Independently of each other, C 1-6 Alkyl or C 1-6 Alkyl-OC 1-6 alkyl;

[0100] or a salt thereof.

[0101] In another aspect [A4], the invention relates to compounds of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0102] R 1 is optionally substituted by one or more identical or different R b1 and / or R c1 The substituted 1-6 Alkyl, C 2-6 Alkenyl and C 1-6 A haloalkyl group;

[0103] Each R b1 are independently selected from -OR c1 and -S(O)2R c1 ;

[0104] Each R c1 are independently of each other and are optionally substituted by one or more identical or different R d1 and / or R e1 The substituted 1-6 Alkyl, C 3-7 Cycloalkyl and C 6-10 Aryl groups;

[0105] Each R d1 are independently selected from -OR e1 , -CN and halogen;

[0106] Each R e1 Independently of each other, C 1-6 Alkyl or C 1-6 Alkyl-OC 1-6 alkyl;

[0107] or a salt thereof.

[0108] In another aspect [A5], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0109] R 1 is optionally substituted by one or more identical or different R b1 and / or R c1 The substituted 1-6 Alkyl, C 2-6 Alkenyl and C 1-6 A haloalkyl group;

[0110] Each R b1 Independently selected from -OR c1 and -S(O)2R c1 ;

[0111] Each R c1 are independently of each other and are optionally substituted by one or more identical or different R d1 and / or R e1 The substituted 1-6 Alkyl, C 3-7 Cycloalkyl and phenyl groups;

[0112] Each R d1 Independently selected from -OR e1 , -CN and halogen;

[0113] Each R e1 Independently of each other, C 1-6 Alkyl or C 1-6 Alkyl-OC 1-6 alkyl;

[0114] or a salt thereof.

[0115] In another aspect [A6], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0116] R 1 Selected from C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl and C 2-6 alkenyl;

[0117] or a salt thereof.

[0118] In another aspect [A7], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0119] R 1 C 3-7 Cycloalkyl-C 1-6 alkyl;

[0120] or a salt thereof.

[0121] In another aspect [A8], the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0122] R 1 is cyclopropylmethyl;

[0123] or a salt thereof.

[0124] In another aspect [B1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0125] R 2 With R 3 are each independently selected from hydrogen, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, wherein the C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups are optionally substituted with one or more identical or different R b2 and / or R c2 replace;

[0126] Each R b2 Independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)R c2 、-C(O)OR c2、-C(O)NR c2 R c2 、-S(O)2R c2 、-S(O)2NR c2 R c2 、-NHC(O)R c2 and-N(C 1-4 alkyl)C(O)R c2 ;

[0127] Each R c2 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d2 and / or R e2 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0128] Each R d2 Independently selected from -OR e2 、-NR e2 R e2 , halogen, -CN, -C(O)R e2 、-C(O)OR e2 、-C(O)NR e2 R e2 、-S(O)2R e2 、-S(O)2NR e2 R e2 、-NHC(O)R e2 and-N(C 1-4 alkyl)C(O)R e2 ;

[0129] Each R e2 independently represent hydrogen or selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0130] or a salt thereof.

[0131] In another aspect [B2], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0132] R 2 With R 3 One of them is hydrogen and the other is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are optionally substituted by one or more identical or different R b2 and / or R c2 replace;

[0133] Each R b2 Independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)R c2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-S(O)2R c2 、-S(O)2NR c2 R c2 、-NHC(O)R c2 and-N(C 1-4 alkyl)C(O)R c2 ;

[0134] Each R c2 independently represent hydrogen or selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, phenyl, 5- to 6-membered heteroaryl and 3- to 7-membered heterocyclic groups;

[0135] or a salt thereof.

[0136] In another aspect [B3], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0137] R 2 With R 3 One of them is hydrogen and the other is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are optionally substituted by one or more identical or different selected from -OC 1-6 Alkyl, halogen, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0138] or a salt thereof.

[0139] In another aspect [B4], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0140] R 2 and R 3 One of them is hydrogen and the other is selected from phenyl, thienyl and pyridinyl, wherein the phenyl, thienyl and pyridinyl are optionally substituted with one or more identical or different radicals selected from -OC 1-6 Alkyl, halogen, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0141] or a salt thereof.

[0142] In another aspect [B5], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0143] R 2 With R 3 One of them is hydrogen and the other is selected from 3-chlorophenyl, 3-chloro-2-fluorophenyl and 3-bromo-2-fluorophenyl;

[0144] or a salt thereof.

[0145] In other aspects [B6], [B7], [B8], [B9], [B10] and [B11], the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) having structural aspects [B0], [B1], [B2], [B3], [B4] and [B5], wherein

[0146] R 3 is hydrogen;

[0147] or a salt thereof.

[0148] In other aspects [B12], [B13], [B14], [B15], [B16] and [B17], the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) having structural aspects [B0], [B1], [B2], [B3], [B4] and [B5], wherein

[0149] R 2 is hydrogen;

[0150] or a salt thereof.

[0151] In another aspect [C1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0152] If F is carbon, then A is selected from phenyl and 5- to 6-membered heteroaryl, or

[0153] If F is nitrogen, then A is a 5- to 6-membered nitrogen-containing heteroaryl group;

[0154] Each R 4 Independently selected from R a4 and R b4 ;

[0155] Each R a4 are independently selected from one or more identical or different R b4 and / or R c4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0156] Each R b4 Independently selected from -OR c4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-C(O)NR g4 OR c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHSO2R c4 、-N(C 1-4 Alkyl)SO2R c4 、-NHC(O)R c4 and-N(C 1-4 alkyl)C(O)R c4 ;

[0157] Each R c4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d4 and / or R e4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0158] Each R d4 Independently selected from -OR e4 、-NR e4 R e4 、Halogen、-CN,、-C(O)R e4 、-C(O)OR e4 、-C(O)NR e4 R e4 、-C(O)NR g4 OR e4 、-S(O)2R e4 、-S(O)2NR e4 R e4 、-NHC(O)R e4 and-N(C 1-4 alkyl)C(O)R e4 ;

[0159] Each R e4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f4 and / or R g4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0160] Each R f4 Independently selected from -OR g4 、-NR g4 R g4 , halogen, -CN, -C(O)R g4 、-C(O)OR g4 、-C(O)NR g4 R g4 、-C(O)NR g4 OR g4 、-S(O)2R g4 、-S(O)2NR g4 R g4 、-NHC(O)R g4 and-N(C 1-4 alkyl)C(O)Rg4 ;

[0161] Each R g4 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group;

[0162] r represents a value of 0, 1, 2, or 3;

[0163] or a salt thereof.

[0164] In another aspect [C2], the invention relates to a compound of formula (I), (Ia), (Ib), (Ia*) or (Ib*), wherein

[0165] A is phenyl and F is carbon;

[0166] Each R 4 Independently selected from R a4 and R b4 ;

[0167] Each R a4 are independently of each other and are optionally substituted by one or more identical or different R b4 and / or R c4 The substituted 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3- to 10-membered heterocyclic groups;

[0168] Each R b4 Independently selected from -OR c4 、-NR c4 R c4 , halogen, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-C(O)NR g4 OR c4 、-S(O)2R c4 and -NHC(O)R c4 ;

[0169] Each R c4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d4 and / or R e4 The substituted 1-6 Alkyl, C 1-6Haloalkyl, C 3-7 Cycloalkyl and 3- to 10-membered heterocyclic groups;

[0170] Each R d4 Independently selected from -OR e4 、-NR e4 R e4 and -S(O)2R e4 ;

[0171] Each R e4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f4 and / or R g4 The substituted 1-6 Alkyl and 3- to 10-membered heterocyclic groups;

[0172] Each R f4 For-OR g4 ;

[0173] Each R g4 are independently selected from hydrogen and C 1-6 alkyl;

[0174] r represents a value of 0, 1, 2, or 3;

[0175] or a salt thereof.

[0176] In another aspect [C3], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0177] If F is carbon, then A is selected from phenyl and 5- to 6-membered heteroaryl, or

[0178] If F is nitrogen, then A is a 5- to 6-membered nitrogen-containing heteroaryl group;

[0179] Each R 4 Independently selected from R a4 and R b4 ;

[0180] Each R a4 are independently selected from one or more identical or different R b4 and / or Rc4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0181] Each Rb4 Independently selected from -OR c4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-C(O)NHOR c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHSO2R c4 、-N(C 1-4 Alkyl)SO2R c4 、-NHC(O)R c4 and-N(C 1-4 alkyl)C(O)R c4 ;

[0182] Each R c4 independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group;

[0183] r represents a value of 0, 1, 2, or 3;

[0184] or a salt thereof.

[0185] In another aspect [C4], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0186] If F is carbon, then A is selected from phenyl and pyridyl, or

[0187] If F is nitrogen, then A is pyridyl;

[0188] Each R 4 Independently selected from R a4 and R b4 ;

[0189] Each R a4 are independently of each other and are optionally substituted by one or more identical or different R b4 Replacement C 1-6 alkyl;

[0190] Each R b4 Independently selected from -ORc4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-C(O)NR g4 OR c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHSO2R c4 、-N(C 1-4 Alkyl)SO2R c4 、-NHC(O)R c4 and-N(C 1-4 alkyl)C(O)R c4 ;

[0191] Each R c4 independently selected from hydrogen and C 1-6 alkyl;

[0192] r represents a value of 0, 1, 2, or 3;

[0193] or a salt thereof.

[0194] In another aspect [C5], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0195] If F is carbon, then A is selected from phenyl and pyridyl, or

[0196] If F is nitrogen, then A is pyridyl;

[0197] Each R 4 Independently selected from R a4 and R b4 ;

[0198] Each R a4 are independently of each other and are optionally substituted by one or more identical or different R b4 Replacement C 1-6 alkyl;

[0199] Each R b4 Independently selected from -OR c4 , halogen, -CN, -C(O)OR c4 、-C(O)NR c4 R c4 and -S(O)2R c4 ;

[0200] Each R c4independently selected from hydrogen and C 1-6 alkyl;

[0201] r represents a value of 0, 1, 2, or 3;

[0202] or a salt thereof.

[0203] In another aspect [C6], the invention relates to a compound of formula (I), (Ia), (Ib), (Ia*) or (Ib*), wherein

[0204] A is phenyl and F is carbon;

[0205] Each R 4 Independently selected from R a4 and R b4 ;

[0206] Each R a4 are independently of each other and are optionally substituted by one or more identical or different R b4 Replacement C 1-6 alkyl;

[0207] Each R b4 Independently selected from -OR c4 , halogen, -CN, -C(O)OR c4 、-C(O)NR c4 R c4 and -S(O)2R c4 ;

[0208] Each R c4 independently selected from hydrogen and C 1-6 alkyl;

[0209] r represents a value of 0, 1, 2, or 3;

[0210] or a salt thereof.

[0211] In other aspects [C7], [C8], [C9], [C10], [C11], [C12] and [C13], the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) having structural aspects [C0], [C1], [C2], [C3], [C4], [C5] and [C6], wherein

[0212] r represents a value of 1 or 2;

[0213] or a salt thereof.

[0214] In another aspect [C14], the invention relates to a compound of formula (I), (Ia), (Ib), (Ia*) or (Ib*), wherein

[0215] A and r substituents R 4 Together for

[0216]

[0217] R 8 Selected from hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -CN, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2 and -S(O)2C 1-6 alkyl;

[0218] R 9 Selected from hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -CN, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2 and -S(O)2C 1-6 alkyl;

[0219] R 10 Selected from hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -CN, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2 and -S(O)2C 1-6 alkyl;

[0220] The restriction condition is R 8 To R 10 At least one of the following other than R 8 To R 10 All hydrogen;

[0221] or a salt thereof.

[0222] In another aspect [C15], the invention relates to a compound of formula (I), (Ia), (Ib), (Ia*) or (Ib*), wherein

[0223] A and r substituents R 4 Together for

[0224]

[0225] R8 is -C(O)OH;

[0226] R 9 With R 10 One of them is C 1-4 alkyl and the other is hydrogen;

[0227] or a salt thereof.

[0228] In another aspect [D1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0229] n represents a value of 1 or 2;

[0230] or a salt thereof.

[0231] In another aspect [D2], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0232] n is 1;

[0233] or a salt thereof.

[0234] In another aspect [D3], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0235] n is 2;

[0236] or a salt thereof.

[0237] In another aspect [E1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0238] Each R 7 are independently halogen or -CN and q is 1 or 2;

[0239] or a salt thereof.

[0240] In another aspect [E2], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0241] Each R 7 are independently chlorine or fluorine and q is 1 or 2;

[0242] or a salt thereof.

[0243] In another aspect [F1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0244] W, X and Y are -CH=, with the proviso that the hydrogen in each -CH= may be replaced by a substituent R 7 (if any) replacement;

[0245] or a salt thereof.

[0246] In another aspect [EF1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0247] The method comprises W, X, Y and q substituents R 7 The 6-membered ring has a substructure selected from (i) and (ii)

[0248]

[0249] or a salt thereof.

[0250] In another aspect [G1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

[0251] V is oxygen;

[0252] or a salt thereof.

[0253] All the above-mentioned structural aspects A1 to A8, B1 to B17, C1 to C15, D1 to D3, E1 and E2, F1, G1 and EF1 are respectively preferred embodiments of the corresponding aspects A0, B0, C0, D0, E0, F0, EF0 and G0, wherein EF0 (EF) represents the combination of E0 (E) and F0 (F). According to the invention, the structural aspects A0 to A8, B0 to B17, C0 to C15, D0 to D3, E0 to E2, F0 and F1, EF0 and EF1, and G0 and G1 related to the different molecular parts of compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) and (Ic*) can be replaced with each other as needed in the form of the combination ABCDEFG to obtain preferred compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) and (Ic*) (aspects E and F can be replaced by the combination aspect EF). Each combination ABCDEFG represents and defines an individual embodiment or a general subset of compounds according to the invention.

[0254] Preferred embodiments of the present invention having structure (Ia) are example compounds Ia-1 to Ia-57.

[0255] Preferred embodiments of the present invention having structure (Ib) are Example Compounds Ib-1 to Ib-254.

[0256] Preferred embodiments of the present invention having structure (Ic) are Example Compounds Ic-1 to Ic-38.

[0257] The general definitions as well as all synthetic intermediates and their salts specifically disclosed herein are also part of the present invention.

[0258] In another aspect, the present invention also relates to synthetic intermediates of formula B-3 and their salts, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0259]

[0260] B-3 Group R 2 , R 3 , R 7 The definitions of , V, W, X, Y, q and n correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], in terms of n [D0], in terms of R 7 [E0] for W / X / Y, [F0] for W / X / Y, and [G0] for V. R is a carboxyl protecting group, such as C 1-6 Alkyl or t-Bu.

[0261] Preferred intermediates B-3 are those which give rise to preferred compounds (Ia) and (Ia*) according to the invention, i.e. preferred embodiments of B-3 having in total a total of 2 / R 3 [B0] to [B17] for n [D0] to [D3] for R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects (including the definition of R) can be replaced with each other as needed in the form of combinations BDEFGR to obtain preferred intermediates B-3 (aspects E and F can be replaced by combination aspect EF). Each combination BDEFGR represents and defines an individual embodiment or a general subset of intermediates B-3.

[0262] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-3 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0263] In another aspect, the present invention also relates to synthetic intermediates of formula B-4 and their salts, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0264]

[0265] B-4 Group R 1 , R 2 , R 3 , R 7 The definitions of , V, W, X, Y, q and n correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 1 As far as [A0] is concerned, 2 / R 3 In terms of [B0], in terms of n [D0], in terms of R 7 [E0] for W / X / Y, [F0] for W / X / Y, and [G0] for V. R is a carboxyl protecting group, such as C 1-6 Alkyl or t-Bu.

[0266] Preferred intermediates B-4 are those which give rise to preferred compounds (Ia) and (Ia*) according to the invention, i.e. preferred embodiments of B-4 having in total a compound selected from the group consisting of 1 For [A0] to [A8], for R 2 / R 3 [B0] to [B17] for n [D0] to [D3] for R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects (including the definition of R) can be replaced with each other as needed in the form of the combination ABDEFGR to obtain the preferred intermediate B-4 (aspects E and F can be replaced by the combination EF). Each combination ABDEFGR represents and defines an individual embodiment or a general subset of intermediate B-4.

[0267] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-4 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0268] In another aspect, the present invention also relates to synthetic intermediates of formula B-7 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0269]

[0270] Group R in B-7 1 , R 2 , R 3 , R 7 The definitions of , V, W, X, Y, q and n correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 1 As far as [A0] is concerned, 2 / R 3 In terms of [B0], in terms of n [D0], in terms of R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0271] Preferred intermediates B-7 are those which give rise to the preferred compounds (Ia) and (Ia*) according to the present invention, i.e., preferred embodiments of B-7 have in total a compound selected from the group consisting of 1 For [A0] to [A8], for R 2 / R 3 [B0] to [B17] for n [D0] to [D3] for R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combinations ABDEFG to obtain the preferred intermediate B-7 (aspects E and F can be replaced by combination aspect EF). Each combination ABDEFG represents and defines an individual embodiment or a general subset of intermediate B-7.

[0272] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-7 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0273] In another aspect, the present invention also relates to synthetic intermediates of formula B-6 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0274]

[0275] Group R in B-6 2 , R 3 , R 7The definitions of , V, W, X, Y, q and n correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], in terms of n [D0], in terms of R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0276] Preferred intermediates B-6 are those such that the preferred compounds (Ia) and (Ia*) according to the present invention (i.e. preferred embodiments of B-6) have a total of 2 / R 3 [B0] to [B17] for n [D0] to [D3] for R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combinations BDEFG to obtain the preferred intermediate B-6 (aspects E and F can be replaced by combination aspect EF). Each combination BDEFG represents and defines an individual embodiment or a general subset of intermediate B-6.

[0277] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-6 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0278] In another aspect, the present invention also relates to synthetic intermediates of formula B-8 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0279]

[0280] B-8 group R 1 , R 2 , R 3 , R 7 The definitions of , V, W, X, Y, q and n correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 1 As far as [A0] is concerned, 2 / R 3 In terms of [B0], in terms of n [D0], in terms of R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0281] Preferred intermediates B-8 are those such that the preferred compounds (Ia) and (Ia*) according to the present invention (i.e., preferred embodiments of B-8) have a total of 1 For [A0] to [A8], for R 2 / R 3 [B0] to [B17] for n [D0] to [D3] for R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combinations ABDEFG to obtain the preferred intermediate B-8 (aspects E and F can be replaced by the combination EF). Each combination ABDEFG represents and defines an individual embodiment or a general subset of intermediate B-8.

[0282] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-8 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0283] In another aspect, the present invention also relates to synthetic intermediates of formula B-10 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0284]

[0285] B-10 group R 1 , R 2 , R 3 , R 4 , R 7 The definitions of A, V, W, X, Y, r, q and n correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 1 As far as [A0] is concerned, 2 / R 3 In terms of [B0], A / R 4 / r[C0], n[D0], R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0286] Preferred intermediates B-10 are those such that the preferred compounds (Ia) and (Ia*) according to the present invention (i.e., preferred embodiments of B-10) have a total of 1 For [A0] to [A8], for R2 / R 3 For [B0] to [B17], for A / R 4 / r [C0] to [C15], n [D0] to [D3], R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combination ABCDEFG to obtain the preferred intermediate B-10 (aspects E and F can be replaced by combination aspect EF). Each combination ABCDEFG represents and defines an individual embodiment or a general subset of intermediate B-10.

[0287] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-10 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0288] In another aspect, the present invention also relates to synthetic intermediates of formula B-11 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0289]

[0290] Group R in B-11 1 , R 2 , R 3 , R 4 , R 7 The definitions of A, V, W, X, Y, r, q and n correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 1 As far as [A0] is concerned, 2 / R 3 In terms of [B0], A / R 4 / r[C0], n[D0], R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0291] Preferred intermediates B-11 are those such that the preferred compounds (Ia) and (Ia*) according to the present invention (i.e. preferred embodiments of B-11) have a total of 1 For [A0] to [A8], for R 2 / R 3 For [B0] to [B17], for A / R 4 / r [C0] to [C15], n [D0] to [D3], R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combination ABCDEFG to obtain the preferred intermediate B-11 (aspects E and F can be replaced by combination aspect EF). Each combination ABCDEFG represents and defines an individual embodiment or a general subset of intermediate B-11.

[0292] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-11 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0293] In another aspect, the present invention also relates to synthetic intermediates of formula B-12 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0294]

[0295] Group R in B-12 1 , R 2 , R 3 , R 4 , R 7 The definitions of A, V, W, X, Y, r, q and n correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 1 As far as [A0] is concerned, 2 / R 3 In terms of [B0], A / R 4 / r[C0], n[D0], R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0296] Preferred intermediates B-12 are those such that the preferred compounds (Ia) and (Ia*) according to the present invention (i.e. preferred embodiments of B-12) have a total of 1 For [A0] to [A8], for R 2 / R 3 For [B0] to [B17], for A / R 4 / r [C0] to [C15], n [D0] to [D3], R 7[E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combinations ABCDEFG to obtain the preferred intermediate B-12 (aspects E and F can be replaced by combination aspect EF). Each combination ABCDEFG represents and defines an individual embodiment or a general subset of intermediate B-12.

[0297] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-12 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0298] In another aspect, the present invention also relates to synthetic intermediates of formula B-16 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0299]

[0300] B-16 group R 4 The definitions of A and r correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to A / R 4 / r for [C0].

[0301] Preferred intermediates B-16 are those that allow the preferred compounds (Ia) and (Ia*) according to the present invention (i.e., preferred embodiments of B-16) to have a 4 / r refers to the structural aspects of [C0] to [C15] (which define individual embodiments or general subsets of intermediate B-16, respectively). Preferred intermediate B-16 is selected from intermediates B-16a to B-16f (see Table 15-2 below), including salts thereof.

[0302] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-16 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0303] In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-16, or a salt thereof,

[0304]

[0305] It comprises brominating a compound of formula B-15 or a salt thereof

[0306] in

[0307] The reaction is carried out in a solvent with an electrophilic bromine source in the presence of a palladium catalyst and an acidic additive, and R 4 , A and r are as defined above. (Step A)

[0308] Example / conditions of step A:

[0309] The selected solvent may be an organic solvent, preferably selected from the group consisting of carboxylic acids, carboxylates, alkanes and aromatic solvents, or mixtures thereof. More preferably, the solvent is selected from the group consisting of AcOH, nBuOAc, iPrOAc, MCH, nHep, toluene and xylene (or mixtures thereof, such as nBuOAc / AcOH (9:1), iPrOAc / AcOH (9:1), toluene / AcOH (9:1)). AcOH is the most preferred.

[0310] The electrophilic bromine source may be, for example, selected from the group consisting of NBS, N-bromosaccharin and 1,3-dibromo-5,5-dimethylhydantoin. Preferably, NBS is selected as the electrophilic bromine source.

[0311] Preferably, the palladium catalyst used may be a Pd(II) catalyst, for example, a Pd(II) catalyst selected from the group consisting of Pd(OAc)2 and Pd(OC(O)CF3)2. The preferred Pd(II) catalyst is Pd(OAc)2.

[0312] Whenever an acidic additive is involved, it is preferably an aromatic acid, preferably an aromatic sulfonic acid. The most preferred acidic additive is TsOH or its hydrate.

[0313] The reaction can be carried out at a temperature ranging from about 70°C to about 100°C, preferably from about 60°C to about 90°C. Most preferably, the temperature range is from about 60°C to about 80°C.

[0314] A preferred intermediate B-16 synthesized by this method is any one selected from the intermediates B-16a to B-16f (see Table 15-2 below), including salts thereof.

[0315] The advantages of the bromination step as described herein are its efficiency and high yields, since it allows almost complete control of the regioselective chemistry of the subsequent installation of the linker between the substituted ring system A and the isatin (indolone) backbone, which is also positively influenced by the anilide protecting group, the temperature range applied and the choice of AcOH as the reaction solvent. Furthermore, the use of NBS is process friendly.

[0316] In another aspect, the present invention also relates to synthetic intermediates of formula B-17 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0317]

[0318] B-17 group R 4 The definitions of A and r correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to A / R 4 / r for [C0].

[0319] Preferred intermediates B-17 are those that allow the preferred compounds (Ia) and (Ia*) according to the present invention (i.e., preferred embodiments of B-17) to have a molecule selected from the group consisting of A / R 4 / r refers to the structural aspects of [C0] to [C15] (which define individual embodiments or general subsets of intermediate B-17, respectively). Preferred intermediate B-17 is selected from intermediates B-17a to B-17f (see Table 15-3 below), including salts thereof.

[0320] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-17 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0321] In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-17 or a salt thereof,

[0322]

[0323] It comprises making a compound of formula B-16 or a salt thereof

[0324]

[0325] Reaction with tert-butyl prop-2-ynylcarbamate

[0326] in

[0327] The reaction is carried out in a solvent in the presence of a palladium catalyst, a ligand, a base and, if necessary, a copper co-catalyst, and R 4 , A and r are as defined above. (Step B)

[0328] Example / conditions of step B:

[0329] The selected solvent may be an organic solvent, which is preferably selected from the group consisting of DMSO, DMF, ACN, THF, dioxane, NMP, iPrOAc, toluene, nBuOH or a mixture thereof, and DMSO is the most preferred.

[0330] Preferably, the palladium catalyst used is a Pd(II) or Pd(0) catalyst, for example, a palladium catalyst selected from the group consisting of Pd(OAc)2 and Pd2(dba)3. The preferred palladium catalyst is Pd2(dba)3.

[0331] The ligand used in the reaction is preferably an organic phosphorus compound, for example, a ligand selected from the group consisting of [(tBu)3PH]BF4, RuPhos and Xphos. The preferred ligand used is [(tBu)3PH]BF4.

[0332] The copper promoter, if present, is preferably a copper salt, more preferably a Cu(I) salt, for example selected from the group consisting of CuI, CuCl and Cu2 O. The preferred copper promoter is CuI.

[0333] The base used is preferably an organic base, more preferably an amine base, for example, a secondary amine, and most preferably DIPA is used.

[0334] The reaction can be carried out at a temperature ranging from about 20°C to about 70°C, preferably from about 20°C to about 40°C. Most preferably, the temperature range is from about 20°C to about 30°C.

[0335] A preferred intermediate B-16 synthesized by this method is any one selected from the intermediates B-17a to B-17f (see Table 15-3 below), including salts thereof.

[0336] In another aspect, the present invention also relates to synthetic intermediates of formula B-18 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0337]

[0338] B-18 group R 4 The definitions of A and r correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to A / R 4 / r for [C0].

[0339] Preferred intermediates B-18 are those that allow the preferred compounds (Ia) and (Ia*) according to the present invention (i.e., preferred embodiments of B-17) to have a molecule selected from the group consisting of A / R 4 / r refers to the structural aspects of [C0] to [C15] (which define individual embodiments or general subsets of intermediate B-18, respectively). Preferred intermediate B-18 is selected from intermediates B-18a to B-181 (see Tables 15-4 and 15-5 below), including salts thereof.

[0340] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-18 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0341] In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-18 or a salt thereof,

[0342]

[0343] It comprises reacting a compound of formula B-17 or a salt thereof with a deprotecting group,

[0344] in

[0345] The hydration step is carried out in the presence of a palladium catalyst in a solvent and the deprotection step is carried out in the presence of an acid, and R 4 , A and r are as defined above. (Step C)

[0346] Example / conditions of step C:

[0347] The solvent selected may be an organic solvent, preferably a carboxylic acid, and most preferably AcOH.

[0348] Preferably, the palladium catalyst used is a Pd(II) catalyst, for example, a Pd(II) catalyst selected from the group consisting of Pd(OAc)2, PdCl2 and Pd(OC(O)CF3)2. The preferred Pd(II) catalyst is Pd(OAc)2.

[0349] The acid used in the step of removing the protecting group is preferably an aqueous solution of an inorganic acid selected from the group consisting of an aqueous solution of HCl, an aqueous solution of HBr and an aqueous solution of H2SO4. The most preferred is an aqueous solution of HCl.

[0350] The hydration step may be carried out at a temperature in the range of about 20°C to about 80°C, preferably in the range of about 20°C to about 50°C, and most preferably in the range of about 20°C to about 30°C.

[0351] The deprotection step may be performed at a temperature ranging from about 20°C to about 80°C.

[0352] A preferred intermediate B-18 synthesized by this method is any one selected from the intermediates B-18a to B-181 (see Tables 15-4 and 15-5 below) and a salt thereof.

[0353] The intermediate (ie, B-18) obtained after the hydration step, which still has the acetyl and Boc protecting groups, is also part of the present invention.

[0354] In another aspect, the present invention also relates to synthetic intermediates of formula B-19 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0355]

[0356] B-19 group R 4 , R 7 The definitions of A, V, W, X, Y, r and q correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e. with respect to A / R 4 / r[C0], as for R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0357] Preferred intermediates B-19 are those such that the preferred compounds (Ia) and (Ia*) according to the present invention (i.e., preferred embodiments of B-19) have a total of 4 / r for [C0] to [C15], for R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combination CEFG to obtain the preferred intermediate B-19 (aspects E and F can be replaced by combination aspect EF). Each combination CEFG represents and defines an individual embodiment or a general subset of intermediate B-19. Preferred intermediate B-19 is selected from intermediates B-19a to B-19f (see Table 15-6 below), including salts thereof.

[0358] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-19 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0359] In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-19, or a salt thereof,

[0360]

[0361] It comprises making the compound of formula B-18 or its salt

[0362]

[0363] Reaction with a compound of formula S-1 or a salt thereof

[0364]

[0365] The reaction is carried out in a solvent in the presence of an acid and a base, and R 4 , R 7 , A, V, W, X, Y, r and q are as defined above. (Step D)

[0366] Example / conditions of step D:

[0367] The selected solvent may be an organic solvent, which is preferably selected from the group consisting of MeOH, DMF, ACN, NMP and THF, or a mixture thereof, and most preferably a mixture of MeOH and DMF.

[0368] The acid used is preferably an organic acid, more preferably a carboxylic acid, and most preferably AcOH.

[0369] The base used is preferably an organic base, more preferably an amine base, for example, a tertiary amine. The tertiary amine is preferably selected from the group consisting of TEA, DIPEA and N-ethyldicyclohexylamine. TEA is most preferably used.

[0370] The reaction can be carried out at a temperature ranging from about -10°C to about 50°C, preferably at about 10°C to about 20°C.

[0371] A preferred intermediate B-19 synthesized by this method is any one selected from intermediates B-19a to B-191 (see Table 15-6 below) (including salts thereof).

[0372] In another aspect, the present invention also relates to synthetic intermediates of formula B-20 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0373]

[0374] B-20 Group R 2 , R 3 , R 4 , R 7 The definitions of A, V, W, X, Y, r and q correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], A / R 4 / r[C0], as for R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0375] Preferred intermediates B-20 are those such that the preferred compounds (Ia) and (Ia*) according to the present invention (i.e., preferred embodiments of B-20) have a total of 2 / R 3 For [B0] to [B17], for A / R 4 / r for [C0] to [C15], for R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced as needed in the form of combinations BCEFG to obtain preferred intermediates B-20 (aspects E and F can be replaced by combination aspects EF). Each combination BCEFG represents and defines an individual embodiment or a general subset of intermediates B-20. Preferred intermediates B-20 are selected from intermediates B-20a to B-20f (see Table 15-7 below), including salts thereof.

[0376] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-20 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0377] In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-20, or a salt thereof,

[0378]

[0379] It comprises making the compound of formula B-2 or its salt

[0380]

[0381] Reaction with a compound of formula B-19 or a salt thereof

[0382] in

[0383] The reaction is carried out in a solvent in the presence of a base, and R 2 , R 3 , R 4 , R 7 , A, V, W, X, Y, r and q are as defined above. (Step E)

[0384] Example / conditions of Step E:

[0385] The selected solvent 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) and water. The most preferred is a mixture of toluene and water.

[0386] The base used is preferably an organic base, more preferably an amine base. The amine base is preferably selected from the group consisting of N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, 1-(2-hydroxyethyl)-pyrrolidine, 3-quinuclidinol and DABCO. The most preferred is N-methylpyrrolidine.

[0387] The reaction can be carried out at a temperature ranging from about 35°C to about 110°C, preferably from about 40°C to about 85°C.

[0388] A preferred intermediate B-20 synthesized by this method is any one selected from the intermediates B-20a to B-20f (see Table 15-7 below) (including salts thereof).

[0389] In another aspect, the present invention also relates to a method for chiral separation of a mixture comprising two enantiomers of an intermediate of formula B-20,

[0390]

[0391] This involves precipitation of one enantiomer as a salt with a chiral acid.

[0392] Examples / conditions for chiral separation:

[0393] The chiral acid used is preferably selected from, for example, (+)-di-O,O'-dibenzoyl-D-tartaric acid, (-)-di-O,O'-dibenzoyl-L-tartaric acid, (+)-di-O,O'-p-toluoyl-D-tartaric acid, (-)-di-O,O'-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. The most preferred are (1R)-(-)- and (1S)-(+)-camphor-10-sulfonic acid. The salt of the enantiomer is precipitated from a solution or suspension of compound B-20 in a suitable solvent (preferably ACN). Without wishing to be bound by theory, it is speculated that the formation of an unstable acetonitrile solvate that precipitates camphor-10-sulfonate may result in the resolution of a racemic mixture of the optimal compound. The salt is selectively precipitated, that is, one enantiomer is precipitated in the form of a salt of a chiral acid and the other enantiomer is retained / substantially dissolved under the conditions applied. The free enantiomer can be recovered from the salt by ion exchange. If complete separation cannot be achieved, the methods described above can also be applied to the enrichment of one enantiomer relative to the other or the steps can be repeated several times to achieve complete separation. Separation means that each enantiomer / salt is obtained in a form that is substantially free of the other enantiomer. Preferably, the chiral acid is used in a substoichiometric amount relative to the enantiomer to be separated, that is, preferably in the range of 0.5 to 0.9 eq (about 0.6 eq is optimal). The total concentration of the racemate in the solution / suspension before separation is preferably in the range of 50 to 150 g / L, with about 100 g / L being optimal.

[0394] A preferred chiral intermediate B-20 (which can be separated from its enantiomer by this method) is any one selected from the intermediates B-20g to B-201 (see Table 15-7 below) (including salts thereof).

[0395] In another aspect, the present invention also relates to synthetic intermediates of formula B-21 and their salts, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0396]

[0397] Group R in B-21 2 , R 3 , R 4 , R 7 The definitions of A, V, W, X, Y, r and q correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], A / R 4 / r[C0], as for R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0398] Preferred intermediates B-21 are those such that the preferred compounds (Ia) and (Ia*) according to the present invention (i.e., preferred embodiments of B-21) have a total of 2 / R 3 For [B0] to [B17], for A / R 4 / r for [C0] to [C15], for R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V, and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combinations BCEFG to obtain preferred intermediates B-21 (aspects E and F can be replaced by combination aspects EF). Each combination BCEFG represents and defines an individual embodiment or a general subset of intermediates B-21. Preferred intermediates B-21 are selected from intermediates B-21a to B-21f (see Table 15-8 below), including salts thereof.

[0399] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-21 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0400] In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-21 or a salt thereof,

[0401]

[0402] It comprises a hydrogenated compound of formula B-20 or a salt thereof,

[0403] in

[0404] The reaction is carried out in a solvent in the presence of a Pt catalyst, and R 2 , R 3 , R 4 , R 7 , A, V, W, X, Y, r and q are as defined above.

[0405] Examples / conditions of this step:

[0406] The selected solvent may be an organic solvent. Preferably, the organic solvent is selected from the group consisting of MeTHF, THF, MeOH, nBuOAc and iPrOAc, or a mixture thereof. The most preferred is MeTHF.

[0407] Preferably, the Pt catalyst used is Pt / C.

[0408] The reaction can be carried out at a temperature ranging from about 20°C to about 100°C, preferably at about 20°C to about 30°C.

[0409] The H2 pressure applied for hydrogenation is preferably in the range of about 20 bar to about 70 bar. The most preferred H2 pressure is in the range of about 60 bar to about 70 bar.

[0410] A preferred intermediate B-21 synthesized by this method is any one selected from the intermediates B-21a to B-21f (see Table 15-8 below) (including salts thereof).

[0411] In another aspect, the present invention also relates to synthetic intermediates of formula B-22 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0412]

[0413] B-22 group R 2 , R 3 , R 4 , R 7 The definitions of A, V, W, X, Y, r and q correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], A / R 4 / r[C0], as for R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0414] Preferred intermediates B-22 are those such that the preferred compounds (Ia) and (Ia*) according to the present invention (i.e., preferred embodiments of B-22) have a total of 2 / R 3 For [B0] to [B17], for A / R 4 / r for [C0] to [C15], for R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combinations BCEFG to obtain preferred intermediates B-22 (aspects E and F can be replaced by combination aspects EF). Each combination BCEFG represents and defines an individual embodiment or a general subset of intermediates B-22. Preferred intermediates B-22 are selected from intermediates B-22a to B-22f (see Table 15-8 below), including salts thereof.

[0415] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-22 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0416] In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-22 or a salt thereof,

[0417]

[0418] It comprises a hydrogenated compound of formula B-21 or a salt thereof,

[0419] in

[0420] The reaction is carried out in a solvent in the presence of a Pt catalyst and a V catalyst, and R 2 , R 3 , R 4 , R 7 , A, V, W, X, Y, r and q are as defined above.

[0421] Examples / conditions of this step:

[0422] The selected solvent may be an organic solvent. Preferably, the organic solvent is selected from the group consisting of MeTHF, THF, MeOH, nBuOAc and iPrOAc, or a mixture thereof. The most preferred is MeTHF.

[0423] Preferably, the Pt catalyst used is Pt / C.

[0424] Preferably, the V catalyst used is a V(IV) catalyst, and most preferably VO(acac)2.

[0425] The reaction can be carried out at a temperature ranging from about 20°C to about 60°C, preferably at about 20°C to about 30°C.

[0426] The H2 pressure applied for hydrogenation is preferably in the range of about 3 to about 70 bar. The most preferred H2 pressure is in the range of about 60 to about 70 bar.

[0427] A preferred intermediate B-22 synthesized by this method is any one selected from the intermediates B-22a to B-22f (see Table 15-8 below) (including salts thereof).

[0428] In another aspect, the present invention also relates to a method for chiral separation of a mixture comprising two enantiomers of an intermediate of formula B-22,

[0429]

[0430] This involves precipitation of one enantiomer as a salt with a chiral acid.

[0431] Examples / conditions for chiral separation:

[0432] The chiral acid used is preferably selected from, for example, (+)-di-O,O'-dibenzoyl-D-tartaric acid, (-)-di-O,O'-benzoyl-L-tartaric acid, (+)-di-O,O'-p-toluoyl-D-tartaric acid, (-)-di-O,O'-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. The best are (+)-di-O,O'-p-toluoyl-D-tartaric acid and (-)-di-O,O'-p-toluoyl-L-tartaric acid. The salts of the enantiomers are precipitated from a solution or suspension of compound B-22 in a suitable solvent (preferably ACN). The salt is selectively precipitated, that is, one enantiomer is precipitated in the form of a salt of a chiral acid and the other enantiomer is retained / substantially dissolved under the conditions applied. The free enantiomer can be recovered from the salt by ion exchange. If complete separation cannot be achieved, the methods described above can also be applied to the enrichment of one enantiomer relative to the other or the steps can be repeated several times to achieve complete separation. Separation means that the various enantiomers / salts are obtained in a form that is substantially free of another enantiomer. Preferably, the chiral acid is used in a substoichiometric amount relative to the enantiomer to be separated, that is, preferably in the range of 0.5 to 1 eq (1 eq is optimal). The total concentration of the racemate in the solution / suspension before separation is preferably in the range of 50 to 150 g / L, with about 100 g / L being optimal.

[0433] A preferred chiral intermediate B-22 (which can be separated from its enantiomer by this method) is any one selected from the intermediates B-22a to B-22f (see Table 15-7 below) (including salts thereof).

[0434] In another aspect, the present invention also relates to synthetic intermediates of formula B-23 and their salts, which can be used as important intermediates in the synthesis of compounds of formula (Ia) and (Ia*):

[0435]

[0436] B-23 group R 2 , R 3 , R 4 , R 7 The definitions of A, V, W, X, Y, r and q correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], A / R 4 / r[C0], as for R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0437] Preferred intermediates B-23 are those such that the preferred compounds (Ia) and (Ia*) according to the present invention (i.e., preferred embodiments of B-23) have a total of 2 / R 3 For [B0] to [B17], for A / R 4 / r for [C0] to [C15], for R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combinations BCEFG to obtain preferred intermediates B-23 (aspects E and F can be replaced by combination aspects EF). Each combination BCEFG represents and defines an individual embodiment or a general subset of intermediates B-23. Preferred intermediates B-23 are selected from intermediates B-23a to B-23f (see Table 15-9 below), including salts thereof.

[0438] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula B-23 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia*).

[0439] In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-23 or a salt thereof,

[0440]

[0441] It includes a compound of the oxidized formula B-22 or a salt thereof,

[0442] in

[0443] The reaction is carried out in a solvent in the presence of a catalyst and an oxidant, and R 2 , R 3 , R 4 , R 7 , A, V, W, X, Y, r and q are as defined above.

[0444] Examples / conditions of this step:

[0445] The selected solvent 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) and water. The most preferred is a mixture of DCM and water.

[0446] The catalyst used may be a Mo-, V- or W-catalyst. Preferably, the catalyst is selected from the group consisting of (NH4)2MoO4, Na2MoO4, VO(acac)2, MoO2(acac)2, Na2WO4*2H2O. The best is Na2WO4*2H2O.

[0447] As far as oxidizing agents are concerned, H2O2 (particularly H2O2 in water) is preferably used.

[0448] The reaction can be carried out at a temperature ranging from about 0°C to about 50°C, preferably at about 35°C to about 40°C.

[0449] A preferred intermediate B-23 synthesized by this method is any one selected from the intermediates B-23a to B-23f (see Table 15-9 below) (including salts thereof).

[0450] The synthetic steps B-20→B-21, B-21→B-22 and B-22→B-23 can also be carried out via the racemic intermediates B-20, B-21 and B-22, respectively (if chiral separation of B-20 is not performed). The racemic intermediates B-21, B-22 and B-23 and the corresponding reaction steps utilizing these racemic intermediates are also part of the present invention.

[0451] In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-18, comprising step A as described above (variant 1). In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-18, comprising step A and step B as described above (variant 2). In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-18, comprising step A and step B and step C as described above (variant 3). The synthesis according to variants 1 to 3 is superior to the alternative methods that can be considered and improves the overall synthesis efficiency and total throughput, reduces costs, and reduces solvents and waste.

[0452] In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-20, comprising step D as described above (variant 4). In another aspect, the present invention also relates to a method for synthesizing an intermediate of formula B-20, comprising step D and step E as described above (variant 5). In another aspect, the present 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 (variant 6) as described above.

[0453] In another aspect, the present invention also relates to a method for synthesizing compounds of formula (Ia) and (Ia*) comprising a variant selected from variants 1 to 6.

[0454] All steps mentioned above include all embodiments / conditions of how such steps may be performed as disclosed above.

[0455] In another aspect, the present invention also relates to synthetic intermediates of formula A-12 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ib) and (Ib*):

[0456]

[0457] A-12 group R 2 , R 3 , R 7 The definitions of , V, W, X, Y, n and q correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], in terms of n [D0], in terms of R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0458] Preferred intermediates A-12 are those such that the preferred compounds (Ib) and (Ib*) according to the present invention (i.e. preferred embodiments of A-12) have a total of 2 / R 3 [B0] to [B17] for n [D0] to [D3] for R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combinations BDEFG to obtain the preferred intermediate A-12 (aspects E and F can be replaced by combination aspect EF). Each combination BDEFG represents and defines an individual embodiment or a general subset of intermediate A-12.

[0459] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula A-12 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ib) and (Ib*).

[0460] In another aspect, the present invention also relates to synthetic intermediates of formula A-13 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ib) and (Ib*):

[0461]

[0462] A-13 group R 2 , R 3 , R 4 , R 7 The definitions of A, V, W, X, Y, n, q and r correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], A / R 4 / r[C0], n[D0], R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0463] Preferred intermediates A-13 are those such that the preferred compounds (Ib) and (Ib*) according to the present invention (i.e. preferred embodiments of A-13) have a total of 2 / R 3 For [B0] to [B17], for A / R 4 / r [C0] to [C15], n [D0] to [D3], R 7[E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combinations BCDEFG to obtain the preferred intermediate A-13 (aspects E and F can be replaced by combination aspect EF). Each combination BCDEFG represents and defines an individual embodiment or a general subset of intermediate A-13.

[0464] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula A-13 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ib) and (Ib*).

[0465] In another aspect, the present invention also relates to synthetic intermediates of formula A-14 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ib) and (Ib*):

[0466]

[0467] A-15 group R 2 , R 3 , R 4 , R 7 The definitions of A, V, W, X, Y, n, q and r correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], A / R 4 / r[C0], n[D0], R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0468] Preferred intermediates A-14 are those such that the preferred compounds (Ib) and (Ib*) according to the present invention (i.e. preferred embodiments of A-14) have a total of 2 / R 3 For [B0] to [B17], for A / R 4 / r [C0] to [C15], n [D0] to [D3], R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combinations BCDEFG to obtain the preferred intermediate A-14 (aspects E and F can be replaced by combination EF). Each combination BCDEFG represents and defines an individual embodiment or a general subset of intermediate A-14.

[0469] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula A-14 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ib) and (Ib*).

[0470] In another aspect, the present invention also relates to synthetic intermediates of formula A-15 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ib) and (Ib*):

[0471]

[0472] A-15 group R 2 , R 3 , R 4 , R 7 The definitions of A, V, W, X, Y, n, q and r correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], A / R 4 / r[C0], n[D0], R 7 For / q [E0], for W / X / Y [F0], and for V [G0].

[0473] Preferred intermediates A-15 are those such that the preferred compounds (Ib) and (Ib*) according to the present invention (i.e. preferred embodiments of A-15) have a total of 2 / R 3 For [B0] to [B17], for A / R 4 / r [C0] to [C15], n [D0] to [D3], R 7 [E0] to [E2] for / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [G1] for R 7 / q / W / X / Y for the structural aspects of [EF0] and [EF1]. These structural aspects can be replaced with each other as needed in the form of combinations BCDEFG to obtain the preferred intermediate A-15 (aspects E and F can be replaced by combination EF). Each combination BCDEFG represents and defines an individual embodiment or a general subset of intermediate A-15.

[0474] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula A-15 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ib) and (Ib*).

[0475] In another aspect, the present invention also relates to synthetic intermediates of formula A-17 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ib) and (Ib*):

[0476]

[0477] A-17 group R 2 , R 3 , R 4 The definitions of A and r correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 For [B0], and for A / R 4 / r for [C0].

[0478] Preferred intermediates A-17 are those that allow the preferred compounds (Ib) and (Ib*) according to the present invention (i.e. preferred embodiments of A-17) to have a residue selected from the group consisting of 2 / R 3 For [B0] to [B17] and for A / R 4 / r refers to the structural aspects of [C0] to [C15]. These structural aspects can be replaced with each other in the form of combination BC as needed to obtain the preferred intermediate A-17. Each combination BC represents and defines an individual embodiment or a general subset of intermediate A-17.

[0479] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula A-17 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ib) and (Ib*).

[0480] In another aspect, the present invention also relates to synthetic intermediates of formula A-18 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ib) and (Ib*):

[0481]

[0482] A-18 group R 2 , R 3 , R 4The definitions of A and r correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 For [B0], and for A / R 4 / r for [C0].

[0483] Preferred intermediates A-18 are those that allow the preferred compounds (Ib) and (Ib*) according to the present invention (i.e. preferred embodiments of A-18) to have a residue selected from the group consisting of 2 / R 3 For [B0] to [B17] and for A / R 4 / r refers to the structural aspects of [C0] to [C15]. These structural aspects can be replaced with each other in the form of combination BC as needed to obtain the preferred intermediate A-18. Each combination BC represents and defines an individual embodiment or a general subset of intermediate A-18.

[0484] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula A-18 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ib) and (Ib*).

[0485] In another aspect, the present invention also relates to synthetic intermediates of formula A-20 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ib) and (Ib*):

[0486]

[0487] A-20 group R 2 , R 3 , R 4 The definitions of A, n and r correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], A / R 4 / r is [C0], and with respect to n is [D0].

[0488] Preferred intermediates A-20 are those that allow the preferred compounds (Ib) and (Ib*) according to the present invention (i.e. preferred embodiments of A-20) to have a residue selected from the group consisting of 2 / R 3 For [B0] to [B17], for A / R 4 / r for [C0] to [C15] and for n for [D0] to [D3]. These structural aspects can be replaced with each other in the form of combination BCD as needed to obtain the preferred intermediate A-20. Each combination BCD represents and defines an individual embodiment or a general subset of intermediate A-20.

[0489] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula A-20 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ib) and (Ib*).

[0490] In another aspect, the present invention also relates to synthetic intermediates of formula A-21 and salts thereof, which can be used as important intermediates in the synthesis of compounds of formula (Ib) and (Ib*):

[0491]

[0492] A-21 group R 2 , R 3 , R 4 The definitions of A, n and r correspond to those given for the above compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), i.e., with respect to R 2 / R 3 In terms of [B0], A / R 4 / r is [C0], and with respect to n is [D0].

[0493] Preferred intermediates A-21 are those that allow the preferred compounds (Ib) and (Ib*) according to the present invention (i.e. preferred embodiments of A-21) to have a residue selected from the group consisting of 2 / R 3 For [B0] to [B17], for A / R 4 / r for [C0] to [C15] and for n for [D0] to [D3]. These structural aspects can be replaced with each other in the form of combinations BCD as needed to obtain the preferred intermediate A-21. Each combination BCD represents and defines an individual embodiment or a general subset of intermediate A-21.

[0494] In another aspect, the present invention also relates to the use of a synthetic intermediate of formula A-21 or a salt thereof (and the various embodiments and subsets as described and / or defined herein) in the synthesis of compounds (Ib) and (Ib*).

[0495] The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, isomers and prodrugs of compounds of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*).

[0496] Compounds of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), which for example have an ester group, are potential prodrugs, the ester being cleaved under physiological conditions.

[0497] The present invention further relates to a pharmaceutically acceptable salt of a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*).

[0498] The present invention further relates to a co-catalyst for a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), preferably a pharmaceutically acceptable co-catalyst.

[0499] In one aspect, compound (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) according to the present invention is in amorphous form.

[0500] The present invention further relates to a pharmaceutically acceptable salt of a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) with an inorganic or organic acid or base.

[0501] The present invention relates to compounds of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), which can be used to prevent and / or treat diseases and / or conditions in which inhibition of the interaction between MDM2 and p53 has therapeutic benefits, including (but not limited to) the treatment and / or prevention of cancer.

[0502] In another aspect, the present invention relates to a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0503] In another aspect, the present invention relates to a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body.

[0504] In another aspect, the present invention relates to a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of diseases and / or conditions in which inhibition of the interaction between MDM2 and p53 is of therapeutic benefit.

[0505] In another aspect, the present invention relates to a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof for use in treating and / or preventing cancer, infection, inflammation or autoimmune disease.

[0506] In another aspect, the present invention relates to a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof for use in a method for treating and / or preventing cancer, infection, inflammation or autoimmune disease in humans and animals.

[0507] In another aspect, the present invention relates to the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) - or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment and / or prevention of cancer, infection, inflammation or autoimmune disease.

[0508] In another aspect, the present invention relates to a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof for use in treating and / or preventing cancer.

[0509] In another aspect, the present invention relates to the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) - or a pharmaceutically acceptable salt thereof, for preparing a pharmaceutical composition for treating and / or preventing cancer.

[0510] In another aspect, the present invention relates to a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), or a pharmaceutically acceptable salt thereof, for use in a method for treating and / or preventing cancer in the human or animal body.

[0511] In another aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof for use in treating and / or preventing acute myeloid leukemia (AML), prostate cancer or lung cancer, wherein the cancer cells have functional p53, preferably, wherein the cancer cells are p53 wild type.

[0512] In another aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing acute myeloid leukemia (AML), prostate cancer or lung cancer, wherein the cancer cells preferably have functional p53, more preferably, wherein the cancer cells are p53 wild type.

[0513] In another aspect, the present invention relates to the use of a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating and / or preventing acute myeloid leukemia (AML), prostate cancer or lung cancer, wherein the cancer cells have functional p53, preferably, wherein the cancer cells are p53 wild type.

[0514] In another aspect, the present invention relates to the use of a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating and / or preventing acute myeloid leukemia (AML), prostate cancer or lung cancer, wherein the cancer cells preferably have functional p53, more preferably, wherein the cancer cells are p53 wild type.

[0515] In another aspect, the present invention relates to a method for treating and / or preventing diseases and / or conditions in which inhibition of the interaction between MDM2 and p53 is therapeutically beneficial, comprising administering to a human a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof.

[0516] In another aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a human a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof.

[0517] In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of Formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0518] In another aspect, the present invention relates to a pharmaceutical formulation comprising a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof and at least one other cytostatic and / or cytotoxic active substance.

[0519] In another aspect, the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of cancer, infection, inflammation or autoimmune diseases, wherein the compound is administered before, after or together with at least one other cytostatic or cytotoxic active substance.

[0520] In another aspect, the present invention relates to the use of a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and / or prevention of cancer, infection, inflammation or autoimmune diseases, wherein the compound is administered before, after or together with at least one other cytostatic or cytotoxic active substance.

[0521] In another aspect, the present invention relates to a cytostatic or cytotoxic active substance prepared for administration before, after or together with a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of cancer, infection, inflammation or autoimmune diseases.

[0522] In another aspect, the present invention relates to a method for the treatment and / or prevention of cancer, infection, inflammation or autoimmune diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) or a pharmaceutically acceptable salt thereof before, after or together with at least one other cytostatic or cytotoxic active substance.

[0523] Definitions

[0524] Terms not explicitly defined herein should be assigned their meanings by those skilled in the art based on the disclosure and context. However, as used in this specification, unless otherwise specified, the following terms have the indicated meanings and are accompanied by the following conventions:

[0525] Use of the prefix C x-y (where x and y each represent natural numbers (x < y)) indicates that the directly linked designated and mentioned chain or ring structure or combination of chain and ring structures as a whole can consist of a maximum of y carbon atoms and a minimum of x carbon atoms.

[0526] Indications of the number of members in groups containing one or more heteroatoms (e.g., heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl) relate to the total number of atoms of all ring members or chain members or the total number of all ring and chain members.

[0527] The indication of the number of carbon atoms in a group consisting of a combination of a carbon chain and a carbon ring structure (e.g., cycloalkylalkyl, arylalkyl) relates to the total number of carbon atoms of all carbon ring and carbon chain members. Obviously, the ring structure has at least three members.

[0528] In general, for groups containing two or more subgroups (e.g., heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, arylalkyl), the last subgroup named is the point of attachment of the group, e.g., the substituent aryl-C 1-6 Alkyl means bonded to C 1-6 The aryl group of an alkyl group is attached to the core or group to which the substituent is attached.

[0529] Alkyl represents a monovalent saturated hydrocarbon chain which may exist in both straight-chain (unbranched) and branched form. If the alkyl group is substituted, the substitution may occur independently of one another in each case in the form of mono- or polysubstitution on all hydrogen-carrying carbon atoms.

[0530] The term "C 1-5 “Alkyl” 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-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)-, and H3C-CH2-CH(CH2CH3)-.

[0531] Other examples of alkyl groups are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (i-Pr; isopropyl; -CH(CH3)2), 1-butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-1-propyl (isobutyl; i-Bu; -CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl; t-Bu; -C(CH3)3), 1-pentyl (n-butyl; n-Bu; -CH2CH2CH2CH3), Pentyl; -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 3-methyl-1-butyl (isopentyl; -CH2CH2CH(CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethyl-1-propyl (neopentyl; -CH2C(CH3)3), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (n-hexyl;-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 2,3- Dimethyl-1-butyl (-CH2CH(CH3)CH(CH3)CH3), 2,2-dimethyl-1-butyl (-CH2C(CH3)2CH2CH3), 3,3-dimethyl-1-butyl (-CH2CH2C(CH3)3), 2-methyl-1-pentyl (-CH2CH(CH3)CH2CH2CH3), 3-methyl-1-pentyl (-CH2CH2CH(CH3)2CH2CH3), 3) CH2CH3), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl), etc.;

[0532] The terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., unless otherwise defined, refer to saturated hydrocarbon groups having the corresponding number of carbon atoms, including all isomeric forms.

[0533] If alkyl is another (combined) group such as (for example) C x-y Alkylamine or C x-y If the alkyl group is part of an alkyloxy group, the above definition of alkyl group also applies.

[0534] The term alkylene can also be derived from alkyl. Unlike alkyl, alkylene is divalent and requires two bonding partners. Usually, the second valency is generated by removing a hydrogen atom from the alkyl. The corresponding groups are, for example, -CH3 and -CH2-, -CH2CH3 and -CH2CH2- or >CHCH3, etc.

[0535] The term "C 1-4The term "alkylene" includes, for example, -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-CH 2-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)-.

[0536] Other examples of alkylene groups 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, and the like.

[0537] The generic terms propylene, butylene, pentylene, hexylene, etc., in the absence of any other definition, mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e., propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

[0538] If alkylene is another (combined) group such as (for example) HO-C x-y Alkyleneamine or H2N-C x-y If the alkylene group is part of an alkyleneoxy group, the above definition of alkylene also applies.

[0539] Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C double bond and a carbon atom can only be part of one C-C double bond. If there are at least two carbon atoms in an alkyl as defined above, two hydrogen atoms on adjacent carbon atoms are usually removed and the free valencies are saturated to form a second bond, forming the corresponding alkenyl.

[0540] Examples of alkenyl groups are vinyl (vinyl / ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methylprop-1-enyl, 1-methyl-prop-2-enyl, 1-methylprop-1-enyl, 1-methylenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methylbut-3-enyl, 3-methylbut-2-enyl, 3-methylbut-3-enyl, 3-methylbut-2-enyl, 3-methylbut-4-enyl, 3-methylbut-4-enyl, 3-methylbut-5-enyl, 3-methylbut-6-enyl, 3-methylbut-7-enyl, 3-methylbut-8-enyl, 3-methylbut-9-enyl, 3-methylbut-10-enyl, 3-methylbut-11-enyl, 3-methylbut-12-enyl, 3-methylbut-13-enyl, 3-methylbut-14-enyl, 3-methylbut-15-enyl, 3-methylbut-2-enyl, 3-methylbut-2-enyl, 3-methylbut-15 ... 1,3-dienyl, 2,3-dimethylbut-2-enyl, 2-methylene-3-methylbutyl, 2,3-dimethylbut-1-enyl, hex-1,3-dienyl, hex-1,4-dienyl, pent-1,4-dienyl, pent-1,3-dienyl, but-1,3-dienyl, 2,3-dimethylbut-1,3-dienyl, etc.

[0541] The generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, etc., in the absence of any other definition, mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e., propenyl includes prop-1-enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methylprop-1-enyl, 1-methylprop-2-enyl, etc.

[0542] An alkenyl group may optionally be present in a cis or trans or E or Z orientation about the double bond.

[0543] When alkenyl is another (combined) group such as (for example) C x-y Alkenylamine or C x-y When the radical is part of an alkenyloxy group, the above definition of alkenyl also applies.

[0544] Unlike alkylene, alkenylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C double bond and the carbon atom can only be part of one C-C double bond. If there are at least two carbon atoms in an alkylene as defined above, two hydrogen atoms at adjacent carbon atoms are usually removed and the free valencies are saturated to form a second bond, forming the corresponding alkenylene.

[0545] Examples of alkenylene are vinylene, propenylene, 1-methylvinylene, butenylene, 1-methylpropenylene, 1,1-dimethylvinylene, 1,2-dimethylvinylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene, and the like.

[0546] The generic terms propenylene, butenylene, pentenylene, hexenylene, etc., without any other definition, mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e., propenylene includes 1-methylvinylene and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylvinylene and 1,2-dimethylvinylene.

[0547] An alkenylene group may optionally be present in a cis or trans, or E or Z orientation about the double bond.

[0548] When alkenylene is another (combined) group such as (for example) HO-C x-y Alkenyleneamine or H2N-C x-y When the radical is part of an alkenyleneoxy group, the above definition of alkenylene also applies.

[0549] Unlike alkyl, alkynyl consists of at least two carbon atoms, of which at least two adjacent carbon atoms are linked together by a C-C triple bond. If there are at least two carbon atoms in an alkyl group as defined above, two hydrogen atoms at adjacent carbon atoms in each case are usually removed and the free valencies are saturated to form two further bonds to form the corresponding alkynyl.

[0550] Examples of alkynyl groups are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methylprop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methylbut-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, and the like.

[0551] The generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc., in the absence of any other definition, are intended to mean all conceivable isomeric forms having 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-methylprop-1-ynyl, 1-methylprop-2-ynyl, etc.

[0552] If the hydrocarbon chain has not only at least one double bond but also at least one triple bond, it is by definition an alkynyl subgroup.

[0553] If alkynyl is another (combined) group such as (for example) C x-y Alkynylamine or C x-y If the alkynyl group is part of an alkynyloxy group, the above definition of alkynyl also applies.

[0554] Unlike alkylene, alkynylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C triple bond. If there are at least two carbon atoms in an alkylene as defined above, two hydrogen atoms at adjacent carbon atoms in each case are usually removed and the free valencies are saturated to form two further bonds to form the corresponding alkynylene.

[0555] Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene, and the like.

[0556] The generic terms propynylene, butynylene, pentynylene, hexynylene, etc., without any other definition, are intended to mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e., propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.

[0557] If alkynylene is another (combined) group such as (for example) HO-C x-y Alkynylideneamine or H2N-C x-y If the alkynylene group is part of an alkynyleneoxy group, the above definition of alkynylene also applies.

[0558] The heteroatom means oxygen, nitrogen and sulfur atoms.

[0559] Haloalkyl (haloalkenyl, haloalkynyl) 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 the haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitutions may be carried out independently of one another in each case in the form of mono- or polysubstitutions on all hydrogen-carrying carbon atoms.

[0560] Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCl=CH2, -CBr=CH2, -C≡C-CF3, -CHFCH2CH3, -CHFCH2CF3, etc.

[0561] From the previously defined haloalkyl (haloalkenyl, haloalkynyl) is also derived the term haloalkylene (haloalkenylene, haloalkynylene). Unlike haloalkyl (haloalkenyl, haloalkynyl), haloalkylene (haloalkenylene, haloalkynylene) is divalent and requires two bonding partners. Typically, the second valency is formed by removing a hydrogen atom from a haloalkyl (haloalkenyl, haloalkynyl) group.

[0562] Corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH2F, etc.

[0563] The above definition also applies if the corresponding halogen-containing group is part of another (composite) group.

[0564] Halogen refers to fluorine, chlorine, bromine and / or iodine atoms.

[0565] Cycloalkyl is composed of sub-monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro hydrocarbon rings. These systems are saturated. In bicyclic hydrocarbon rings, two rings are linked together so that they have at least two carbon atoms together. In spiro hydrocarbon rings, one carbon atom (spiro atom) belongs to two rings together.

[0566] If the cycloalkyl radical is to be further substituted, the substitution may take place independently of one another in each case in the form of mono- or polysubstitution on all hydrogen-carrying carbon atoms. The cycloalkyl radical itself can be attached to the molecule as a substituent via every suitable position of the ring system.

[0567] 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 (octahydroindolyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornenyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl, and the like.

[0568] If cycloalkyl is another (combined) group such as (for example) C x-y Cycloalkylamino, C x-y Cycloalkyloxy or C x-y If the cycloalkyl group is part of an alkyl group, the above definition of cycloalkyl group also applies.

[0569] If the free valencies of the cycloalkyl group are saturated, an aliphatic radical is obtained.

[0570] The term cycloalkylene can thus be derived from the cycloalkyl defined above. Unlike cycloalkyl, cycloalkylene is divalent and requires two bonding partners. Usually, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are, for example:

[0571] Cyclohexyl and (cyclohexylene).

[0572] If cycloalkylene is another (combined) group such as (for example) HO-C x-y Cycloalkyleneamine or H2N-C x-y If the cycloalkylene group is part of a cycloalkyleneoxy group, the above definition of cycloalkylene also applies.

[0573] Cycloalkenyl groups are also composed of subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro hydrocarbon rings. However, these systems are unsaturated, i.e., at least one CC double bond is present, but there is no aromatic system. If two hydrogen atoms at adjacent ring carbon atoms in a cycloalkyl group as defined above are usually removed and the free valences are saturated to form a second chemical bond, the corresponding cycloalkenyl group is obtained.

[0574] If cycloalkenyl is substituted, the substitution may take place independently of one another and in each case in the form of mono- or polysubstitution on all hydrogen-carrying carbon atoms. Cycloalkenyl itself can be attached to the molecule as a substituent via every suitable position of the ring system.

[0575] Examples of cycloalkenyl groups are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, 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-1,4-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]hept-2,5-dienyl (norbornene--2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornene), spiro[4,5]dec-2-enyl, etc.

[0576] When cycloalkenyl is another (combined) group such as (for example) C x-y Cycloalkenylamine, C x-y Cycloalkenyloxy or C x-y When the radical is part of a cycloalkenylalkyl group, the above definition of cycloalkenyl also applies.

[0577] If the free valencies of the cycloalkenyl group are saturated, an unsaturated aliphatic radical is obtained.

[0578] The term cycloalkenylene can thus be derived from the cycloalkenyl group defined above. Unlike cycloalkenyl, cycloalkenylene is divalent and requires two binding partners. Usually, the second valency is obtained by removing a hydrogen atom from a cycloalkenyl group. Corresponding groups are, for example:

[0579] Cyclopentenyl and (cyclopentenylene), etc.

[0580] If cycloalkenylene is another (combined) group such as (for example) HO-C x-y Cycloalkenylamine or H2N-C x-y As a part of a cycloalkenyleneoxy group, the above definition of cycloalkenylene also applies.

[0581] Aryl represents a monocyclic, bicyclic or tricyclic carbocycle having at least one aromatic carbocyclic ring. Preferably, it represents a monocyclic group having six carbon atoms (phenyl) or a bicyclic group having nine or ten carbon atoms (two six-membered rings or one six-membered ring and one five-membered ring), wherein the second ring may also be aromatic or, however, may also be partially saturated.

[0582] If aryl is substituted, the substitution may take place independently of one another in each case in the form of mono- or polysubstitution on all hydrogen-carrying carbon atoms. Aryl itself can be attached to the molecule as a substituent via every suitable position of the ring system.

[0583] Examples of aryl groups are phenyl, naphthyl, dihydroindenyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorenyl, and the like.

[0584] The above definition of aryl also applies if aryl is part of another (composite) group such as for example arylamino, aryloxy or arylalkyl.

[0585] If the free valencies of the aryl group are saturated, an aromatic radical is obtained.

[0586] The term arylene can also be derived from the aryl group defined above. Unlike aryl, arylene is divalent and requires two bonding partners. Usually, the second valency is obtained by removing a hydrogen atom from the aryl group. Corresponding groups are, for example:

[0587] Phenyl and (o-phenylene, m-phenylene, p-phenylene), naphthyl and wait.

[0588] The above definition of arylene also applies if arylene is part of another (composite) group such as for example HO--aryleneamino or H2N-aryleneoxy.

[0589] Heterocyclyl is a ring system derived from the cycloalkyl, cycloalkenyl and aryl groups defined above by replacing one or more -CH2- radicals in the hydrocarbon ring independently of one another by -O-, -S- or -NH- radicals or by replacing one or more =CH- radicals by =N- radicals, in which a total of not more than five heteroatoms may be present, at least one carbon atom must be present between two oxygen atoms and between two sulfur atoms or between an oxygen atom and a sulfur atom and the ring as a whole must be chemically stable. The heteroatoms may optionally be present in all possible oxidation stages (sulfur→sulfoxide -SO-, sulfone -SO2-; nitrogen→N-oxide). There are no heteroaromatic rings in heterocyclyl, i.e. the heteroatoms are not part of an aromatic system.

[0590] As a direct consequence of being derived from cycloalkyl, cycloalkenyl and aryl, heterocyclyl consists of the subgroups monocyclic heterocycle, bicyclic heterocycle, tricyclic heterocycle and spiroheterocycle, which may be present in saturated or unsaturated form.

[0591] By unsaturation is meant that at least one double bond is present in the ring system, but a heteroaromatic system is not formed. In a bicyclic heterocycle, the two rings are linked together so that they have at least two (hetero)atoms in common. In a spiro heterocycle, one carbon atom (spiro atom) belongs to both rings together.

[0592] If the heterocyclyl radical is substituted, the substitution may occur independently of one another in each case in the form of mono- or polysubstitution on all hydrogen-carrying carbon and / or nitrogen atoms. The heterocyclyl radical itself can be attached to the molecule as a substituent at every suitable position of the ring system.

[0593] Examples of heterocyclic groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridine, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxanyl, Cyclopentyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl, tetrahydrothiophenyl, high-thiomorpholinyl-S,S-dioxide, oxazolidinone, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuranyl, dihydropyranyl, tetrahydrothiophenyl-S-oxide, tetrahydrothiophenyl-S,S-dioxide, high-thiomorpholinyl-S-oxide, 2,3-dihydroazetidinyl, 2H-pyrrolyl, 4H -pyranyl, 1,4-dihydropyridinyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl [4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[4.4]nonyl, 2,6-diazaspiro[3.4]octyl, 3,9-diazaspiro[5.5]undecyl, 2.8-diazaspiro[4,5]decyl, and the like.

[0594] Other examples are the structures listed below that can be connected (exchanged hydrogen) via each hydrogen-carrying atom:

[0595]

[0596]

[0597]

[0598]

[0599] Preferably, the heterocyclyl group is a 4-8 membered monocyclic ring having one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0600] Preferred heterocyclic groups are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl.

[0601] The above definition of heterocyclyl also applies if heterocyclyl is part of another (composite) group such as for example heterocyclylamino, heterocyclyloxy or heterocyclylalkyl.

[0602] If the free valencies of the heterocyclyl radical are saturated, a heterocyclic radical is obtained.

[0603] The term heterocyclylene is also derived from the previously defined heterocyclyl. Unlike heterocyclyl, heterocyclylene is divalent and requires two binding partners. Usually, the second valency is obtained by removing a hydrogen atom from the heterocyclyl. Corresponding groups are, for example:

[0604] Piperidinyl and

[0605] 2,3-Dihydro-1H-pyrrolyl and wait.

[0606] If heterocyclylene is part of another (composite) group such as for example HO-heterocyclyleneamino or H2N-heterocyclyleneoxy, the above definition of heterocyclylene also applies.

[0607] Heteroaryl is a monocyclic heteroaromatic or polycyclic ring having at least one heteroaromatic ring which, compared to the corresponding aryl or cycloalkyl (cycloalkenyl) radicals, contains one or more identical or different heteroatoms independently selected from nitrogen, sulfur and oxygen instead of one or more carbon atoms, wherein the resulting radical must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic system.

[0608] If heteroaryl is to be substituted, the substitution may take place independently of one another in each case in the form of mono- or polysubstitution on all hydrogen-carrying carbon and / or nitrogen atoms. Heteroaryl itself can be attached as a substituent to the molecule via every suitable position of the ring system (both carbon and nitrogen).

[0609] Examples of heteroaryl are furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl , benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolyl, quinolyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridinyl, imidazopyridinyl, naphthyridinyl, benzoxazolyl, pyridopyridinyl, pyrimidopyridinyl, purinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, quinolyl-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 and the like.

[0610] Other examples are the structures listed below that can be connected (exchanged hydrogen) via each hydrogen-carrying atom:

[0611]

[0612]

[0613] Preferably, the heteroaryl group is a 5- to 6-membered monocyclic ring or a 9- to 10-membered bicyclic ring, each having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0614] The above definition of heteroaryl also applies if heteroaryl is part of another (composite) group such as for example heteroarylamino, heteroaryloxy or heteroarylalkyl.

[0615] If the free valencies of the heteroaryl group are saturated, a heteroaromatic radical is obtained.

[0616] The term heteroarylene is also derived from the previously defined heteroaryl. Unlike heteroaryl, heteroarylene is divalent and requires two binding partners. Usually, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are, for example:

[0617] Pyrrolyl and wait.

[0618] If heteroarylene is part of another (composite) group such as for example HO-heteroaryleneamino or H2N-heteroaryleneoxy, the above definition of heteroarylene also applies.

[0619] By substituted is meant that a hydrogen atom directly bonded to the atom in question is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms), mono- or polysubstitution is possible on an atom. Substitution by a particular substituent is only possible if the permitted valences of the substituent and the permitted valences of the atom to be substituted correspond to one another and the substitution results in a stable compound (i.e. a compound which does not spontaneously transform, for example, by rearrangement, cyclization or elimination).

[0620] Divalent substituents such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2 or the like are only possible as substituents on carbon atoms, wherein the divalent substituent =O may also be a substituent on sulfur. In general, substitution is possible by divalent substituents only at the ring system and requires the replacement of two geminal hydrogen atoms (i.e. hydrogen atoms bound to the same saturated carbon atom) prior to substitution. Substitution by divalent substituents is therefore only possible at groups -CH2- or sulfur atoms (only =O) in the ring system.

[0621] Stereochemistry / solvates / hydrates: Unless expressly indicated otherwise, throughout this specification and the accompanying claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemic isomers thereof, as well as mixtures of individual enantiomers in varying proportions, mixtures of diastereomers, or mixtures in which any of the foregoing forms of such isomers and enantiomers are present, and salts, including pharmaceutically acceptable salts thereof, and solvates thereof, such as, for example, hydrates, including solvates of the free compound or of a salt of the compound.

[0622] Salt: The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms which are, within the reasonable scope of medical judgment, suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problems or complications and commensurate with a reasonable benefit / risk ratio.

[0623] As used herein, "pharmaceutically acceptable salts" refer 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; alkaline or organic salts of acidic residues such as carboxylic acids; and the like.

[0624] For example, such salts include salts derived from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, dimethylaminoethanol, diethanolamine (2,2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucosamine, hydrabamine, 1H-imidazole, lysine (L-lysine), proline (L-proline), magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, morpholine, Piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidone, sodium hydroxide, triethanolamine (2,2',2"-nitrilotri(ethanol), tromethamine, zinc hydroxide, acetic acid, 2,2-dichloroacetic 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, formic acid, cinnamic acid, citric acid, cyclamic acid 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-hydroxyglutaric 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 acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid.

[0625] Salts include acetate, ascorbate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide / hydrobromide, edetate Ca / oxalate tetraacetate, camsylate, carbonate, camphorsulfonate, chloride / hydrochloride, theophylline, citrate, edisylate, edisylate, estolate, esylate, fumarate, glucoheptonate, gluconate, glucuronate, glutamate, glycolate, glycolylparaaminophenylarsonic acid salt, hexylresorcinate, hippurate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isethionate, hydroxyethyl isothionate, lactate, lactobionate, lauryl sulfate, malate, maleate, mandelate, methanesulfonate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthoate, naphthoate, nitrate, octadecanoate, oleate, oxalate, pamoate, pantothenate, phenylacetate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfonamide, sulfate, sulfosalicylate, tannate, tartrate, theoclorate, toluenesulfonate, triethiodide, trifluoroacetate, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine.

[0626] Other pharmaceutically acceptable salts can be formed with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and the like (see also Pharmaceutical salts, Berge, SM et al., J. Pharm. Sci., (1977), 66, 1-19).

[0627] Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally speaking, the salts can be prepared by reacting the free acid or base forms of the compounds with a sufficient amount of a suitable base or acid in water or in an organic diluent (e.g., ether, ethyl acetate, ethanol, isopropanol or acetonitrile, or a mixture thereof).

[0628] Salts of acids other than those mentioned above, such as trifluoroacetate, which are useful in purifying or isolating the compounds of the invention also form part of the invention.

[0629] The present invention also includes co-crystals of any compound according to the invention, i.e. crystalline forms thereof consisting of at least two components (one being a compound according to the invention and the other being a co-crystal former) which form a unique crystalline structure without proton transfer from one component to the other, unlike a crystalline salt. Potential co-crystal formers are acids and bases as listed above for salts / salt formers.

[0630] In a representation such as (for example)

[0631]

[0632] The letter A has a ring naming function to make it easier, for example, to indicate the connections of the ring to other rings.

[0633] For divalent groups where it is critical to determine to which neighboring groups and with which valency they bind, for the sake of clarity, the corresponding binding partners are indicated in brackets where necessary, as in the following representation:

[0634] or (R 2 )-C(O)NH- or (R 2 )-NHC(O)-;

[0635] The radical or substituent is usually selected from a number of groups with corresponding radical nomenclature (e.g., R a , R b If this group is used repeatedly to define the compounds according to the invention in different parts of the molecule, it should be pointed out that the various uses are to be regarded as completely independent of each other.

[0636] A therapeutically effective amount for the purposes of the present invention is an amount of the substance that is capable of eliminating disease symptoms or preventing or alleviating such symptoms, or prolonging the survival of the patient being treated.

[0637] The term "about" when used to specify a temperature or temperature range generally means a given temperature ± 5 ° C., and when used to specify a pressure or pressure range, it means a given pressure ± 0.5 bar. In all other cases, "about" includes a range of ± 5% above and below the given specific value.

[0638] List of abbreviations

[0639]

[0640]

[0641]

[0642] The features and advantages of the present invention will be apparent from the following detailed examples, which are provided by way of example to illustrate the principles of the present invention and are not intended to limit the scope of the present invention:

[0643] Preparation of compounds according to the invention

[0644] Overview

[0645] Unless specified to the contrary, all reactions were performed in commercially available equipment using methods customary in chemical laboratories. Starting materials sensitive to air and / or moisture were stored under protective gas and the corresponding reactions and work-ups were performed under protective gas (nitrogen or argon).

[0646] The compounds according to the present invention are named according to CAS rules using the software Autonom (Beilstein). If a compound is to be expressed by both a structural formula and its nomenclature, in the event of a conflict, the structural formula is decisive.

[0647] Microwave reactions are performed in an initiator / reactor manufactured by Biotage or in a probe manufactured by CEM or in a Synthos 3000 or Monowave 3000 manufactured by Anton Paar in a sealed vessel (preferably, 2, 5 or 20 mL), preferably with stirring.

[0648] Chromatography

[0649] Thin layer chromatography was performed on ready-made silica gel 60 TLC plates on glass manufactured by Merck with fluorescent indicator F-254.

[0650] Preparative high pressure chromatography (RP HPLC) of the example compounds according to the present invention was carried out on a column manufactured by Waters (name: SunFire TM Prep C18,OBD TM 10μm, 50x 150mm or SunFire TM Prep C18 OBD TM 5μm, 30x 50mm or XBridge TM Prep C18,OBD TM 10μm, 50x 150mm or XBridge TM Prep C18,OBD TM 5μm,30x150mm or XBridge TM Prep C18,OBD TM5μm, 30x 50mm) and columns manufactured by YMC (name: Actus-TriartPrep C18, 5μm, 30x 50mm) were used on Agilent or Gilson systems.

[0651] Different gradients of H2O / acetonitrile were used to elute the compounds, however, for the Agilent system, 5% acidic modifier (20 mL HCOOH to 1 L H2O / acetonitrile (1 / 1)) was added to water (acidic conditions). For the Gilson system, water was added to 0.1% HCOOH.

[0652] For chromatography under basic conditions, the Agilent system also used a H2O / acetonitrile gradient, however, the water was made basic by adding a 5% basic regulator (50 g NH4HCO3 + 50 mL NH3 (25% in H2O), made up to 1 L with H2O). For the Gilson system, the water was made basic as follows: 5 mL NH4HCO3 solution (158 g in 1 L H2O) and 2 mL NH3 (28% in H2O) were made up to 1 L with H2O.

[0653] Supercritical fluid chromatography (SFC) of the intermediates and example compounds according to the present invention was carried out on a JASCO SFC system with the following columns: Chiralcel OJ (250 x 20 mm, 5 μm), Chiralpak AD (250 x 20 mm, 5 μm), Chiralpak AS (250 x 20 mm, 5 μm), Chiralpak IC (250 x 20 mm, 5 μm), Chiralpak IA (250 x 20 mm, 5 μm), Chiralcel OJ (250 x 20 mm, 5 μm), Chiralcel OD (250 x 20 mm, 5 μm), Phenomenex Lux C2 (250 x 20 mm, 5 μm).

[0654] The analytical HPLC (reaction control) of the intermediates and final compounds was performed using a column manufactured by Waters (name: XBridge TM C18, 2.5μm, 2.1x 20mm or XBridge TMC18, 2.5 μm, 2.1 x 30 mm or Aquity UPLCBEH C18, 1.7 μm, 2.1 x 50 mm) and columns manufactured by YMC (name: Triart C18, 3.0 μm, 2.0 x 30 mm) and columns manufactured by Phenomenex (name: Luna C18, 5.0 μm, 2.0 x 30 mm). The analytical equipment was also equipped with a mass detector in each case.

[0655] HPLC-mass spectrometry / UV-spectroscopy

[0656] Retention time / MS-ESI for characterization of example compounds according to the present invention + It is generated using an HPLC-MS device (high performance liquid chromatography with mass spectrometry). Compounds eluting at the injected peak are given a retention time t Ret =0.00.

[0657] HPLC method:

[0658] Method A

[0659] HPLC Agilent 1100 Series

[0660] MS Agilent LC / MSD SL

[0661] Column Waters, Xbridge TM C18, 2.5μm, 2.1x 20mm, product model 186003201

[0662] Solvent A: 20 mM NH4HCO3 / NH3 pH 9

[0663] B: Acetonitrile (HPLC grade)

[0664] Detection of MS: Positive and Negative

[0665] Mass range: 120 to 900 m / z

[0666] Crusher: 120

[0667] EMV increment: 1

[0668] Threshold: 150

[0669] Step size: 0.2

[0670] UV: 315nm

[0671] Bandwidth: 170nm

[0672] Reference: Disconnect

[0673] Range: 230 to 400nm

[0674] Range step: 1.00nm

[0675] Peak width: <0.01min

[0676] Slit: 1nm

[0677] Injection volume 5 μL

[0678] Flow rate 1.00mL / min

[0679] Column temperature 60℃

[0680] Gradient 0.00min 10% B

[0681] 0.00 to 1.50 min 10% → 95% B

[0682] 1.50 to 2.00min 95%B

[0683] 2.00 to 2.10 min 95% → 10% B

[0684] Method B

[0685] HPLC Agilent 1200 Series

[0686] MS Agilent 6130 Quadrupole LC / MS

[0687] Column Waters, Xbridge TM C18, 2.5 μm, 2.1 x 30 mm

[0688] Solvent A: 20 mM NH4HCO3 / NH3 (in water); pH 9.3

[0689] B: Acetonitrile (HPLC grade)

[0690] Detection of MS:

[0691] Polarity: Positive

[0692] Ionizer: MM-ES+APCI

[0693] Mass range: 150 to 750 m / z

[0694] Fragmentor Value:

[0695] quality Disintegrator 150 70 750 110

[0696] EMV increment: 1.00

[0697] Threshold: 150

[0698] Step size: 0.2

[0699] UV:

[0700] 254nm: Reference disconnect

[0701] 214nm: Reference disconnect

[0702] Range: 190 to 400nm

[0703] Range step: 2.00nm

[0704] Threshold: 1.00mAU

[0705] Peak width: 0.0025min (0.05s)

[0706] Slit: 4nm

[0707] Injection volume 0.5 μL

[0708] Flow rate: 1.400mL / min

[0709] Column temperature 45℃

[0710] Gradient 0.00 to 1.00 min 15%->95% B

[0711] 1.00 to 1.30min 95% B

[0712] Method C HPLC Agilent 1200 Series

[0713] MS Agilent 6130 Quadrupole LC / MS

[0714] Column YMC, Triart C18, 3.0μm, 2.0x 30mm, 12nm Solvent A: Water + 0.1% HCOOH B: Acetonitrile + 0.1% HCOOH (HPLC grade)

[0715] Detection of MS:

[0716] Polarity: Positive

[0717] Mass range: 150 to 750 m / z

[0718] Fragmentor Value:

[0719] quality Disintegrator 150 70 750 110

[0720] EMV increment: 1.00

[0721] Threshold: 150

[0722] Step size: 0.20

[0723] UV:

[0724] 254nm: Reference disconnect

[0725] 214nm: Reference off range: 190 to 400nm

[0726] Range step: 4.00nm

[0727] Threshold: 1.00mAU

[0728] Peak width: 0.005min (0.1s)

[0729] Slit: 4nm

[0730] Injection volume 0.5 μL

[0731] Flow rate: 1.400mL / min

[0732] Column temperature 45℃

[0733] Gradient 0.00 to 1.00 min 15% → 100% B

[0734] 1.00 to 1.13min 100% B

[0735] Method D HPLC Agilent 1200 Series

[0736] MS Agilent 6130 Quadrupole LC / MS

[0737] Column Waters, Xbridge TM C18, 2.5 μm, 2.1 x 30 mm Solvent A: 20 mM NH4HCO3 / NH3 (in water); pH 9.3 B: acetonitrile (HPLC grade)

[0738] Detection of MS:

[0739] Polarity: Positive + Negative Ionization: MM-ES

[0740] Mass range: 150 to 750 m / z

[0741] Fragmentor Value:

[0742] quality Disintegrator 150 70 750 110

[0743] EMV increment: 1.00

[0744] Threshold: 150

[0745] Step size: 0.2

[0746] UV:

[0747] 254nm: Reference disconnect

[0748] 214nm: Reference off range: 190 to 400nm

[0749] Range step: 2.00nm

[0750] Threshold: 1.00mAU

[0751] Peak width: 0.0025min (0.05s)

[0752] Slit: 4nm

[0753] Injection volume 0.5 μL

[0754] Flow rate: 1.400mL / min

[0755] Column temperature 45℃

[0756] Gradient 0.00 to 1.00 min 15% → 95% B

[0757] 1.00 to 1.30min 95% B

[0758] Method E

[0759] HPLC Agilent 1200 Series:

[0760] MS Agilent 6130 Quadrupole LC / MS

[0761] Column Waters, Xbridge TM C18, 2.5μm, 2.1x 30mm column XP; Product model 186006028

[0762] Solvent A: 20 mM NH4HCO3 / NH3 (in water); pH 9.3

[0763] B: Acetonitrile (HPLC grade)

[0764] Detection of MS:

[0765] Polarity: Positive + Negative

[0766] Ionizer: API-ES

[0767] Mass range: 150 to 750 m / z

[0768] Fragmentor Value:

[0769] quality Disintegrator 150 70 750 110

[0770] EMV increment: 1.00

[0771] Threshold: 150

[0772] Step size: 0.2

[0773] UV:

[0774] 254nm: Reference disconnect

[0775] 214nm: Reference disconnect

[0776] Range: 190 to 400nm

[0777] Range step: 2.00nm

[0778] Threshold: 1.00mAU

[0779] Peak width: 0.0025min (0.05s)

[0780] Slit: 4nm

[0781] Injection volume 0.5 μL

[0782] Flow rate: 1.400mL / min

[0783] Column temperature 45℃

[0784] Gradient 0.00 to 1.00 min 15% → 95% B

[0785] 1.00 to 1.30min 95% B

[0786] Method F HPLC Agilent 1200 Series

[0787] MS Agilent 6130 Quadrupole LC / MS

[0788] Column YMC, Triart C18, 3.0μm, 2.0x 30mm, 12nm Solvent A: Water + 0.1% HCOOH B: Acetonitrile + 0.1% HCOOH (HPLC grade)

[0789] Detection of MS:

[0790] Polarity: Positive + Negative

[0791] Mass range: 150 to 750 m / z

[0792] Fragmentor Value:

[0793] quality Disintegrator 150 70 750 110

[0794] EMV increment: 1.00

[0795] Threshold: 150

[0796] Step size: 0.20

[0797] UV:

[0798] 254nm: Reference disconnect

[0799] 214nm: Reference off range: 190 to 400nm

[0800] Range step: 4.00nm

[0801] Threshold: 1.00mAU

[0802] Peak width: 0.0063min (0.13s)

[0803] Slit: 4nm

[0804] Injection volume 0.5 μL

[0805] Flow rate: 1.400mL / min

[0806] Column temperature 45℃

[0807] Gradient 0.00 to 1.00 min 15% → 100% B

[0808] 1.00 to 1.13min 100% B

[0809] Method G HPLC Agilent 1200 Series

[0810] MS Agilent 6130 Quadrupole LC / MS

[0811] Column YMC, Triart C18, 3.0μm, 2.0x 30mm, 12nm Solvent A: Water + 0.1% HCOOH B: Acetonitrile + 0.1% HCOOH (HPLC grade)

[0812] Detection of MS:

[0813] Polarity: Positive + Negative

[0814] Mass range: 150 to 750 m / z

[0815] Fragmentor Value:

[0816] quality Disintegrator 150 70 750 110

[0817] EMV increment: 1.00

[0818] Threshold: 150

[0819] Step size: 0.20

[0820] UV:

[0821] 254nm: Reference disconnect

[0822] 230nm: Reference disconnection

[0823] 214nm: Reference off range: 190 to 400nm

[0824] Range step: 4.00nm

[0825] Threshold: 1.00mAU

[0826] Peak width: 0.005min (0.1s)

[0827] Slit: 4nm

[0828] Injection volume 0.5 μL

[0829] Flow rate: 1.400mL / min

[0830] Column temperature 45℃

[0831] Gradient 0.00 to 1.00 min 15% → 100% B

[0832] 1.00 to 1.13min 100% B

[0833] Method H HPLC Agilent 1200 Series

[0834] MS Agilent 6130 Quadrupole LC / MS

[0835] Column YMC, Triart C18, 3.0μm, 2.0x 30mm, 12nm Solvent A: Water + 0.1% HCOOH B: Acetonitrile + 0.1% HCOOH (HPLC grade)

[0836] Detection of MS:

[0837] Polarity: Positive + Negative

[0838] Mass range: 200 to 800 m / z

[0839] Crusher: 70

[0840] Increment: 1.00

[0841] Threshold: 150

[0842] Step size: 0.20

[0843] UV:

[0844] 254nm: Reference disconnect

[0845] 230nm: Reference off range: 190 to 400nm

[0846] Range step: 2.00nm

[0847] Peak width: >0.01min(0.2s)

[0848] Slit: 4nm

[0849] Injection volume 1.0 μL

[0850] Flow rate 1.000mL / min

[0851] Column temperature 45℃

[0852] Gradient 0.00 to 0.10 min 5% B

[0853] 0.10 to 1.85 min 5% B → 95.0% B

[0854] 1.85 to 1.90 min 95% B

[0855] 1.95 to 1.92 min 95% B → 5.0% B

[0856] Method I HPLC Agilent 1200 Series

[0857] MS Agilent 6130 Quadrupole LC / MS

[0858] Column YMC, Triart C18, 3.0μm, 2.0x 30mm, 12nm Solvent A: Water + 0.1% HCOOH B: Acetonitrile + 0.1% HCOOH (HPLC grade)

[0859] Detection of MS:

[0860] Polarity: Positive + Negative

[0861] Mass range: 200 to 800 m / z

[0862] Crusher: 70

[0863] Increment: 1.00

[0864] Threshold: 150

[0865] Step size: 0.20

[0866] UV:

[0867] 254nm: Reference disconnect

[0868] 230nm: Reference off range: 190 to 400nm

[0869] Range step: 2.00nm

[0870] Peak width: >0.01min(0.2s)

[0871] Slit: 4nm

[0872] Injection volume 1.0 μL

[0873] Flow rate 1.000mL / min

[0874] Column temperature 45℃

[0875] Gradient 0.00 to 0.10 min 15% B

[0876] 0.10 to 1.55 min 15% B → 95.0% B

[0877] 1.55 to 1.90 min 95% B

[0878] 1.95 to 1.92 min 95% B → 15.0% B

[0879] Method J HPLC Agilent 1260 Series

[0880] MS Agilent 6130 Quadrupole LC / MS

[0881] Column YMC, Triart C18, 3.0μm, 2.0x 30mm, 12nm Solvent A: Water + 0.1% HCOOH B: Acetonitrile (HPLC grade)

[0882] Detection of MS:

[0883] Polarity: Positive + Negative

[0884] Mass range: 100 to 800 m / z

[0885] Crusher: 70

[0886] Increment: 1.00

[0887] Threshold: 100

[0888] Step size: 0.15

[0889] UV:

[0890] 254nm: Reference disconnect

[0891] 230nm: Reference off range: 190 to 400nm

[0892] Range step: 4.00nm

[0893] Peak width: >0.013min (0.25s)

[0894] Slit: 4nm

[0895] Injection volume 0.5 μL

[0896] Flow rate: 1.400mL / min

[0897] Column temperature 45℃

[0898] Gradient 0.00 to 1.00 min 5% → 100% B

[0899] 1.00 to 1.37 min 100% B

[0900] 1.37 to 1.40 min 100% → 5% B

[0901] Method K HPLC Agilent 1260 Series

[0902] MS Agilent 6130 Quadrupole LC / MS

[0903] Column Waters, Xbridge TM C18, 2.5 μm, 2.1 x 30 mm Solvent A: 5 mM NH4HCO3 / 19 mM NH3 (in water) B: acetonitrile (HPLC grade)

[0904] Detection of MS:

[0905] Polarity: Positive + Negative

[0906] Mass range: 100 to 800 m / z

[0907] Crusher: 70

[0908] Increment: 1.00

[0909] Threshold: 100

[0910] Step size: 0.15

[0911] UV:

[0912] 254nm: Reference disconnect

[0913] 230nm: Reference off range: 190 to 400nm

[0914] Range step: 4.00nm

[0915] Peak width: >0.013min (0.25s)

[0916] Slit: 4nm

[0917] Injection volume 0.5 μL

[0918] Flow rate: 1.400mL / min

[0919] Column temperature 45℃

[0920] Gradient 0.00 to 0.01 min 5% B

[0921] 0.01 to 1.00 min 5% → 100% B

[0922] 1.00 to 1.37 min 100% B

[0923] 1.37 to 1.40 min 100% → 5% B

[0924] Method L HPLC / MS Waters UPLC-micromass triple quadrupole column Aquity UPLC BEH C18, 1.7 μM, 2.1 x 50 mm Solvent A: water + 0.1% HCOOH

[0925] B: Acetonitrile (HPLC grade) + 0.1% HCOOH

[0926] Detection of MS:

[0927] ES / APCI positive and negative modes

[0928] Mass range: 100 to 1000 m / z

[0929] Capillary voltage: 3500V

[0930] Cone voltage: 30 to 50V

[0931] Dissolved gas: 600L / h

[0932] Dissolving temperature: 300℃

[0933] UV:

[0934] Bandwidth: 190nm

[0935] Range: 210 to 400nm

[0936] Resolution: 1.20nm

[0937] Sampling rate: 5

[0938] Injection volume 0.5 μL

[0939] Flow rate 0.400mL / min

[0940] Column temperature 40℃

[0941] Gradient 0.00 to 1.80 min 0% B

[0942] 1.80 to 3.80 min 0% → 75% B

[0943] 3.80 to 4.50 min 75% → 95% B

[0944] 4.50 to 6.00 min 95% B

[0945] 6.00 to 6.01 min 95% → 0% B

[0946] Method M

[0947] HPLC / MS Agilent 1200,6120MS

[0948] Column Luna C18(2)5μm,30x 2.0mm

[0949] Solvent A: water + 0.037% TFA

[0950] B: Acetonitrile + 0.018% TFA

[0951] Detection of MS: Positive and Negative Modes

[0952] Mass range: 100 to 1000 m / z

[0953] Crusher: 70

[0954] EMV increment: 1

[0955] Threshold: 150

[0956] Step size: 0.1

[0957] UV: 220 / 254nm

[0958] Bandwidth: 200nm

[0959] Reference: Disconnect

[0960] Range: 200 to 400nm

[0961] Range step: 0.4nm

[0962] Peak width: >0.05min

[0963] Slit: 4nm

[0964] Injection volume 0.5 μL

[0965] Flow rate 1.0mL / min

[0966] Column temperature 50℃

[0967] Gradient 0.00 to 0.30 min 0% B

[0968] 0.30 to 1.40 min 0% → 60% B

[0969] 1.40 to 1.55 min 60% B

[0970] 1.55 to 1.56 min 60% → 0% B

[0971] 1.56 to 2.00 min 0% B

[0972] The compounds according to the invention are prepared by the synthetic methods described hereinafter, wherein the substituents of the general formula have the meanings given above. These methods are intended to illustrate the invention without limiting the scope of their subject matter and the claimed compounds to these examples. Where the preparation of the starting compounds is not described, they can be purchased from the market or can be prepared analogously to known prior art compounds or the methods described herein. The substances described in the literature are prepared according to the disclosed synthetic methods.

[0973] Compound (Ia)

[0974] General reaction diagram and summary of synthetic pathways

[0975] Reaction Figure 1

[0976]

[0977] Reaction Figure 2

[0978]

[0979] *The location of peroxide / N-oxide formation is not entirely clear. B-13 as depicted in Scheme 2 appears possible.

[0980] Reaction Figure 3

[0981]

[0982] Compounds of formula (Ia) can be prepared stepwise starting from the isatin derivative S-1 by decarboxylative 1,3 dipolar cycloaddition with amino acid B-1 (method A) or B-5 (method D) and nitroethylene B-2 in the synthetic route depicted in reaction scheme 1 to establish spiro systems B-3 and B-6 as racemic mixtures possibly together with other 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. In addition, all other known methods for separating enantiomers can also be applied here or after any later synthetic step described herein, such as crystallization, chiral resolution, chiral HPLC, etc. (see also Enantiomers, racemates, and resolutions, Jean Jacques, André Collet, Samuel H Wilen John Wiley and Sons, NY, 1981).

[0983] 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, B-3 and B-6 can be subjected to alkylation, addition, acylation or sulfonylation reactions to give intermediates B-4 and B-7.

[0984] Intermediate B-4 can be reduced with DIBAL or another reducing agent and will then also provide intermediate B-7 (Method C).

[0985] The hydroxyl group of intermediate B-7 is oxidized to the corresponding carbonyl compound B-8 (Method F, Reaction Scheme 2) by, for example, Dess-Martin periodinane, IBX or another oxidizing agent, which can be further reacted with a nucleophile (especially an organometallic reagent, such as a Grignard or organozinc reagent) (which can be obtained from B-9 by a metal-halogen exchange reaction) to give an intermediate B-10 as a mixture of two diastereomers (Method G). The diastereomers of intermediate B-10 are not separated and used as a mixture for other reactions.

[0986] Intermediate B-10 can be oxidized to ketone intermediate B-11 by using Dess-Martin periodinane, IBX or other oxidation methods (Method H).

[0987] The reduction of the two nitro groups of intermediate B-11 and the subsequent reductive cyclization were triggered by treating intermediate B-11 with hydrogen under Raney-Ni catalysis or with an alternative reducing agent, and intermediate B-12 was obtained as a mixture of two diastereomers (Method I). The diastereomers of intermediate B-12 were not separated and used as a mixture for other reactions.

[0988] By using (potassium peroxymonosulfate) in a mixture of water and DCM, or by treatment with an alternative oxidizing agent to oxidize the cyclized intermediate B-12 to give the compound (Ia) according to the invention (Method J). If overoxidation occurs during the treatment, the crude mixture containing the overoxidation product B-13 can be subsequently reduced with bis(pinacolato)diboron or other reducing agents to obtain compound (Ia).

[0989] Compound (Ia) obtained starting from B-12 or B-13 can be optionally derivatized in a derivatization step not explicitly depicted in the reaction diagram by well-established organic chemical transformations (such as metal-catalyzed cross-coupling reactions, acylation, amidation, addition, reduction or (reductive) alkylation or cleavage of protective groups) at all residues, especially at R 4 (If they have functional groups that can be further modified, such as (for example) halogen atoms, amine groups and hydroxyl groups (including cyclic amines), carboxylic acid or ester functional groups, nitriles, etc.) derivatized into other compounds (Ia). These additional steps are not depicted in the general reaction diagram. Similarly, these additional steps can also be included in the synthetic pathway depicted in the general reaction diagram, that is, to carry out the derivatization reaction with intermediate compounds. In addition, building blocks with protecting groups can also be used, that is, additional steps for removing the protecting groups are necessary.

[0990] Alternatively, compound (Ia) can also be prepared according to the following reaction sequence:

[0991] Starting from aniline or aminoheteroaryl B-14, the amine functionality can be acetylated by acetic anhydride or other standard acetylation methods to give intermediate B-15. Intermediate B-15 is brominated with NBS, TsOH and Pd(OAc)2 to give bromo intermediate B-16. Sonogashira coupling with Boc-prop-2-ynylamine under Pd and Cu catalysis gives intermediate B-17, which can be completely deprotected under acidic conditions (HCl) by hydration under Pd(OAc)2 catalysis to give amine B-18. The intermediate thus obtained can be modified, for example, by esterification of the free carboxyl group (if R 4=COOH) or an alternative esterification method to obtain additional intermediate B-18. Intermediate B-18 is formed with the imine of isatin S-1 to give the imine intermediate B-19, which can then react with nitroethylene B-2 in a 1,3 dipolar cycloaddition to give the racemic intermediate 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, for example, when intermediate B-22 is reached. All other known methods for separating enantiomers can also be applied here or after any later synthetic step described herein, such as crystallization, chiral resolution, chiral HPLC, etc. (see also Enantiomers, racemates, and resolutions, Jean Jacques, André Collet, Samuel H Wilen John Wiley and Sons, NY, 1981). Reduction and cyclization of intermediate B-20 with H2 under Pt / C catalysis affords intermediate B-21, which can be subsequently reduced by adding VO(acac)2 to the reaction mixture and continuing to stir under H2 pressure to afford intermediate B-22. Oxidation of intermediate B-22 with Na2WO4 dihydrate and H2O2, or treatment with an alternative oxidizing agent, affords intermediate B-23, which can be converted to compound (Ia) by reaction with an aldehyde or ketone in a reductive amination reaction. Alternatively, alkylation, addition, acylation, or sulfonylation reactions can be performed with B-23 to afford additional compound (Ia).

[0992] Compound (Ia) has been tested for its activity in influencing the MDM2-p53 interaction in its racemic form or in enantiopure form (specifically (Ia*)). Each of the two enantiomers of the racemic mixture may have anti-MDM2 activity, however, with different binding modes. Enantiopure compounds are marked with the label "Chiral". The compounds marked "Chiral" listed in any of the tables below (both intermediates according to the invention and compound (Ib)) can be separated from their enantiomers by chiral SFC chromatography or synthesized from enantiopure starting materials separated by chiral SFC.

[0993] Examples:

[0994]

[0995] Formula A defines a racemic mixture of compounds having formulae B and C, i.e., formula A encompasses two formulae (compounds B and C), while formulae B and C are enantiomerically pure and define only one specific compound. 1 To R 4 , R 7, V, W, X, Y, n, r and q are specifically defined in formula (Ia) and (Ia*)

[0996]

[0997] represents a racemic mixture of two enantiomers (→(Ia); the above formula A is a specific example of such a racemic mixture) or a single enantiomer (→(Ia*); the above formula B is a specific enantiomer), unless additional stereocenters are present in one or more of the substituents. The same definition applies to synthetic intermediates.

[0998] Synthesis of intermediate B-6

[0999] Experimental Procedure for the Synthesis of B-6a (Method D)

[1000]

[1001] 6-Chlorosindigo carmine S-1a (31.5 g, 174 mmol), 1-(3-chloro-2-fluorophenyl)-2-nitroethylene B-2a (35 g, 174 mmol) and L-homoserine B-5a (20.7 g, 174 mmol) were refluxed in MeOH for 4 h. The reaction mixture was concentrated in vacuo and purified by crystallization or chromatography as needed.

[1002] The following intermediates B-6 (Table 1) can be obtained in a similar manner starting from different cyclized 1H-pyrrole-2,3-dione S-1, amino acid B-5 and nitroethylene B-2.

[1003] Table 1

[1004]

[1005]

[1006] Synthesis of intermediate B-7

[1007] Experimental Procedure for the Synthesis of B-7a (Method E)

[1008]

[1009] Intermediate B-6a (1.60 g, 3.8 mmol) was added to a solution of cyclopropanecarboxaldehyde (1.7 mL, 22.7 mmol) in AcOH (19.5 mL) and the reaction mixture was stirred for 15 min. Sodium triacetoxyborohydride (1.34 g, 6.3 mmol) was added and the reaction mixture was stirred overnight. Water was added to the reaction mixture and the reaction mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and the crude product B-7a was purified by chromatography as needed.

[1010] The following intermediates B-7 (Table 2) can be obtained by similar methods starting from different intermediates B-6 and aldehydes.

[1011] Table 2

[1012]

[1013]

[1014]

[1015]

[1016] Synthesis of intermediate B-3

[1017] Experimental Procedure for the Synthesis of B-3a (Method A)

[1018]

[1019] 6-Chlorosindigo red S-1a (5 g, 27.0 mmol), 1-(3-chloro-2-fluorophenyl)-2-nitroethylene B-2a (5.5 g, 27.0 mmol) and amino acid B-1a (4.4 g, 27.0 mmol) were refluxed in MeOH for 4 h. The reaction mixture was concentrated in vacuo and purified by crystallization or chromatography as needed.

[1020] The following intermediate B-3 (Table 3) can be obtained by similar methods starting from different cyclized 1H-pyrrole-2,3-dione S-1, amino acid B-1 and nitroethylene B-2.

[1021] Table 3

[1022]

[1023] Synthesis of intermediate B-4

[1024] Experimental Procedure for the Synthesis of B-4a (Method B)

[1025]

[1026] Intermediate B-3a (2.68 g, 4.4 mmol) was added to a solution of cyclopropanecarboxaldehyde (0.64 g, 8.9 mmol) in AcOH (0.5 mL) and the reaction mixture was stirred for 15 min. Sodium triacetoxyborohydride (2.8 g, 13.3 mmol) was added and the reaction mixture was stirred overnight. Water was added to the reaction mixture and the reaction mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and the crude product B-4a was purified by chromatography as needed.

[1027] The following intermediates B-4 (Table 4) can be obtained by similar methods starting from different intermediates B-3 and different aldehydes.

[1028] Table 4

[1029]

[1030] Synthesis of other intermediates B-7

[1031] Experimental Procedure for the Synthesis of B-7t (Method C)

[1032]

[1033] DIBAL (18.0 mL, 18 mmol, 1.0 M in DCM) is slowly added to a solution of B-4a (2.38 g, 4.0 mmol) in DCM at 0°C and the reaction mixture is stirred for 1 h. Water and saturated aqueous potassium sodium tartrate solution are added to the reaction mixture and the mixture is stirred at rt overnight. The phases are separated and the aqueous phase is extracted with DCM. The combined organic layers are dried (MgSO4), filtered, concentrated in vacuo and the crude product B-7t is purified by chromatography as needed.

[1034] The following intermediates B-7 (Table 5) can be obtained starting from different intermediates B-4 in a similar manner.

[1035] Table 5

[1036]

[1037] Synthesis of intermediate B-8

[1038] Experimental Procedure for the Synthesis of B-8b (Method F)

[1039]

[1040] NaHCO3 (0.34 g, 4.05 mmol) was added to a solution of intermediate B-7b (1 g, 2.02 mmol) in ACN (20 mL) and stirred for 5 min, and Dess-Martin periodinane ((1.72 g, 4.05 mmol) was added portionwise to the mixture. The reaction mixture was stirred for another 30 min, and then the reaction mixture was diluted with H2O, saturated NaHCO3 and EtOAc. The reaction mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and the crude product B-8b was purified by chromatography as needed.

[1041] The following intermediates B-8 (Table 6) can be obtained starting from different intermediates B-7 in a similar manner.

[1042] Table 6

[1043]

[1044]

[1045]

[1046]

[1047] Synthesis of intermediate B-10

[1048] Experimental Procedure for the Synthesis of B-10a (Method G)

[1049]

[1050] A solution of methyl 4-iodo-3-nitrobenzoate B-9a (2.60 g, 8.48 mmol) in THF (17 mL) was cooled to -50 °C and phenylmagnesium chloride (4.05 mL, 8.09 mmol, 2 M) was added dropwise and the reaction mixture was stirred at -50 °C for another 30 min. A solution of intermediate B-8b (1.90 g, 3.85 mmol) in THF (7.7 mL) was added dropwise to the reaction mixture at -50 °C and the reaction mixture was stirred at the same temperature for another 15 min. The reaction mixture was slowly warmed to rt and stirred for another 2 h, then saturated aqueous KHSO4 and EtOAc were added. The reaction mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and the crude product B-10a was purified by chromatography. B-10a was obtained as a mixture of two enantiomers, which were used in the next step without separation.

[1051] The following intermediates B-10 (Table 7) can be obtained by similar methods starting from different intermediates B-8 and different iodides B-9.

[1052] Table 7

[1053]

[1054]

[1055]

[1056]

[1057]

[1058] Synthesis of intermediate B-9

[1059] Experimental procedures for the synthesis of B-9b

[1060]

[1061] Sodium nitrite is slowly added to a solution of methyl 4-amino-2-methyl-3-nitrobenzoate (2.4 g, 11.0 mmol) in HCl (25 mL) at 0°C and the mixture is stirred for 30 min at the same temperature. Potassium iodide (5.7 g, 34.0 mmol) is added portionwise at 0°C and the mixture is stirred for 1 h at rt. Water and Et2O are added to the reaction mixture. The phases are separated and the aqueous phase is extracted with Et2O. The combined organic layers are dried (MgSO4), filtered, concentrated in vacuo and the crude product B-9b is purified by chromatography as needed.

[1062] Experimental procedures for the synthesis of B-9c

[1063]

[1064] Potassium carbonate (1.3 g, 9.3 mmol) and methyl iodide (0.4 mL, 6.2 mmol) were added to a solution of methyl 2-hydroxy-4-iodo-3-nitrobenzoate (1.0 g, 3.1 mmol) at rt. The reaction mixture was stirred at rt for 4 h. Water was added to the mixture and the solid formed was filtered and dried to give intermediate B-9c.

[1065] Table 8

[1066]

[1067] Synthesis of intermediate B-11

[1068] Experimental procedures for the synthesis of B-11a

[1069]

[1070] NaHCO3 (0.34 g, 1.49 mmol) was added to a solution of intermediate B-10a (1 g, 1.49 mmol) in THF (10 mL) and stirred for 5 min, then Dess-Martin periodinane (1.26 g, 2.97 mmol) was added portionwise to the mixture. The reaction mixture was stirred for another 2 h at rt, then diluted with H2O, saturated NaHCO3 and EtOAc. The reaction mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and the crude product B-11a was purified by chromatography as needed.

[1071] The following intermediates B-11 (Table 9) can be obtained starting from different intermediates B-10 in a similar manner.

[1072] Table 9

[1073]

[1074]

[1075]

[1076]

[1077]

[1078] Synthesis of Intermediate B-12 Experimental Procedure for Synthesis of B-12a (Method I)

[1079]

[1080] A catalytic amount of Raney Nickel was added to a solution of intermediate B-11a (1.10 g, 1.60 mmol) in MeOH (6 mL) and DCM (9 mL) in an autoclave and the reaction mixture was stirred under a hydrogen atmosphere (8 bar) for 24 h. Another portion of Raney Nickel was added and the reaction mixture was stirred under a hydrogen atmosphere (8 bar) for another 24 h. Filter The reaction mixture is then desolventized in vacuo. The residue is dissolved in EtOAc and saturated NaHCO3 aqueous solution is added. The reaction mixture is extracted with EtOAc. The combined organic layers are dried (MgSO4), filtered, concentrated in vacuo and the crude product B-12a is purified by chromatography as needed. Intermediate B-12a is obtained as a mixture of two enantiomers, which can be used in the next step without further separation.

[1081] The following intermediates B-12 (Table 10) can be obtained starting from different intermediates B-11 in a similar manner.

[1082] Table 10

[1083]

[1084]

[1085]

[1086]

[1087]

[1088] Synthesis of Compound (Ia) According to the Invention Experimental Procedure for the Synthesis of Ia-1 (Method J)

[1089]

[1090] At 0°C, A solution of (793 mg, 1.29 mmol) in H2O (7 mL) was added dropwise to a solution of intermediate B-12a (329 mg, 0.65 mmol) in DCM (7 mL). The biphasic reaction mixture was stirred vigorously at 0°C for 20 min and stirred for another 2 h at rt. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and the crude product was purified by chromatography to give compound Ia-1.

[1091] The following compounds (Ia) (Table 11) can be obtained starting from different intermediates B-12 by similar methods.

[1092] Table 11

[1093]

[1094]

[1095]

[1096]

[1097]

[1098] Synthesis of other compounds (Ia) according to the present invention

[1099] Experimental Procedure for Synthesis of Ia-20 (Method J + Method K)

[1100]

[1101] *The location of peroxide / N-oxide formation is not entirely clear. The depicted B-13a appears possible.

[1102] At 0°C, A solution of (841 mg, 1.37 mmol) in H2O (7 mL) was added dropwise to a solution of intermediate B-12j (417 mg, 0.68 mmol) in DCM (10 mL). The biphasic reaction mixture was stirred vigorously for 20 min at 0 °C and stirred for another 6 h at rt. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo to give a crude mixture of Ia-20 and oxidized form B-13a (M+H=621). The mixture was dissolved in MeCN (4.2 mL) and bis(pinacolato)diboron (326 mg, 1.28 mmol) was added. The reaction mixture was heated to 100 °C for 30 min under microwave irradiation. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and the crude product was purified by chromatography to give compound Ia-20.

[1103] The following overoxidized compounds B-13 (Table 12) can be obtained starting from different intermediates B-12 in a similar manner and can be reduced to other compounds (Ia) (Table 13).

[1104] Table 12

[1105]

[1106]

[1107] Table 13

[1108]

[1109]

[1110] Synthesis of other compounds (Ia) via ester saponification

[1111] Experimental Procedure for the Synthesis of Ia-25

[1112]

[1113] Ia-1 (405 mg, 0.69 mmol) was dissolved in THF (30 mL) and aqueous NaOH (2 mL, 8 M) was added. The reaction mixture was stirred at 70 °C for 8 h. After acidification with 2 M aqueous HCl and extraction with EtOAc, the organic phase was dried over MgSO4. Purification by reverse phase HPLC gave pure Ia-25.

[1114] The following compounds (Ia) (Table 14) can be obtained by a similar method starting from the initially obtained compound (Ia).

[1115] Table 14

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122] Synthesis of other compounds (Ia) via amidation

[1123] Experimental Procedure for the Synthesis of Ia-46

[1124]

[1125] Ia-26 (10 mg, 0.02 mmol) was dissolved in anhydrous THF (1 mL) and HATU (8 mg, 0.02 mmol) was added at rt. After adding DIPEA (3.4 mg, 0.03 mmol), the reaction mixture was stirred at rt for 15 min. 1-amino-2-methylpropan-2-ol (2 M in THF, 1.5 mg, 0.02 mmol) was added and the reaction was allowed to stir for another 60 min. The crude reaction mixture was subjected to reverse phase column chromatography to give pure Ia-46.

[1126] The following compounds (Ia) (Table 15) can be obtained by a similar method starting from the initially obtained compound (Ia).

[1127] Table 15

[1128]

[1129]

[1130]

[1131]

[1132] Synthesis of starting material S-1

[1133] Experimental Procedure for the Synthesis of S-1b

[1134]

[1135] 3,3-Dibromo-6-chloro-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (7.6 g, 23.3 mmol) was suspended in acetonitrile (500 mL) and water (25 mL). AgNO3 (8.9 g, 52.7 mmol) was added and the reaction mixture was stirred at rt for 1 h. Acetonitrile was removed under reduced pressure and EtOAc was added. The phases were separated and the organic layer was dried over MgSO4. The solvent was removed to give pure 6-chloro-1H-pyrrolo[2,3-b]pyridine-2,3-dione S-1b.

[1136] Synthesis of intermediate B-15

[1137] Experimental procedures for the synthesis of B-15a

[1138]

[1139] Ac2O (1.05 eq.) was added dropwise to a solution of B-14a (1 eq.) in toluene under reflux and the mixture was stirred under reflux for a few minutes. The product B-15a can be crystallized from the mixture by cooling and further dilution.

[1140] The following intermediates B-15 (Table 15-1) can be obtained starting from different anilines B-14 by similar methods.

[1141] Table 15-1

[1142]

[1143] Synthesis of intermediate B-16

[1144] Experimental procedures for the synthesis of B-16a

[1145]

[1146] TsOH monohydrate (0.5 eq.) and Pd(OAc)2 (0.03 eq.) are added to a solution of B-15a (1 eq.) in AcOH. The mixture is heated to 75-80°C and NBS (1.1 eq.) is added in small portions. After stirring at 75-80°C for a few minutes, the solution is cooled and water is added. The product B-16a can be isolated by filtration.

[1147] The following intermediate B-16 (Table 15-2) can be obtained by similar methods starting from different acetamides B-15.

[1148] Table 15-2

[1149]

[1150] Synthesis of intermediate B-17

[1151] Experimental procedures for the synthesis of B-17a

[1152]

[1153] Boc-prop-2-ynylamine (1.3 eq.), CuI (0.02 eq.), Pd2(dba)3 (0.01 eq.), [(tBu)3P]BF4 (0.04 eq.) and DIPA (5 eq.) were added to a suspension of B-16a (1 eq.) in DMSO. The mixture was stirred at room temperature for 3 days. After cooling the suspension and adding water, the product B-17a can be isolated by filtration.

[1154] The following intermediate B-17 (Table 15-3) can be obtained by similar methods starting from different bromoacetamide B-16.

[1155] Table 15-3

[1156]

[1157]

[1158] Synthesis of intermediate B-18

[1159] Experimental procedures for the synthesis of B-18a

[1160]

[1161] Pd(OAc)2 (0.02 eq.) is added to a solution of B-17a (1 eq.) in AcOH and the mixture is stirred at room temperature until B-17a is completely consumed. Subsequently, water and concentrated HCl are added. After cleavage of the Boc group (reduction of CO2 formation), the mixture is heated to 70°C and stirred at this temperature for 3 days. The product B-18a can be crystallized from the reaction mixture by cooling.

[1162] The following intermediates B-18 (Table 15-4) can be obtained starting from different benzynes B-17 in a similar manner.

[1163] Table 15-4

[1164]

[1165]

[1166]

[1167] Experimental procedures for the synthesis of B-18g

[1168]

[1169] SOCl2 (3 eq.) is added dropwise to a suspension of B-18a (1 eq.) in MeOH at 60°C and the mixture is stirred at this temperature overnight. After cooling down to room temperature, the mixture is filtered on an activated carbon filter and the solvent is subsequently removed under reduced pressure. The product B-18g can be purified by crystallization.

[1170] The following benzoate intermediates B-18 (Table 15-5) can be obtained by similar methods starting from different benzoic acid B-18 obtained initially.

[1171] Table 15-5

[1172]

[1173]

[1174] Synthesis of intermediate B-19 Experimental procedures for the synthesis of B-19a

[1175]

[1176] 6-Chloroisatin S-1a (1.1 eq.), AcOH (2.4 eq.) and TEA (2 eq.) are added to a suspension of B-18g (1 eq.) in MeOH. After stirring at room temperature for 3 days, the product B-19a can be filtered.

[1177] The following imine intermediates B-19 (Table 15-6) can be obtained starting from different benzoate B-18 by similar methods.

[1178] Table 15-6

[1179]

[1180]

[1181] Synthesis of intermediate B-20

[1182] Experimental procedures for the synthesis of B-20a

[1183]

[1184] 1-Chloro-2-fluoro-3-(E)-2-nitrovinyl)benzene (1.1 eq.) is suspended in toluene and water and heated to temperature. Subsequently, imine B-19a (1 eq.) and 1-methylpyrrolidine (4 eq.) are added. The mixture is stirred under reflux. The reaction is quenched by adding AcOH at 0°C. The organic phase is washed with water and brine and then added dropwise to nHep. The product B-20a can be purified by crystallization.

[1185] If chiral separation of the enantiomers of the racemic mixture of intermediate B-20a is desired, crystallization with a chiral acid such as (S,S)-(+)-2,3-dibenzoyl-D-tartaric acid, (S,S)-(+)-2,3-p-tolyl-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 may be considered. Preferably, (1R)-(-)camphor-10-sulfonic acid is used.

[1186] The following intermediates B-20 (Table 15-7) can be obtained starting from different imines B-19 in a similar manner.

[1187] Table 15-7

[1188]

[1189]

[1190]

[1191] Synthesis of intermediate B-22

[1192] Experimental procedures for the synthesis of B-22a

[1193]

[1194] Water and Pt / C (15 wt%) are added to a solution of B-20 g (1 eq.) in MeTHF. The mixture is hydrogenated at 30° C. under 70 bar H2 pressure for 3 days. After complete conversion to B-21a, VO(acac)2 (0.11 eq.) is added and the mixture is further hydrogenated at 30° C. under 70 bar for 2 days. The catalyst is filtered off and the solvent is removed under reduced pressure. The product B-22a is dissolved in toluene and the sulfate salt of B-22a can be precipitated by adding 2M H2SO4 (1.11 eq.).

[1195] For racemic B-20, the reaction sequence B-20 → B-21 → B-22 is also possible (if chiral separation of B-20 is not required). In this case, chiral separation can also be performed at the stage of B-22 by crystallization with a chiral acid such as (S,S)-(+)-2,3-dibenzoyl-D-tartaric acid, (S,S)-(+)-2,3-p-tolyl-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-tolyl-D-tartaric acid is preferred).

[1196] The following intermediates B-21 and B-22 (Table 15-8) can be obtained starting from different intermediates B-20 by similar methods.

[1197] Table 15-8

[1198]

[1199]

[1200]

[1201] Synthesis of intermediate B-23

[1202] Experimental procedures for the synthesis of B-23a

[1203] Na2WO4 dihydrate (0.01 eq.) and H2O2 solution (30% in water, 2.5 eq.) are added to a suspension of B-22a (1 eq.) in CH2Cl2 and water (4:1) and the mixture is stirred at reflux for 2 h. Then a solution of K2CO3 (2 eq.) in water is added and CH2Cl2 is removed under reduced pressure. The solid product B-23a can be purified by slurrying in a suitable solvent.

[1204] The following intermediates B-23 (Tables 15 to 10) can be obtained starting from different intermediates B-22 in a similar manner.

[1205] Table 15-9

[1206]

[1207]

[1208] Compound (Ib)

[1209] General reaction diagram and summary of synthetic pathways

[1210] Reaction Figure 3

[1211]

[1212] Compounds of formula (Ib) can be prepared stepwise from protected amino acid A-1 according to the synthetic route (reaction diagram 3). First, an acylation reaction is carried out using acrylic acid derivative A-2 to obtain a compound of formula A-3 (method A). Acrylic acid that cannot be obtained directly can be obtained, for example, by Wittig reaction (D-1, D-2, not depicted in reaction diagram 3). Intermediate A-3 is preferentially treated with trifluoroacetic acid under acidic conditions to form a free unsaturated amino acid derivative A-4 (method B). A-4 is subjected to a decarboxylative 1,3-dipolar cycloaddition with an indigo derivative S-1 to obtain a cycloaddition product A-5 as a mixture of diastereoisomers and establish a spiro system (method C). The diastereoisomers can be separated, for example, by HPLC or SFC. The obtainable racemic mixture can be separated by chiral SFC or resolved at any later stage of the synthesis. All other known methods for the separation of enantiomers may also be applied here or after any later synthetic step described herein, e.g. crystallization, chiral resolution, chiral HPLC, etc. (see also Enantiomers, racemates, and resolutions, Jean Jacques, André Collet, Samuel H Wilen John Wiley and Sons, NY, 1981).

[1213] Alternatively, cycloadduct A-5 can be prepared as a mixture of diastereoisomers by 1,3-dipolar cycloaddition of amine A-8 with isatin derivative S-1 (Method E). Intermediate A-8 can be prepared in one pot from amine A-6 by acylation reaction with acrylic acid derivative A-2 and subsequent cleavage of the Boc protecting group by addition of HCl (Method D).

[1214] Intermediate A-5 can be reacted with an aldehyde or ketone in a reductive amination reaction to obtain intermediate A-9 (introducing R 1 , Method F). Alternatively, A-5 can be used for alkylation, addition, acylation or sulfonylation to obtain other intermediates of formula A-9. Intermediate A-9 is subjected to a metal-catalyzed cross-coupling reaction (e.g., Buchwald amidation) with a substituted nitro(hetero)aryl halide A-10 to obtain intermediate A-11 (Method G). Cyclization intermediate A-11 is reduced by treatment with iron powder in acetic acid or an alternative reducing agent to obtain compound (Ib).

[1215] The initially obtained compound (Ib) can be optionally derivatized in a derivatization step not explicitly depicted in the reaction diagram by well-established organic chemical transformations (such as metal-catalyzed cross-coupling reactions, acylation, amidation, addition, reduction or (reductive) alkylation or cleavage of protective groups) at all residues, especially at R 4(If they have functional groups that can be further modified such as, for example, halogen atoms, amine groups and hydroxyl groups (including cyclic amines), carboxylic acid or ester functional groups, nitriles, etc.) derivatized into other compounds (Ia). These additional steps are not depicted in the general reaction diagram. Similarly, these additional steps can also be included in the synthetic pathway depicted in the general reaction diagram, that is, to carry out the derivatization reaction with intermediate compounds. In addition, building blocks with protecting groups can also be used, that is, additional steps of removing the protecting groups are necessary.

[1216] Reaction Figure 4

[1217]

[1218] Alternatively, the compound of formula (Ib) can be prepared stepwise starting from intermediate A-5 according to the synthetic route (Scheme 4). Intermediate A-5 is treated with acetic anhydride in formic acid to produce intermediate A-12 (Method I). Intermediate A-12 is subjected to a metal-catalyzed cross-coupling reaction (e.g., Buchwald amidation) with a substituted nitro(hetero)aryl halide A-10 to obtain intermediate A-13 (Method G). The cyclized intermediate A-13 is reduced by treatment with iron powder in acetic acid or an alternative reducing agent to obtain intermediate A-14. Deformylation mediated by hydrochloric acid in MeOH gives intermediate A-15 (Method J). Intermediate A-15 can be reacted with an aldehyde or ketone in a reductive amination reaction to obtain compound (Ib) (introduction of R 1 , Methods K and L). Alternatively, A-15 can be used for alkylation, addition, acylation or sulfonylation to obtain other compounds of formula (Ib).

[1219] Reaction Figure 5

[1220]

[1221] Alternatively, the compound of formula (Ib) can be prepared stepwise from the diamino (hetero)aryl A-16 according to the synthetic route (reaction scheme 5). First, an acylation reaction is carried out using an acrylic acid derivative A-2 to obtain a compound of formula A-17 (method M). Acrylic acid that cannot be obtained directly can be obtained, for example, by the Wittig reaction (D-1, D-2, not depicted in reaction scheme 5). Intermediate A-17 is treated with hydrochloric acid to obtain a condensed imidazole (e.g., benzimidazole) intermediate A-18 (method N). Intermediate A-18 is alkylated with a bromide A-19 or an alternative alkylating agent to obtain intermediate A-20 (method O). Intermediate A-20 is preferentially treated with trifluoroacetic acid under acidic conditions to form a free unsaturated amine derivative A-21 (method P). A-21 undergoes a 1,3-dipolar cycloaddition with an isatin derivative S-1 to obtain a cycloaddition product A-15 as a mixture of diastereoisomers and establish a spiro system (method Q). The intermediate A-15 described above can be reacted with an aldehyde or a ketone in a reductive amination reaction to obtain compound (Ib) (introducing R 1 , Methods K and L). Alternatively, A-15 can be used for alkylation, addition, acylation or sulfonylation to obtain other compounds of formula (Ib).

[1222] Compound (Ib) has been tested in its racemic form or in enantiopure form for its activity influencing the MDM2-p53 interaction. Each of the two enantiomers of the racemic mixture may have anti-MDM2 activity, however, with different binding modes. Enantiopure compounds are marked with the label "Chiral". The compounds marked "Chiral" listed in any of the tables below (both intermediates according to the invention and compound (Ib)) can be separated from their enantiomers by chiral SFC chromatography or synthesized from enantiopure starting materials separated by chiral SFC.

[1223] Examples:

[1224]

[1225] Formula A defines a racemic mixture of compounds having formulae B and C, i.e., formula A encompasses two formulae (compounds B and C), while formulae B and C are each enantiomerically pure and define only one specific compound. 1 To R 4 , R 7 , V, W, X, Y, n, r and q are specifically defined in formula (Ib) and (Ib*)

[1226]

[1227] represents a racemic mixture of two enantiomers (→(Ib); the above formula A is a specific example of such a racemic mixture) or a single enantiomer (→(Ib*); the above formula B is a specific enantiomer), unless additional stereocenters are present in one or more of the substituents. The same definition applies to synthetic intermediates.

[1228] Synthesis of Intermediate A-2

[1229] Experimental Procedure for Synthesis of A-2a

[1230]

[1231] Under argon atmosphere, 2-chloro-3-fluoropyridine-4-carbaldehyde D-1a (1 g, 6.3 mmol) was dissolved in anhydrous MTBE (10 mL). Methyl (triphenylphosphinyl)acetate (2.1 g, 6.3 mmol) was added in one portion and the reaction mixture was stirred at rt for 1 h. Water and EtOAc were added and the phases were separated. The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was purified by reverse phase column chromatography to give pure (E)-3-(2-chloro-3-fluoropyridin-4-yl)-acrylic acid methyl ester D-2a.

[1232] D-2a (780 mg, 3.6 mmol) was dissolved in THF (3 mL) and 2 M NaOH (3.6 mL, 7.2 mmol) was added. The reaction mixture was stirred at 60 °C for 1 h and quenched by adding 2 M HCl. The organic phase was extracted with EtOAc and then dried over MgSO4 to obtain crude A-2a after removing the solvent under reduced pressure. Reverse phase column chromatography was performed to obtain pure (E)-3-(2-chloro-3-fluoropyridin-4-yl)-acrylic acid A-2a.

[1233] Other building blocks A-2 can be obtained in a similar manner starting from different formaldehydes D-1.

[1234] Table 16

[1235]

[1236] Synthesis of Intermediate A-3 (Method A)

[1237] Experimental Procedure for Synthesis of A-3a

[1238]

[1239] 3-Chloro-2-fluorocinnamic acid A-2b (10.3 g, 50.67 mmol) was 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) were added to the reaction mixture. The reaction mixture was stirred at 0°C for 30 min. A solution of (S)-4-amino-2-tert-butoxycarbonylaminobutyric acid tert-butyl ester hydrochloride A-1a (15.0 g, 48.26 mmol) in DMF (100 mL) was added dropwise over a period of 15 min. The reaction mixture was stirred for another 60 min and saturated aqueous NH4Cl solution was added. Deionized water was added and the mixture was extracted with a 1:1 mixture of EtOAc and cyclohexane. The layers were separated and the organic phase was washed with deionized water and dried over MgSO4. The solvent was removed under reduced pressure and (S)-2-tert-butoxycarbonylamino-4-[(E)-3-(3-chloro-2-fluorophenyl)-acryloylamino]-butyric acid tert-butyl ester A-3a was used without further purification.

[1240] The following intermediates A-3 (Table 17) can be obtained by similar methods starting from different acrylic acids A-2 and protected amino acids A-1.

[1241] Table 17

[1242]

[1243]

[1244] Synthesis of Intermediate A-4 (Method B)

[1245] Experimental Procedure for Synthesis of A-4a

[1246]

[1247] (S)-2-tert-Butyloxycarbonylamino-4-[(E)-3-(3-chloro-2-fluorophenyl)-acryloylamino]-butyric acid tert-butyl ester A-3a (22.4 g, 48.9 mmol) was dissolved in DCM (150 mL). TFA (35 mL) was added at 0°C and the reaction mixture was slowly warmed to rt. The reaction mixture was heated to reflux for 24 h. NaOH (4 M) was added at 0°C until pH 12 was reached and the reaction mixture was concentrated in vacuo. Aqueous HCl solution (2 M) was added and a precipitate formed at pH 6 to 7 which was filtered off. The solid residue (S)-2-amino-4-[(E)-3-(3-chloro-2-fluorophenyl)-acryloylamino]-butyric acid hydrochloride A-4a was washed with water and acetonitrile and dried at 50°C under reduced pressure.

[1248] The following intermediates A-4 (Table 18) can be obtained starting from different intermediates A-3 in a similar manner.

[1249] Table 18

[1250]

[1251] Synthesis of Intermediate A-5 (Method C)

[1252] Experimental procedures for the synthesis of A-5a and A-5c

[1253]

[1254] In a microwave vial, (S)-2-amino-4-[(E)-3-(3-chloro-2-fluorophenyl)-acryloylamino]-butyric acid A-4a (0.34 g, 1.13 mmol), 6-chloro-1H-indole-2,3-dione S-1a (2.1 g, 1.13 mmol) and the ground activated The molecular sieves were suspended in anhydrous MeOH (15 mL). The reaction bottle was sealed with a Teflon cap and irradiated at a final temperature of 100°C for 30 min. After cooling to rt, The crude mixture was filtered through a pad of Celite® and the solvent was removed under reduced pressure. The crude reaction mixture was purified by reverse phase HPLC to give diastereomers A-5a and A-5c.

[1255] The following intermediate A-5 (Table 19) can be obtained by similar methods starting from different intermediates A-4 and S-1.

[1256] Table 19

[1257]

[1258]

[1259]

[1260] Synthesis of Intermediate A-8 (Method D)

[1261] Experimental procedures for the synthesis of A-8a

[1262]

[1263] (E)-3-(4-Chlorothiophen-2-yl)-acrylic acid A-2c (554 mg, 2.94 mmol) was 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) were added to the reaction mixture. The mixture was stirred at 0°C for 30 min. A solution of tert-butyl (2-aminoethyl)carbamate A-6a (470 mg, 2.94 mmol) in DMF (1 mL) was added dropwise over a period of 15 min. The reaction mixture was stirred for another 30 min. Concentrated HCl (2.89 g, 29.37 mmol) was added and the mixture was heated to 90°C and stirred for 90 min. Sodium hydroxide (8N in H2O) was added until pH 12 was reached and the mixture was extracted with EtOAc. The layers were separated and the organic phase was washed with deionized water and dried over MgSO4. The solvent is removed under reduced pressure and the crude reaction mixture is purified by reverse phase HPLC if necessary to give intermediate A-8a.

[1264] The following intermediates A-8 (Table 20) can be obtained by similar methods starting from different acrylic acids A-2 and amines A-6.

[1265] Table 20

[1266]

[1267] Synthesis of other intermediates A-5 (Method E)

[1268] Experimental procedures for the synthesis of A-5r and A-5t

[1269]

[1270] In a microwave vial, (E)-N-(2-aminoethyl)-3-(4-chlorothiophen-2-yl)acrylamide A-8a (0.37 g, 1.60 mmol), 6-chloro-1H-indole-2,3-dione S-1a (306 mg, 1.60 mmol) and triethylamine (162 mg, 1.60 mmol) were suspended in anhydrous NMP (12 mL). The reaction vessel was sealed with a Teflon cap and irradiated at a final temperature of 110 °C for 30 min. After cooling to rt, the solvent was removed under reduced pressure. The crude product was used for the next step or purified by reverse phase HPLC to give diastereomers A-5r and A-5t.

[1271] The following intermediate A-5 (Table 21) can be obtained by similar methods starting from different intermediates S-1 and A-8.

[1272] Table 21

[1273]

[1274]

[1275]

[1276] Synthesis of Intermediate A-9 (Method F)

[1277] Experimental procedures for the synthesis of A-9a

[1278]

[1279] 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 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 continued for another 30 min, then deionized water is added. EtOAc is added and the phases are separated. After washing with water, the organic phase is dried over MgSO4 and the solvent is removed under reduced pressure. If necessary, the product is purified using reverse phase HPLC to give purified A-9a.

[1280] The following intermediates A-9 (Table 22) can be obtained starting from different intermediates A-5 by similar methods.

[1281] Table 22

[1282]

[1283]

[1284]

[1285]

[1286]

[1287]

[1288] Synthesis of Intermediate A-11 (Method G)

[1289] Experimental procedures for the synthesis of A-11a

[1290]

[1291] In a microwave vial, intermediate A-9a (400 mg, 0.84 mmol), methyl 4-bromo-3-nitrobenzoate (A-10a, 334 mg, 0.1.26 mol), cesium carbonate (410 mg, 1.26 mmol), xanthenephosphine (97.2 mg, 0.17 mmol) and palladium trifluoroacetate (Pd(TFA)2; 28 mg, 0.08 mmol) were suspended in 1,4-dioxane (8 mL). The reaction was sealed and stirred at 130 °C for 5 h. After the starting material was consumed, the reaction was diluted with acetonitrile and filtered through a plug of silica. The solvent was removed under reduced pressure to give crude A-11a, which was purified by reverse phase column chromatography as needed.

[1292] The following intermediate A-11 (Table 23) can be obtained starting from different intermediates A-9 and A-10 in a similar manner.

[1293] Table 23

[1294]

[1295]

[1296]

[1297]

[1298]

[1299]

[1300]

[1301]

[1302]

[1303]

[1304]

[1305]

[1306]

[1307]

[1308]

[1309]

[1310]

[1311] Synthesis of Compound (Ib) According to the Invention (Method H)

[1312] Experimental Procedure for Synthesis of Ib-1

[1313]

[1314] A-11a (533 mg, 0.8 mmol) was dissolved in acetic acid (10 mL) and iron powder (469 mg, 8.4 mmol) was added. The suspension was heated to 130 °C overnight. After addition of EtOAc and saturated aqueous Na2CO3, the phases were separated and the organic phase was dried by addition of MgSO4. Removal of the solvent gave crude Ib-1, which was pure enough for further derivatization or purification by reverse phase column chromatography.

[1315] The following compounds (Ib) according to the invention can be obtained in a similar manner starting from different intermediates A-11 (Table 24).

[1316] Table 24

[1317]

[1318]

[1319]

[1320]

[1321]

[1322]

[1323]

[1324]

[1325]

[1326]

[1327]

[1328]

[1329]

[1330]

[1331]

[1332]

[1333]

[1334] Synthesis of Intermediate A-12 (Method I)

[1335] Experimental procedures for the synthesis of A-12a

[1336]

[1337] Intermediate A-5a (2.0 g, 4.8 mmol) was dissolved in formic acid (10 mL) and acetic anhydride (3.5 mL, 38.1 mmol) was added. The reaction mixture was stirred at 50 °C for 16 h and then quenched by adding water. Purification by reverse phase column chromatography gave Intermediate A-12a.

[1338] The following intermediates A-12 (Table 25) can be obtained starting from different intermediates A-5 by similar methods.

[1339] Table 25

[1340]

[1341] Synthesis of Intermediate A-13 (Method G)

[1342] Synthesis of A-13a

[1343]

[1344] 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).

[1345] Table 26

[1346]

[1347] Synthesis of Intermediate A-14 (Method H)

[1348] Synthesis of A-14a

[1349]

[1350] Intermediate A-14 can be synthesized from intermediate A-13 in analogy to the synthesis of compound (Ib) according to the invention from intermediate A-11 (Method H, see above).

[1351] Table 27

[1352]

[1353] Synthesis of intermediate A-15 (Method J) Experimental procedures for the synthesis of A-15a

[1354]

[1355] A-14a (840 mg, 1.45 mmol) was dissolved in MeOH (2 mL) and concentrated HCl (37%, 500 μL) was added. The reaction mixture was heated to 100 °C for 30 min. The reaction was quenched by adding saturated aqueous NaHCO3 and then extracted with EtOAc. The phases were separated and the organic phase was dried over MgSO4. The solvent was removed under reduced pressure. Reverse phase column chromatography was performed to obtain pure A-15a.

[1356] The following compounds A-15 (Table 28) can be obtained starting from different compounds A-14 by similar methods.

[1357] Table 28

[1358]

[1359]

[1360] Synthesis of Intermediate A-17 (Method M)

[1361] Experimental procedures for the synthesis of A-17a

[1362]

[1363] 3-Chloro-2-fluorocinnamic acid A-2b (3.0 g, 14.81 mmol) was 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) were added to the reaction mixture. The reaction mixture was stirred at 0°C for 30 min. A solution of methyl 3,4-diaminobenzoate A-16a (2.95 g, 17.77 mmol) in DMF (5 mL) was added dropwise over a period of 15 min. The mixture was stirred for another 3 h and aqueous K2CO3 solution (8 mL, 2N) was added. Deionized water was added and the mixture was extracted with DCM. The layers were separated and the organic phase was washed with deionized water and dried with MgSO4. The solvent was removed under reduced pressure and the mixture was used without further purification or purified by reverse phase column chromatography to obtain A-17a.

[1364] The following intermediate A-17 (Table 29) can be obtained starting from different intermediates A-2 and A-16 by a similar method.

[1365] Table 29

[1366]

[1367] Synthesis of Intermediate A-18 (Method N)

[1368] Experimental procedures for the synthesis of A-18a

[1369]

[1370] Intermediate A-17a (839 mg, 2.4 mmol) was dissolved in dioxane (5 mL) and concentrated HCl (1.76 g) and MeOH (24 mL) were added. The resulting mixture was stirred at 70 °C for 15 h. The mixture was diluted with EtOAc and aqueous NaOH (4 N) until pH = 10 was reached. Concentrated HCl was added and the resulting solid was collected by filtration. Intermediate A-18a was used in the next step without further purification.

[1371] The following intermediates A-18 (Table 30) can be obtained starting from different intermediates A-17 in a similar manner.

[1372] Table 30

[1373]

[1374] Synthesis of Intermediate A-20 (Method O)

[1375] Experimental procedures for the synthesis of A-20a and A-20b

[1376]

[1377] Intermediate A-18a (100 mg, 0.30 mmol) was dissolved in NMP (3 mL) and NaH (38 mg, 1.51 mmol) was added at rt. The resulting mixture was stirred for 5 min and A-19a was added. The reaction mixture was stirred at 70 °C for 15 h. Deionized water was added and the mixture was extracted with EtOAc. The layers were separated and the organic phase was washed with deionized water and dried with MgSO4. The solvent was removed under reduced pressure and the mixture was purified by reverse phase column chromatography to give A-20a and A-20b.

[1378] The following intermediate A-20 (Table 31) can be obtained by similar methods starting from different intermediates A-18 and / or A-19.

[1379] Table 31

[1380]

[1381] Synthesis of Intermediate A-21 (Method P)

[1382] Experimental procedures for the synthesis of A-21a

[1383]

[1384] Intermediate A-20a (50 mg, 0.05 mmol) was dissolved in DCM (1 mL). TFA (40 μL) was added at 0 °C and the reaction mixture was slowly allowed to warm to rt. The reaction mixture was heated to reflux for 24 h and concentrated in vacuo. The residue was dissolved in EtOAc and water and aqueous NaOH solution (4 M) were added until pH 12 was reached. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure and the mixture was purified by reverse phase column chromatography to give A-21a.

[1385] The following intermediates A-21 (Table 32) can be obtained starting from different intermediates A-20 by similar methods.

[1386] Table 32

[1387]

[1388] Synthesis of other intermediates A-15 (Method Q)

[1389] Experimental Procedure for the Synthesis of A-15c (Alternative Synthesis, see also Method J)

[1390]

[1391] In a microwave vial, intermediate A-21a (20 mg, 0.027 mmol), 6-chloro-1H-indole-2,3-dione S-1a (5 mg, 0.027 mmol) and triethylamine (17 μL, 0.13 mmol) were suspended in anhydrous NMP (500 μL). The reaction vessel was sealed with a Teflon cap and irradiated at a final temperature of 100 °C for 45 min. After cooling to rt, the solvent was removed under reduced pressure. The product was purified by reverse phase HPLC to give intermediate A-15c.

[1392] The following intermediates A-15 (Table 33) can be obtained by similar methods starting from different intermediates A-21 and / or S-1.

[1393] Table 33

[1394]

[1395]

[1396] Synthesis of other compounds (Ib) according to the present invention (Method K)

[1397]

[1398] A-15a (0.030 g, 0.054 mmol) and 3-methylbutanal (0.14 mg, 0.163 mmol) were dissolved in acetic acid (1 mL) and sodium triacetoxyborohydride (0.06 g, 0.272 mmol) was added. The reaction mixture was allowed to stir at ambient temperature for 1 h and then quenched by careful addition of saturated aqueous NaHCO3 at 0°C. Deionized water and EtOAc were added and the phases were separated. After washing with saturated aqueous NaHCO3 and water, the organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. Reverse phase column chromatography gave pure Ib-64.

[1399] The following compounds (Ib) (Table 34) can be obtained by similar methods starting from different intermediates A-15.

[1400] Table 34

[1401]

[1402]

[1403]

[1404]

[1405]

[1406]

[1407]

[1408]

[1409]

[1410]

[1411] Synthesis of other compounds (Ib) according to the present invention (Method L)

[1412]

[1413] (3,3-Difluorocyclobutyl)methanol (100 mg, 0.819 mmol) was dissolved in acetic acid (500 μL) and IBX (298 mg, 1.065 mmol) was added. The reaction mixture was stirred at 40° C. for 3 h and then the reaction mixture was passed through The mixture was filtered through a plug. A solution of A-15a (30 mg, 0.054 mmol) in acetic acid (500 μL) was added to the filtrate at rt. Sodium triacetoxyborohydride (58 mg, 0.272 mmol) was added to the reaction mixture in one portion and the reaction was allowed to stir at rt for 30 min, then the reaction was quenched by carefully adding saturated aqueous NaHCO3 at 0°C. Deionized water and EtOAc were added and the phases were separated. After washing with saturated aqueous NaHCO3 and water, the organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. Reverse phase column chromatography was performed to obtain pure Ib-100.

[1414] The following compounds (Ib) (Table 35) can be obtained by similar methods starting from different intermediates A-15 and / or different alcohols.

[1415] Table 35

[1416]

[1417]

[1418] Synthesis of other compounds (Ib) by ester saponification

[1419] Experimental Procedure for the Synthesis of Ib-106

[1420]

[1421] Ib-3 (484 mg, 0.8 mmol) was dissolved in MeOH (10 mL) and aqueous NaOH (2 mL, 4 M) was added. The reaction mixture was heated to reflux for 1 h. After acidification with 2 M aqueous HCl and extraction with EtOAc, the organic phase was dried over MgSO4. Purification by reverse phase HPLC gave pure Ib-106.

[1422] The following compounds (Ib) (Table 36) can be obtained from the initially obtained compound (Ib) in a similar manner.

[1423] Table 36

[1424]

[1425]

[1426]

[1427]

[1428]

[1429]

[1430]

[1431]

[1432]

[1433]

[1434]

[1435]

[1436]

[1437]

[1438]

[1439]

[1440]

[1441]

[1442]

[1443]

[1444]

[1445]

[1446]

[1447]

[1448]

[1449]

[1450] Synthesis of other compounds (Ib) by amidation

[1451] Experimental procedures for the synthesis of b-209

[1452]

[1453] Ib-107 (52 mg, 0.09 mmol) was dissolved in anhydrous DMF (1 mL) and HATU (40 mg, 0.11 mmol) was added at rt. After adding DIPEA (44.7 μL, 0.26 mmol), the reaction mixture was allowed to stir for 15 min at rt. Methylamine (2 M in THF, 52.6 μL, 0.11 mmol) was added and the reaction was allowed to stir for another 30 min. The crude reaction mixture was subjected to reverse phase column chromatography to obtain pure Ib-209.

[1454] The following compounds (Ib) (Table 37) can be obtained by a similar method starting from the initially obtained compound (Ib).

[1455] Table 37

[1456]

[1457]

[1458]

[1459]

[1460]

[1461]

[1462]

[1463]

[1464]

[1465]

[1466]

[1467] Synthesis of other compounds (Ib) by ester reduction

[1468] Experimental Procedure for the Synthesis of Ib-245

[1469]

[1470] Ib-3 (30 mg, 0.05 mmol) was dissolved in anhydrous toluene (1 mL) and added The reaction mixture was heated to 90°C for 16 h. After this time, another portion of (24 μL) and continued heating for 1 h. The reaction was quenched by adding water and extracted with EtOAc. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. Reverse phase column chromatography was performed to obtain pure Ib-245.

[1471] The following compounds (Ib) (Table 38) can be obtained by a similar method starting from the initially obtained compound (Ib).

[1472] Table 38

[1473]

[1474] Synthesis of other compounds by deacetylation (Ib)

[1475] Experimental Procedure for the Synthesis of Ib-247

[1476]

[1477] Ib-59 (55 mg, 0.09 mmol) was dissolved in MeOH (500 μL) and concentrated aqueous HCl (37%, 40 μL) was added. The reaction mixture was heated to 65 °C for 3 h. The reaction was quenched by adding 4 M NaOH and EtOAc. The phases were separated and the organic phase was dried over MgSO4. After removing the solvent under reduced pressure, reverse phase column chromatography was performed to give Ib-247.

[1478] The following compounds (Ib) (Table 39) can be obtained by a similar method starting from the initially obtained compound (Ib).

[1479] Table 39

[1480]

[1481] Synthesis of other compounds (Ib) by reductive amination

[1482] Experimental Procedure for the Synthesis of Ib-249

[1483] Glutaraldehyde (25% in water, 20 μL, 0.055 mmol) was dissolved in DMF (600 μL) and Ib-247 (10 mg, 0.018 mmol) was added as a solution in DMF (400 μL). The reaction mixture was treated with AcOH (5.1 μL, 0.05 mmol) and stirred at rt for 15 min. After this time, sodium triacetoxyborohydride (11.3 mg, 0.05 mmol) was added in one portion and the reaction mixture was allowed to stir at ambient temperature for 2 h. The reaction was quenched by the addition of water, filtered through a syringe filter and purified by reverse phase column chromatography to give Ib-249.

[1484] The following compounds (Ib) (Table 40) can be obtained starting from different compounds (Ib) in a similar manner.

[1485] Table 40

[1486]

[1487] Synthesis of other compounds (Ib) by amine cleavage

[1488] Experimental Procedure for the Synthesis of Ib-253

[1489]

[1490] Ib-247 (12 mg, 0.021 mmol) is added to a mixture of hypophosphorous acid (50% in water, 300 μL, 2.7 mmol), sulfuric acid (15 μL, 0.26 mmol) and copper (II) sulfate (3.75 mg, 0.023 mmol). The reaction mixture is stirred at rt for 5 min, then sodium nitrite (6 mg, 0.085 mmol) and two drops of water are added. The reaction is allowed to stir for 5 min. After quenching by addition of dilute NaOH and extraction with EtOAc, the phases are separated and the organic phase is dried over MgSO4. The solvent is removed under reduced pressure and reverse phase column chromatography is performed to give pure Ib-253.

[1491] The following compounds (Ib) (Table 41) can be obtained from the initially obtained compound (Ib) in a similar manner.

[1492] Table 41

[1493]

[1494] Compound (Ic)

[1495] General reaction diagram and summary of synthetic pathways

[1496] Reaction Figure 6

[1497]

[1498] Compounds of formula (Ic) can be prepared stepwise by the synthetic pathway depicted in reaction scheme 6: starting from (hetero)arylamine C-1 via a copper-catalyzed three-component coupling reaction with protected alkynamine C-2 (e.g., bis- or mono-Boc protected) and α,β-unsaturated aldehyde C-3 to establish the imidazo ring system (e.g., imidazopyrimidinyl) C-4 (Angew. Chem. Int. Ed. 2010, 49, 2743). The protecting group on C-4 can be removed by a suitable method. For mono- or di-Boc protection, acidic conditions such as TFA in dioxane can be used to generate intermediate C-5. Intermediate C-6 is obtained from intermediate C-5 and isatin derivative S-1 via 1,3-dipolar cycloaddition to establish the spiro system which may be in a racemic mixture with other regio- and / or diastereoisomers of C-6. The enantiomers of C-6 can be separated by chiral SFC at this stage or alternatively, the racemic mixture can be separated at any later stage of the synthesis. All other known methods for separating enantiomers can also be applied here or after any later synthetic step described herein, such as crystallization, chiral resolution, chiral HPLC, etc. (see also Enantiomers, racemates, and resolutions, Jean Jacques, André Collet, Samuel H Wilen John Wiley and Sons, NY, 1981).

[1499] C-6 can be reacted with an aldehyde or ketone in a reductive amination reaction to give compound (Ic). Alternatively, C-6 can be subjected to an alkylation, addition, acylation or sulfonylation reaction to give additional compound (Ic).

[1500] The compound (Ic) initially obtained from C-6 can be converted to all residues, especially R by well-established organic chemical transformations (such as metal-catalyzed cross-coupling reactions, acylation, amidation, addition, reduction or (reductive) alkylation or cleavage of protective groups) in an optional derivatization step not explicitly depicted in the reaction diagram. 4 (if they have functional groups that can be further modified such as, for example, halogen atoms, amine groups and hydroxyl groups (including cyclic amines), carboxylic acid or ester functional groups, nitriles, etc.) to derivatize into other compounds (Ic). These additional steps are not depicted in the general reaction diagram. Similarly, these additional steps can also be included in the synthetic pathways depicted in the general reaction diagram, that is, to carry out derivatization reactions with intermediate compounds. In addition, building blocks with protecting groups can also be used, that is, additional steps of removing protecting groups are necessary.

[1501] Compound (Ic) has been tested in its racemic form or in enantiopure form for its activity influencing the MDM2-p53 interaction. Each of the two enantiomers of the racemic mixture may have anti-MDM2 activity, however, with different binding modes. Enantiopure compounds are marked with the label "Chiral". The compounds marked "Chiral" listed in any of the tables below (both intermediates according to the invention and compound (Ic)) can be separated from their enantiomers by chiral SFC chromatography or synthesized from enantiopure starting materials separated by chiral SFC.

[1502] Examples:

[1503]

[1504] Formula A defines a racemic mixture of compounds having formulae B and C, i.e., formula A encompasses two formulae (compounds B and C), while formulae B and C are each enantiomerically pure and define only one specific compound. 1 To R 7 , A, V, W, X, Y, n, r and q are specifically defined in formula (Ic) and (Ic*)

[1505]

[1506] represents a racemic mixture of two enantiomers (→(Ic); the above formula A is a specific example of such a racemic mixture) or a single enantiomer (→(Ic*); the above formula B is a specific enantiomer), unless additional stereocenters are present in one or more of the substituents. The same definition applies to synthetic intermediates.

[1507] Synthesis of intermediate C-3

[1508] Experimental Procedure for the Synthesis of C-3a

[1509]

[1510] 2-Chloro-3-fluoropyridine-4-carbaldehyde D-1a (1.00 g, 6.27 mmol) and (triphenylphosphinyl)acetaldehyde (1.91 g, 6.27 mmol) were dissolved in DMF and stirred at rt for 16 h. The mixture was poured into ice water and the precipitate was filtered. The crude product was purified by chromatography to give intermediate C-3a.

[1511] The following intermediates C-3a (Table 42) can be obtained by similar methods starting from different aldehydes D-1.

[1512] Table 42

[1513]

[1514] Synthesis of intermediate C-4

[1515] Experimental Procedure for the Synthesis of C-4a (Method A)

[1516]

[1517] Under argon, 2-amino-isonicotinic acid methyl ester C-1a (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) acrolein C-3b (1.34 g, 7.23 mmol), Cu(OTf)2 (0.24 g, 0.66 mmol) and CuCl (0.06 g, 0.07 mmol) were dissolved in toluene and stirred at 100° C. for 20 h. The solvent was removed under vacuum and the crude product was purified by chromatography to give intermediate C-4a.

[1518] The following intermediate C-4 (Table 43) can be obtained starting from different intermediates C-1, C-2 and C-3 by a similar method.

[1519] Table 43

[1520]

[1521]

[1522] Synthesis of Intermediate C-5 Experimental Procedure for the Synthesis of C-5a (Method B)

[1523]

[1524] Intermediate C-4a (1.00 g, 1.372 mmol) was dissolved in 1,4-dioxane and stirred at rt for 3 h. The solvent was removed under vacuum and the crude product was purified by chromatography if necessary to give intermediate C-5a.

[1525] The following intermediates C-5 (Table 44) can be obtained starting from different intermediates C-4 by similar methods.

[1526] Table 44

[1527]

[1528]

[1529] Synthesis of Intermediate C-6 Experimental Procedure for the Synthesis of C-6a (Method C)

[1530]

[1531] A solution of intermediate C-5a (735 mg, 1.792 mmol), 6-chloroisatin S-1a (813 mg, 4.479 mmol) and N-methylpyrrolidine (763 mg, 8.958 mmol) in MeOH (30 mL) was heated at 120 °C under microwave irradiation for 20 min. The reaction mixture was diluted with DCM and extracted with saturated aqueous NaHCO3. The organic layer was separated and the solvent was removed under vacuum and the resulting crude product was purified by chromatography and reverse phase HPLC to give intermediate C-6a.

[1532] The following intermediate C-6 (Table 45) can be obtained by similar methods starting from different intermediates C-5 and S-1.

[1533] Table 45

[1534]

[1535]

[1536]

[1537]

[1538] Synthesis of Compound (Ic) According to the Invention

[1539] Experimental Procedure for the Synthesis of Ic-1 (Method D)

[1540]

[1541] Intermediate C-6a (18 mg, 0.033 mmol) was added to a solution of cyclopropanecarboxaldehyde (2.7 mg, 0.039 mmol) in AcOH (1 mL) and the reaction mixture was stirred for 15 min. Sodium triacetoxyborohydride (14.2 g, 0.065 mmol) was added and the reaction mixture was stirred overnight. Water was added to the reaction mixture and the reaction mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and the crude product was purified by chromatography to give compound Ic-1.

[1542] The following compounds (Ic) (Table 46) can be obtained by similar methods starting from different intermediates C-6 and different aldehydes.

[1543] Table 46

[1544]

[1545]

[1546]

[1547]

[1548] Synthesis of other compounds by ester saponification (Ic)

[1549] Experimental Procedure for the Synthesis of Ic-15 (Method E)

[1550]

[1551] Ic-1 (12 mg, 0.022 mmol) was dissolved in THF (0.5 mL) and water (1 mL) and NaOH (25 mg, 0.45 mmol) was added. The reaction mixture was stirred at 70 °C for 8 h. After acidification with 2M aqueous HCl and extraction with EtOAc, the organic phase was dried over MgSO4. Purification by reverse phase HPLC gave pure Ic-15.

[1552] The following compounds (Ic) (Table 47) can be obtained in a similar manner starting from the initially obtained compound (Ic).

[1553] Table 47

[1554]

[1555]

[1556]

[1557]

[1558] Experimental Procedure for the Synthesis of Other Compounds (Ic) by Amidation (Method F)

[1559]

[1560] Ic-23 (7 mg, 0.012 mmol) was dissolved in anhydrous THF (1 mL) and HATU (5 mg, 0.05 mmol) was added at rt. After adding DIPEA (5 mg, 0.05 mmol), the reaction mixture was allowed to stir for 15 min at rt. Dimethylamine (4 mg, 0.035 mmol) was added and the reaction was allowed to stir for another 60 min. The crude reaction mixture was subjected to reverse phase column chromatography to obtain pure Ic-29.

[1561] The following compounds (Ic) (Table 48) can be obtained by a similar method starting from the initially obtained compound (Ic).

[1562] Table 48

[1563]

[1564]

[1565]

[1566] The following examples illustrate the biological activities of the compounds according to the invention without limiting the invention to these examples.

[1567] The compounds of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) and (Ic*) are characterized by their numerous possible applications in the field of therapy. Particular mention should be made of their applications involving an inhibitory effect on the proliferation of cultured human tumor cells but also on the proliferation of other cells such as, for example, endothelial cells.

[1568] Mdm2-p53 inhibits AlphaScreen

[1569] This assay is used to determine whether the compounds inhibit the p53-MDM2 interaction and thereby restore p53 function.

[1570] 15 μL of compound (in 20% DMSO) was pipetted (serial predilutions of compound were done in 100% DMSO) into the wells of a white OptiPlate-96 (PerkinElmer). A mixture consisting of 20 nM GST-MDM2 protein (aa 23 to 117) and 20 nM biotinylated p53 wt peptide (containing aa 16 to 27 of wt human p53, amino acid sequence QETFSDLWKLLP-Ttds-Lys-Biotin, molecular weight 2132.56 g / mol) was prepared in assay buffer (50 mM Tris / HCl pH 7.2; 120 mM NaCl; 0.1% bovine serum albumin (BSA); 5 mM dithiothreitol (DTT); 1 mM ethylenediaminetetraacetic acid (EDTA); 0.01% Tween 20). 30 μL of this mixture was added to the compound dilution and incubated for 15 min at rt while gently shaking the plate at 300 rpm. Subsequently, 15 μL of premixed AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads (purchased from PerkinElmer) (10 μg / mL each in the assay plate) were added and the samples were incubated for 30 min at rt in the dark (shaking at 300 rpm). Afterwards, the signal was measured using the AlphaScreen protocol (purchased from PerkinElmer) in a PerkinElmer Envision HTS multilabel reader.

[1571] Each plate contains a negative control in which the biotinylated p53-peptide and GST-MDM2 are removed and replaced with assay buffer. When using the software GraphPad Prism for calculations, the negative control value is entered as a low basal value. In addition, a positive control (test compound replaced with 5% DMSO; with protein / protein mixture) is pipetted. IC is performed using GraphPad Prism 3.03 software (or later versions) 50 Determination of value.

[1572] Table 49 shows the IC values ​​of example compounds determined using the above assay. 50 value.

[1573] Table 49

[1574]

[1575]

[1576] Cell proliferation analysis

[1577] Cell Titer Glo analysis for SJSA-1, SKOV-3, RS4-11 and KG-1 cells:

[1578] SJSA-1 cells (osteosarcoma, wild-type p53, ATCC CRL-2098™) were seeded at 2500 cells / well in 90 μL RPMI medium, 10% fetal calf serum (FCS, purchased from, e.g., JRH Biosciences #12103-500M, lot number: 3N0207) in duplicate on day 1 in flat-bottom 96-well microtiter plates (white Packard View 96-well plates, catalog number 6005181). Any other luminescence-compatible plate format is feasible.

[1579] Similarly, p53 mutant SKOV-3 cells (ovarian adenocarcinoma, ATCC HTB-77 TM ) were seeded at a density of 3000 cells / well in 90 μL McCoy medium, 10% FCS in a flat-bottom 96-well microtiter plate.

[1580] On day 2, 5 μL of dilutions of test compounds covering a concentration range between approximately 0.6 nM and 50000 nM were added to the cells. Cells were cultured at 37° C. in a humidified controlled CO 2 incubator for three days.

[1581] Wild-type p53 RS4-11 cells (acute lymphoblastic leukemia, ATCC CRL-1873 TM ):

[1582] Day 1: RS4-11 cells were seeded at a density of 5000 cells / well in a flat-bottom 96-well microtiter plate (white Packard View 96-well plate, catalog number 6005181) in 90 μL RPMI medium, 10% fetal calf serum (FCS, purchased from, e.g., JRH Biosciences #12103-500M, lot number: 3N0207). Any other luminescence-compatible plate format is feasible.

[1583] Day 2: Add 5 μL of dilutions of test compound covering a concentration range between approximately 0.3 nM and 25000 nM (alternative dilution schemes are possible) to the cells. Grow cells for three days at 37° C. in a humidified controlled CO 2 incubator. Final DMSO concentration is 0.5%.

[1584] p53 mutant KG-1 cells (acute myeloid leukemia, ATCC CCL-246):

[1585] Day 1: KG-1 cells with p53 mutations at the exon 6 / intron 6 junction donor site were seeded at a density of 10,000 cells / well in a flat-bottom 96-well microtiter plate (white Packard View 96-well plate, catalog number 6005181) in 90 μL of IMDM medium, 10% FCS (JRH Biosciences #12103-500M, lot number: 3N0207). Any other luminescence-compatible plate format is feasible.

[1586] Day 2: Add 5 μL of dilutions of test compound covering a concentration range between approximately 0.3 nM and 25000 nM (alternative dilution schemes are possible) to the cells. Grow cells for three days at 37° C. in a humidified controlled CO 2 incubator. Final DMSO concentration is 0.5%.

[1587] All Cell Titer Glo assays were evaluated on day 5 after inoculation. On day 5, 95 μL of Cell Titer Glo reagent (Cell titer Glo luminescent agent, catalog number G7571, Promega) was added to each well and incubated for another 10 min at rt (with stirring). Luminescence was measured using standard luminescence readings on a Wallac Victor. IC was calculated using the standard Levenburg Marquard algorithm (GraphPad Prism). 50 value.

[1588] In addition, several other cancer cell lines derived from different tissues are sensitive to compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) and (Ic*). Examples include NCI-H460 (lung), Molp-8 (myeloma) and MV4-11 (AML).

[1589] Based on their biological properties, the compounds of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) according to the present invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and salts of all the aforementioned forms are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation.

[1590] 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; leukemias, lymphomas and solid tumors (e.g., carcinomas and sarcomas), skin diseases (e.g., psoriasis); proliferation-based diseases characterized by an increase in the number of lineage cells (e.g., fibroblasts, hepatocytes, bone 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 overgrowth). 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.

[1591] For example, the following cancers / proliferative diseases may be treated with compounds according to the present invention, but are not limited to those:

[1592] Brain tumors, such as, for example, acoustic neuromas, astrocytomas (such as, pilocytic astrocytomas, fibrillary astrocytomas, protoplasmic astrocytomas, gemistocytary astrocytomas, anaplastic astrocytomas and glioblastomas), gliomas, brain lymphomas, brain metastases, pituitary tumors (such as prolactinomas, HGH (human growth hormone) producing tumors and ACTH (adrenocorticotropic hormone) producing tumors), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; neural tumors (neoplasms), such as, for example, tumors of the autonomic nervous system (such as choroidal hyperplasia), cerebral lymphomas, brain metastases, pituitary tumors (such as prolactinomas, HGH (human growth hormone) producing tumors and ACTH (adrenocorticotropic hormone) producing tumors), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; neural tumors (neoplasms), such as, for example, tumors of the autonomic nervous system (such as Tumors of the peripheral nervous system (such as stump neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant Schwannoma) and of the central nervous system (such as brain tumors and myeloma); intestinal cancers such as, for example, rectal cancer, colon cancer, colorectal cancer, anal cancer, large intestine cancer, small intestine and duodenum tumors; eyelid tumors such as basal cell tumors (basalioma / basal cell carcinoma); pancreatic cancer (pancreatic cancer / carcinoma of the pancreas); bladder cancer (bladder cancer / carcinoma of the bladder) and other urothelial cancers; lung cancer (bronchial cancer), such as, for example, small cell bronchial cancer (oat cell carcinoma) and non-small cell bronchial cancer (NSCLC) (such as plate epithelial carcinoma, adenocarcinoma and large cell bronchial carcinoma); breast cancer, such as, for example, breast cancer (such as invasive ductal carcinoma, colloid carcinoma, invasive lobular carcinoma, tubular carcinoma, adenoid cystic 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 (Burkitt's lymphoma, low-grade non-Hodgkin's lymphoma (NHL) and mycosis fungoides; uterine or endometrial cancer or corpus carcinoma; CUP syndrome (cancer of unknown primary site); ovarian cancer (ovarian carcinoma), such as mucinous carcinoma, endometrial carcinoma or serous carcinoma; gallbladder cancer; bile duct cancer, such as, for example, Klatskin tumor;Testicular cancer, such as, for example, spermatocytoma and non-spermoma; lymphoma (lymphosarcoma), such as, for example, malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (NHL), such as chronic lymphatic leukemia, leukemic reticuloendotheliosis, immunocytoma, plasmacytoma, multiple myeloma (MM), immunoblastic carcinoma, Burnet's lymphoma, T-zone mycosis fungoides, large cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer, such as, for example, tumors of the vocal cords, supraglottic and subglottic laryngeal tumors; bone cancer, such as, for example, osteochondroma, enchondroma, chondroblastoma, chondromyxofibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumor, chondrosarcoma, osteosarcoma, Ewing's sarcoma (Ewing's head and neck tumors, such as, for example, tumors of the lip, tongue, floor of mouth, oral cavity, gums, jaw, salivary glands, throat, nasal cavity, paranasal sinuses, larynx, and middle ear; liver cancer, such as, for example, liver cell carcinoma / hepatocellular carcinoma (HCC); leukemias, such as, for example, acute leukemias, such as acute lymphoblastic / lymphoblastic leukemia (ALL), acute myeloid leukemia (AML); chronic leukemias, such as chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML); myelodysplasia syndrome (MDS); stomach cancer / gastric carcinoma, such as, for example, papillary, tubular and mucinous adenocarcinomas, signet ring cell carcinoma (SCC); carcinoma), adenosquamous carcinoma, small cell carcinoma, and undifferentiated carcinoma; melanoma, such as, for example, superficial spreading, nodular, malignant lentigo, and acral lentigo; renal cancer, such as, for example, renal cell carcinoma or adrenal tumor or Grawitz's tumor; oesophageal cancer (carcinoma of the oesophagus); penile cancer; prostate cancer (e.g., castration-resistant prostate cancer); throat cancer (carcinomas of the pharynx), such as, for example, nasopharyngeal carcinoma, oropharyngeal carcinoma, and hypopharyngeal carcinoma; retinoblastoma, vaginal cancer (vaginal carcinoma), mesothelioma; squamous cell carcinoma, adenocarcinoma, carcinoma in situ, malignant melanoma, and sarcoma; thyroid cancer, such as, for example, papillary, follicular, and medullary thyroid carcinoma, and anaplastic carcinoma;Spinalioma, epidermoid carcinoma and squamous cell carcinoma of the skin; thymoma, urethral cancer, cervical cancer, adenoid cystic carcinoma (AdCC), adrenal cortical carcinoma and vulvar cancer.

[1593] Preferably, the proliferative disease / cancer to be treated has 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.

[1594] The compounds can be used for the prevention, short-term or long-term treatment of the above diseases, optionally in combination with radiation therapy or other "state of the art" compounds such as (for example) cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.

[1595] The compounds of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) can be used alone or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.

[1596] Therapeutic agents (= cytostatic and / or cytotoxic active substances) which can be administered in combination with the compounds of the invention include, but are not limited to, hormones, hormone analogs and anti-hormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, 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, 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), insulin-like growth factor (IGF), human epidermal growth factor (HER, such as HER2, HER3, HER4) and hepatocyte growth factor (HGF)), inhibitors such as, for example, growth factor antibodies, growth factor receptor antibodies and tyrosine kinase inhibitors such as, for example, cetuximab, gefitinib, nib), imatinib, lapatinib, bosutinib, and trastuzumab); antimetabolites (e.g., antifolates (e.g., methotrexate, raltitrexed), pyrimidine analogs (e.g., 5-fluorouracil (5-FU), capecitabine, and gemcitabine), purine and adenosine analogs (e.g., mercaptopurine, thioguanine, cladribine, and pentostatin), cytarabine (arabinoside), and sirolimus.C), fludarabine); antitumor antibiotics (e.g., anthracyclines (such as doxorubicin), doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozotocin ( streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas (such as, for example, carmustine); rmustin 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), tubulin 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 inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g. PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g. IAP activators, Mcl-1, MDM2 / MDMX), MEK inhibitors (e.g. pimasertib), ERK inhibitors, FLT3 inhibitors (e.g. quizartinib), BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors (e.g. venetoclax), Bcl-2 / Bcl-xL inhibitors, ErbB receptors antagonists, 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), immunotherapeutics (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), immunotherapeutics (e.g., poxvirus-based vaccines, ipilimumab Antibodies to the treatment of leukemia (ipilimumab, immune checkpoint inhibitors) and various chemotherapeutic agents (such as amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer).

[1597] Other possible combinations include 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-alethine, 131-I-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-azaepothilone B, ABT-199, ABT-263 / navitoclax, ABT-737, A 105972, A204197, aldesleukin, alisertib / MLN8237, alitretinoin, allovectin-7, altretamine, alvcidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE PE), AVLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), AMG-232, AMG-511, AMG 2520765, AMG2112819, 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, BAY80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235 / dactolisib, biricodardicitrate, birinapant, BCX-1777, BKM-120 / 5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (buparlisib), bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW2992 / afatinib, BIBF 1120 / nintedanib, BI 836845, BI 2536, BI6727 / volasertib, BI 836845, BI 847325, BI 853520, BIIB-022, bleomycinic acidacid), bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib, brostallicin, busulfan, BYL-719 / alpelisib, CA-4 prodrug, CA-4, cabazitaxel, cabozantinib, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthaloplatin, CCI-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CGM-097, CH4987655 / RO-4987655, chlorotrianisene, cilengitide, ciclosporin, CD20 antibody, CDA-II, CDC-394, CKD-602, CKI-27, clofarabine, colchicin, combretastatin A4 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, cyanomorpholino doxorubicin, cytarabine, D 24851, dasatinib, decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone BB), dexamethasone, dexrazoxanet, diethylstilbestrol, diflomotecan, didox, DMDC, 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, erlotinib, ET-18-OCH3, ethynylcytidine, ethinyl estradiol, exatecan, exatecan mesylate mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, FOLFOX, FOLFOX4, FOLFIRI, formestane, fostamatinib, fotemustine, galarubicin, gallium maltolate, ganetespib, gefinitib, gemtuzumab, gemtuzumab ozogamicinozogamicin), gimatecan, glufosfamide, GCS-IOO, GDC-0623, GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine (pictrelisib)), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT antigen, GMK, GMX-1778, GPX-100, gp100-peptide vaccine, GSK-5126766, GSK-690693, G SK-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, herceptin, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acidacid), hydroxyurea, hydroxyprogesterone caproate, HDM-201, ibandronate, ibritumomab, ibrutinib / PCI-32765, idasanutlin, idatrexate, idelalisib / CAL-101, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12 (cixutumumab), immunol, N-(3-chloro-1H-indol-7-yl)-1,4-phenyl indisulam, interferon α-2a, interferon α-2b, pegylated interferon α-2b, interleukin-2, INK-1117, INK-128, INSM-18, ionafarnib, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, JQ-1, J-107088, conjugated estrogens, kahalid-F 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, LU223651, 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 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, oncoVEX GM-CSF, ormiplatin, ortataxel, OX44 antibody, OSI-027, OSI-906 (linsitinib), 4-1BB antibody, oxantrazole, estrogen, onapristone, palbociclib / PD-0332991, panitumumab, panobinostat, patupilone, paz opanib), pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PBI-05204, PD0325901, PD-1 and PD-L1 antibodies (e.g., pembrolizumab, nivolumab, pidilizumab, MEDI-4736 / durvalumab, RG-7446 / atezolizumab), PD-616, PE PEG-paclitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PF-3758309, PHA-665752, PHT-427, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine, perillylalcohol hol), pertuzumab, pevonedistat, PI3K inhibitors, PI3K / mTOR inhibitors, PG-TXL, PG2, PLX-4032 / RO-5185426 (vemurafenib), PLX-3603 / RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethyl butyrate, pixantrone, phenoxodiol O, PKI166, plevitrexed, plicamycin, polyprenicacid), ponatinib, porfiromycin, posaconazole, prednisone, prednisolone, PRT-062607, quinamed, quinupristin, quizartinib / AC220, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119 / BAY 869766, RDEA-436, rebeccamycin analogs, 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-0 15. 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, suberoylanilide hydroxamic acid, sutent, T900607, T138067, TAE-684, TAK-733, TAS-103, tacedinaline, talaporfin, tanespimycin, Tarceva, tariquitar, tasisulam, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin, thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin, tosedostat, trabectedin, TransMID-107, transretinic acid acid), traszutumab, tremelimumab, tretinoin, triacetyluridine, felodipine, triapine, triciribine, trimetrexate, TLK-286TXD258, Tykerb / Lapatinib, Urocidin, Valproic Acid, Valrubicin, Vandetanib, Vatalanib, Vincristine, Vinflunine, Virulizin, Vismodegib, Vosaroxin, WX-UK1, WX-554, Vectibix bix), 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.

[1598] Particularly preferred are methods of treatment and medical uses, comprising the use of Compound (I) of the invention in combination with an immunotherapeutic agent, such as a checkpoint inhibitor, including an anti-PD-1 agent and an anti-PD-L1 agent (such as, for example, pembrolizumab, nivolumab, bediluzumab, MEDI-4736 / dofrumab and RG-7446 / atezumab) and an anti-LAG3 agent. Thus, one aspect of the invention is a method of treatment and medical use, comprising the use of Compound (I) of the invention in combination with an anti-PD-1 or anti-PD-L1 agent (such as, for example, pembrolizumab, nivolumab, bediluzumab, MEDI-4736 / dofrumab and RG-7446 / atezumab). Another aspect of the invention is a method of treatment and medical use, comprising the use of Compound (I) of the invention in combination with an anti-LAG3 agent. Another aspect of the present invention is a method of treatment and a medical use, which comprises the use of the compound (I) of the present invention in combination with an anti-PD-1 agent and an anti-LAG3 agent.

[1599] Suitable formulations include, for example, tablets, pills, capsules, suppositories, lozenges, tablets, solutions (particularly solutions for injection (sc, iv, im) and infusions (injections)), elixirs, syrups, sachets, emulsions, inhalants or dispersible powders. The content of the pharmaceutically active compound should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the composition as a whole, i.e., an amount sufficient to achieve the dosage range specified below. The specified dosage can be given several times a day if necessary.

[1600] Suitable tablets can be obtained, for example, by mixing the active substance 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 gelatin), lubricants (magnesium stearate or talc), agents for delayed release (such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate), carriers, adjuvants, surfactants. Tablets may also contain several layers.

[1601] Coated tablets can be prepared accordingly by coating a core similar to that prepared for tablets with substances commonly used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities, the core can also consist of multiple layers. Similarly, the tablet coating can consist of multiple layers to achieve delayed release, which can use the excipients mentioned above for the tablets.

[1602] Syrups or elixirs containing the active substances according to the invention or their combination may additionally contain sweeteners (such as saccharin, cyclamates, glycerol or sugar) and flavor enhancers (e.g. flavoring agents such as vanillin or orange extract). They may also contain suspending adjuvants or thickeners (such as sodium carboxymethylcellulose), wetting agents (such as, for example, condensation products of fatty alcohols with ethylene oxide) or preservatives (such as parabens).

[1603] Solutions for injection and infusion are prepared in a conventional manner, for example, by adding isotonic agents, preservatives (such as p-hydroxybenzoates) or stabilizers (such as alkali metal salts of ethylenediaminetetraacetic acid), optionally using emulsifiers and / or dispersants, and if water is used as a diluent, optionally using, for example, organic solvents as solvating agents or dissolution aids, and transferred to injection bottles or ampoules or infusion bottles.

[1604] Capsules containing one or more active substances or a combination of active substances can be prepared, for example, by mixing the active substances with inert carriers such as lactose or sorbitol and packing them in gelatin capsules.

[1605] Suitable suppositories can be prepared, for example, by mixing with carriers provided for this purpose such as neutral fats or polyethylene glycol or its derivatives.

[1606] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents (such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerol)), carriers (such as, for example, natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates)), sugars (e.g., sucrose, lactose and glucose), emulsifiers (e.g., lignin, sulfite waste liquor, methylcellulose, starch and polyvinyl pyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

[1607] These preparations are administered in the usual manner, preferably by oral or transdermal route, most preferably by oral route. For oral administration, the tablets may of course contain, in addition to the above-mentioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate and various additives such as starch, preferably potato starch, gelatin and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used at the same time in the tableting process. For aqueous suspensions, the active substance may be combined with various flavor enhancers or colorants in addition to the above-mentioned excipients.

[1608] For parenteral use, solutions of the active substance with suitable liquid carriers may be used.

[1609] The compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) can be administered in a dosage range of generally 1 mg to 2000 mg per day, preferably 50 to 1000 mg, more preferably 100 to 500 mg.

[1610] The dosage for intravenous use is 1 mg to 1000 mg / hour, preferably between 5 mg and 500 mg / hour.

[1611] However, it may be necessary to deviate from the specified amount at times, depending on body weight, route of administration, individual response to the drug, the nature of its formulation and the time or interval of administration of the drug. Thus, in some cases, it may be sufficient to use a dose less than the minimum dose given above, while in other cases, the upper limit may have to be exceeded. When administering a large amount, it may be appropriate to divide it into a number of small doses per day.

[1612] The following formulation examples illustrate the invention without limiting the scope of the invention (the active substance in all examples is a compound according to formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)):

[1613] Examples of pharmaceutical preparations

[1614]

[1615]

[1616] The finely ground active substance, lactose and part of the corn starch are mixed together. The mixture is sieved, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the remaining corn starch and magnesium stearate are sieved and mixed together. The mixture is compressed to obtain tablets of suitable shape and size.

[1617]

[1618] The finely ground active substance, part of the corn starch, lactose, microcrystalline cellulose and polyvinyl pyrrolidone are mixed together, the mixture is sieved and treated with the remaining corn starch and water to form granules, which are dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added and mixed and the mixture is compressed to form tablets of suitable size.

[1619]

[1620]

[1621] The active substance, lactose and cellulose are mixed together. The mixture is sieved, then moistened with water, kneaded, wet granulated and dried, or dry granulated or directly blended with magnesium stearate and compressed to tablets of suitable shape and size. When wet granulated, additional lactose or cellulose and magnesium stearate are added and the mixture is compressed to obtain tablets of suitable shape and size.

[1622] D) Ampoule solution

[1623] Active substance 50mg

[1624] Sodium chloride 50mg

[1625] Water for injection 5mL

[1626] 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 resulting solution is filtered pyrogen-free and the filtrate is transferred under aseptic conditions into ampoules which are then sterilized and fusion-sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

[1627] In summary, the present invention includes but is not limited to the following technical items:

[1628] 1. Compound of formula (I)

[1629] in

[1630] --

[1631] R 1 is optionally substituted by one or more identical or different R b1 and / or R c1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1632] Each R b1 Independently selected from -OR c1 、-NR c1 R c1 , halogen, -CN, -C(O)R c1 、-C(O)OR c1 ,

[1633] -C(O)NR c1 R c1 、-S(O)2R c1 、-S(O)2NR c1 R c1 、-NHC(O)R c1 、-N(C 1-4 alkyl)C(O)R c1 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[1634] Each R c1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d1 and / or R e1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1635] Each R d1 Independently selected from -OR e1 、-NR e1 R e1 , halogen, -CN, -C(O)R e1 、-C(O)OR e1 ,

[1636] -C(O)NRe1 R e1 、-S(O)2R e1 、-S(O)2NR e1 R e1 、-NHC(O)R e1 、-N(C 1-4 alkyl)C(O)R e1 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system.

[1637] Each R e1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f1 and / or R g1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1638] Each R f1 Independently selected from -OR g1 、-NR g1 R g1 , halogen, -CN, -C(O)R g1 、-C(O)OR g1 ,

[1639] -C(O)NR g1 R g1 、-S(O)2R g1 、-S(O)2NR g1 R g1 、-NHC(O)R g1 、-N(C 1-4 alkyl)C(O)R g1 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[1640] Each R g1 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group;

[1642] --

[1643] R 2 With R 3 are each independently selected from hydrogen, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, wherein the C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups are optionally substituted with one or more identical or different R b2 and / or R c2 replace;

[1644] Each R b2 Independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)R c2 、-C(O)OR c2 ,

[1645] -C(O)NR c2 R c2 、-S(O)2R c2 、-S(O)2NR c2 R c2 、-NHC(O)R c2 、-N(C 1-4 alkyl)C(O)R c2 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[1646] Each R c2 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d2 and / or R e2 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1647] Each R d2 Independently selected from -OR e2 、-NR e2 R e2 , halogen, -CN, -C(O)R e2 、-C(O)OR e2 、-C(O)NR e2 R e2 、-S(O)2R e2 、-S(O)2NR e2 R e2 、-NHC(O)Re2 、-N(C 1-4 alkyl)C(O)R e2 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system;

[1648] Each R e2 independently represent hydrogen or selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1649] --

[1650] If F is carbon, A is selected from phenyl and 5- to 6-membered heteroaryl, or if F is nitrogen, A is a 5- to 6-membered nitrogen-containing heteroaryl;

[1651] Each R 4 Independently selected from R a4 and R b4 ;

[1652] Each R a4 are independently selected from one or more identical or different R b4 and / or R c4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1653] Each R b4 Independently selected from -OR c4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-C(O)NR g4 OR c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHSO2R c4 、-N(C 1-4 Alkyl)SO2Rc4 、-NHC(O)R c4 and-N(C 1-4 alkyl)C(O)R c4 ;

[1654] Each R c4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d4 and / or R e4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1655] Each R d4 Independently selected from -OR e4 、-NR e4 R e4 , halogen, -CN, -C(O)R e4 、-C(O)OR e4 、-C(O)NR e4 R e4 、-C(O)NR g4 OR e4 、-S(O)2R e4 、-S(O)2NR e4 R e4 、-NHC(O)R e4 and-N(C 1-4 alkyl)C(O)R e4 ;

[1656] Each R e4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f4 and / or R g4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1657] Each R f4 are independently selected from -OR g4 、-NR g4 R g4 , halogen, -CN, -C(O)Rg4 、-C(O)OR g4 、-C(O)NR g4 R g4 、-C(O)NR g4 OR g4 、-S(O)2R g4 、-S(O)2NR g4 R g4 、-NHC(O)R g4 and-N(C 1-4 alkyl)C(O)R g4 ;

[1658] Each R g4 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered

[1659] Heterocyclic group;

[1660] r represents a value of 0, 1, 2, or 3;

[1661] --

[1662] n represents a value of 1, 2, or 3;

[1663] --

[1664] Each R 7 is independently selected from halogen, C 1-4 Alkyl, -CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl and -OC 1-4 Haloalkyl;

[1665] q represents a value of 0, 1, 2, or 3;

[1666] --

[1667] W, X and Y are each independently selected from -N= and -CH=

[1668] The restriction is that each hydrogen in -CH= can be replaced by a substituent R 7 (if any) permutation and at most two of W, X and Y may be -N=;

[1669] --

[1670] V is oxygen or sulfur;

[1671] --

[1672] D is nitrogen, E is carbon and F is carbon; or

[1673] D is carbon, E is nitrogen and F is carbon; or

[1674] D is carbon, E is carbon and F is nitrogen;

[1675] or a salt thereof.

[1676] 2. The compound according to technical item 1, which is of formula (Ia) or (Ib) or (Ic)

[1677]

[1678] or a salt thereof.

[1679] 3. The compound according to technical item 2, which is of formula (Ia*) or (Ib*) or (Ic*)

[1680]

[1681] or a salt thereof.

[1682] 4. A compound according to any one of the preceding technical items, wherein

[1683] R 1 is optionally substituted by one or more identical or different R b1 and / or R c1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1684] Each R b1 Independently selected from -OR c1 、-NR c1 R c1 , halogen, -CN, -C(O)R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O)2R c1 、-S(O)2NR c1 R c1 、-NHC(O)R c1 and-N(C 1-4 alkyl)C(O)R c1 ;

[1685] Each R c1independently of one another represent hydrogen or optionally substituted by one or more identical or different R d1 and / or R e1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1686] Each R d1 Independently selected from -OR e1 、-NR e1 R e1 , halogen, -CN, -C(O)R e1 、-C(O)OR e1 、-C(O)NR e1 R e1 、-S(O)2R e1 、-S(O)2NR e1 R e1 、-NHC(O)R e1 and-N(C 1-4 alkyl)C(O)R e1 ;

[1687] Each R e1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f1 and / or R g1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1688] Each R f1 Independently selected from -OR g1 、-NR g1 R g1 , halogen, -CN, -C(O)R g1 、-C(O)OR g1 、-C(O)NR g1 R g1 、-S(O)2R g1 、-S(O)2NR g1 R g1 、-NHC(O)R g1 and-N(C1-4 alkyl)C(O)R g1 ;

[1689] Each R g1 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group;

[1690] or a salt thereof.

[1691] 5. A compound according to any one of the preceding technical items, wherein

[1692] R 2 With R 3 are each independently selected from hydrogen, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, wherein the C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups are optionally substituted with one or more identical or different R b2 and / or R c2 replace;

[1693] Each R b2 Independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)R c2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-S(O)2R c2 、-S(O)2NR c2 R c2 、-NHC(O)R c2 and-N(C 1-4 alkyl)C(O)R c2 ;

[1694] Each R c2 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d2 and / or R e2 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1695] Each R d2 Independently selected from -OR e2 、-NR e2 R e2 , halogen, -CN, -C(O)R e2 、-C(O)OR e2 、-C(O)NR e2 R e2 、-S(O)2R e2 、-S(O)2NR e2 R e2 、-NHC(O)R e2 and-N(C 1-4 alkyl)C(O)R e2 ;

[1696] Each R e2 independently represent hydrogen or selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1697] or a salt thereof.

[1698] 6. The compound according to claim 5, wherein

[1699] R 2 With R 3 One of them is hydrogen and the other is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are optionally substituted by one or more identical or different R b2 and / or R c2 replace;

[1700] Each R b2 Independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)R c2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-S(O)2R c2 、-S(O)2NR c2 R c2 、-NHC(O)R c2 and-N(C 1-4alkyl)C(O)R c2 ;

[1701] Each R c2 independently represent hydrogen or selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, phenyl, 5- to 6-membered heteroaryl and 3- to 7-membered heterocyclic groups;

[1702] or a salt thereof.

[1703] 7. The compound according to claim 6, wherein

[1704] R 2 With R 3 One of them is hydrogen and the other is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are optionally substituted by one or more identical or different selected from -OC 1-6 Alkyl, halogen, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[1705] or a salt thereof.

[1706] 8. A compound according to any one of the preceding technical items, wherein

[1707] R 3 is hydrogen;

[1708] or a salt thereof.

[1709] 9. A compound according to any one of the preceding technical items, wherein

[1710] A is phenyl and F is carbon;

[1711] Each R 4 Independently selected from R a4 and R b4 ;

[1712] Each R a4 are independently of each other and are optionally substituted by one or more identical or different R b4 and / or R c4 The substituted 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3- to 10-membered heterocyclic groups;

[1713] Each R b4 Independently selected from -OR c4 、-NR c4 R c4, halogen, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-C(O)NR g4 OR c4 、-S(O)2R c4 and -NHC(O)R c4 ;

[1714] Each R c4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d4 and / or R e4 The substituted 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3- to 10-membered heterocyclic groups;

[1715] Each R d4 Independently selected from -OR e4 、-NR e4 R e4 and -S(O)2R e4 ;

[1716] Each R e4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f4 and / or R g4 The substituted 1-6 Alkyl and 3- to 10-membered heterocyclic groups;

[1717] Each R f4 For-OR g4 ;

[1718] Each R g4 are independently selected from hydrogen and C 1-6 alkyl;

[1719] r represents a value of 0, 1, 2, or 3;

[1720] or a salt thereof.

[1721] 10. A compound according to any one of the preceding technical items, wherein

[1722] If F is carbon, then A is selected from phenyl and 5- to 6-membered heteroaryl, or

[1723] If F is nitrogen, then A is a 5- to 6-membered nitrogen-containing heteroaryl group;

[1724] Each R 4 are independently selected from R a4 and R b4 ;

[1725] Each R a4 are independently selected from one or more identical or different R b4 and / or R c4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[1726] Each R b4 Independently selected from -OR c4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-C(O)NHOR c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHSO2R c4 、-N(C 1-4 Alkyl)SO2R c4 、-NHC(O)R c4 and-N(C 1-4 alkyl)C(O)R c4 ;

[1727] Each R c4 independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group;

[1728] r represents a value of 0, 1, 2, or 3;

[1729] or a salt thereof.

[1730] 11. A compound according to any one of the preceding technical items, wherein

[1731] A and r substituents R 4 Together for

[1732]

[1733] R 8 Selected from hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -CN, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2 and -S(O)2C 1-6 alkyl;

[1734] R 9 Selected from hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -CN, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2 and -S(O)2C 1-6 alkyl;

[1735] R 10 Selected from hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -CN, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2 and -S(O)2C 1-6 alkyl;

[1736] The restriction condition is R 8 To R 10 At least one of the following other than R 8 To R 10 All hydrogen;

[1737] or a salt thereof.

[1738] 12. A compound according to any one of the preceding technical items, wherein

[1739] n represents a value of 1 or 2;

[1740] or a salt thereof.

[1741] 13. A compound according to any one of the preceding technical items, wherein

[1742] Each R 7 are independently halogen or -CN and q is 1 or 2;

[1743] or a salt thereof.

[1744] 14. A compound according to any one of the preceding technical items, wherein

[1745] W, X and Y are -CH=, with the restriction that the hydrogen in each -CH= may be replaced by a substituent R 7 (if any) replacement;

[1746] or a salt thereof.

[1747] 15. A compound selected from the group consisting of:

[1748]

[1749]

[1750]

[1751]

[1752] or a salt thereof.

[1753] 16. A compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof for use as a medicament.

[1754] 17. A compound according to any one of technical items 1 to 15 or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing diseases and / or disorders in which inhibition of the interaction between MDM2 and p53 has a therapeutic benefit.

[1755] 18. A compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing cancer, infection, inflammation or autoimmune disease.

[1756] 19. A method for treating and / or preventing diseases and / or disorders in which inhibition of the interaction between MDM2 and p53 has therapeutic benefits, comprising administering to a human a therapeutically effective amount of a compound according to any one of technical items 1 to 15 or a pharmaceutically acceptable salt thereof.

[1757] 20. A method for treating and / or preventing cancer, comprising administering to a human a therapeutically effective amount of a compound according to any one of technical items 1 to 15 or a pharmaceutically acceptable salt thereof.

[1758] 21. A pharmaceutical composition comprising at least one compound according to any one of technical items 1 to 15 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[1759] 22. A pharmaceutical preparation comprising a compound according to any one of technical items 1 to 15 or a pharmaceutically acceptable salt thereof and at least one other cell growth inhibitory and / or cytotoxic active substance.

[1760] 23. A compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof for use in treating and / or preventing cancer, infection, inflammation or autoimmune disease, wherein the compound is administered before, after or together with at least one other cytostatic or cytotoxic active substance.

[1761] 24. A cell growth inhibitory and / or cytotoxic active substance for administration before, after or together with a compound according to any one of technical items 1 to 15 or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, infection, inflammation or autoimmune disease.

[1762] 25. A method for treating and / or preventing cancer, infection, inflammation or autoimmune disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of technical items 1 to 15 or a pharmaceutically acceptable salt thereof before, after or together with administration of at least one other cytostatic and / or cytotoxic active substance.

Claims

1. Compound of formula (I) in -- R 1 is optionally substituted by one or more identical or different R b1 and / or R c1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R b1 Independently selected from -OR c1 、-NR c1 R c1 , halogen, -CN, -C(O)R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O)2R c1 、-S(O)2NR c1 R c1 、-NHC(O)R c1 、-N(C 1-4 alkyl)C(O)R c1 and a divalent substituent =O, however, =O can only be a substituent in a non-aromatic ring system; Each R c1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d1 and / or R e1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R d1 Independently selected from -OR e1 、-NR e1 R e1 , halogen, -CN, -C(O)R e1 、-C(O)OR e1 、-C(O)NR e1 R e1 、-S(O)2R e1 、-S(O)2NR e1 R e1 、-NHC(O)R e1 、-N(C 1-4 alkyl)C(O)R e1 and a divalent substituent =0, however, =0 can only be a substituent in a non-aromatic ring system. Each R e1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f1 and / or R g1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R f1 Independently selected from -OR g1 、-NR g1 R g1 , halogen, -CN, -C(O)R g1 、-C(O)OR g1 、-C(O)NR g1 R g1 、-S(O)2R g1 、-S(O)2NR g1 R g1 、-NHC(O)R g1 、-N(C 1-4 alkyl)C(O)R g1 and a divalent substituent =O, however, =O can only be a substituent in a non-aromatic ring system; Each R g1 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group; -- R 2 With R 3 are each independently selected from hydrogen, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, wherein the C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups are optionally substituted with one or more identical or different R b2 and / or R c2 replace; Each R b2 Independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)R c2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-S(O)2R c2 、-S(O)2NR c2 R c2 、-NHC(O)R c2 、-N(C 1-4 alkyl)C(O)R c2 and a divalent substituent =O, however, =O can only be a substituent in a non-aromatic ring system; Each R c2 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d2 and / or R e2 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R d2 Independently selected from -OR e2 、-NR e2 R e2 , halogen, -CN, -C(O)R e2 、-C(O)OR e2 、-C(O)NR e2 R e2 、-S(O)2R e2 、-S(O)2NR e2 R e2 、-NHC(O)R e2 、-N(C 1-4 alkyl)C(O)R e2 and a divalent substituent =O, however, =O can only be a substituent in a non-aromatic ring system; Each R e2 independently represent hydrogen or selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; -- If F is carbon, then A is selected from phenyl and 5- to 6-membered heteroaryl, or If F is nitrogen, then A is a 5- to 6-membered nitrogen-containing heteroaryl group; Each R 4 Independently selected from R a4 and R b4 ; Each R a4 are independently selected from one or more identical or different R b4 and / or R c4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R b4 Independently selected from -OR c4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-C(O)NR g4 OR c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHSO2R c4 、-N(C 1-4 Alkyl)SO2R c4 、-NHC(O)R c4 and-N(C 1-4 alkyl)C(O)R c4 ; Each R c4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d4 and / or R e4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R d4 Independently selected from -OR e4 、-NR e4 R e4 , halogen, -CN, -C(O)R e4 、-C(O)OR e4 、-C(O)NR e4 R e4 、-C(O)NR g4 OR e4 、-S(O)2R e4 、-S(O)2NR e4 R e4 、-NHC(O)R e4 and-N(C 1-4 alkyl)C(O)R e4 ; Each R e4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f4 and / or R g4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R f4 are independently selected from -OR g4 、-NR g4 R g4 , halogen, -CN, -C(O)R g4 、-C(O)OR g4 、-C(O)NR g4 R g4 、-C(O)NR g4 OR g4 、-S(O)2R g4 、-S(O)2NR g4 R g4 、-NHC(O)R g4 and-N(C 1-4 alkyl)C(O)R g4 ; Each R g4 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group; r represents a value of 0, 1, 2, or 3; -- n represents a value of 1, 2, or 3; -- Each R 7 is independently selected from halogen, C 1-4 Alkyl, -CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl and -OC 1-4 Haloalkyl; q represents a value of 0, 1, 2, or 3; -- W, X and Y are each independently selected from -N= and -CH= The restriction is that each hydrogen in -CH= can be replaced by a substituent R 7 (if any) permutation and at most two of W, X and Y may be -N=; -- V is oxygen or sulfur; -- 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.

2. A compound according to claim 1, which is of formula (Ia) or (Ib) or (Ic) or a salt thereof.

3. A compound according to claim 2, which is of formula (Ia*) or (Ib*) or (Ic*) or a salt thereof.

4. A compound according to any one of the preceding claims, wherein R 1 is optionally substituted by one or more identical or different R b1 and / or R c1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R b1 Independently selected from -OR c1 、-NR c1 R c1 , halogen, -CN, -C(O)R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O)2R c1 、-S(O)2NR c1 R c1 、-NHC(O)R c1 and-N(C 1-4 alkyl)C(O)R c1 ; Each R c1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d1 and / or R e1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R d1 Independently selected from -OR e1 、-NR e1 R e1 , halogen, -CN, -C(O)R e1 、-C(O)OR e1 、-C(O)NR e1 R e1 、-S(O)2R e1 、-S(O)2NR e1 R e1 、-NHC(O)R e1 and-N(C 1-4 alkyl)C(O)R e1 ; Each R e1 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f1 and / or R g1 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R f1 Independently selected from -OR g1 、-NR g1 R g1 , halogen, -CN, -C(O)R g1 、-C(O)OR g1 、-C(O)NR g1 R g1 、-S(O)2R g1 、-S(O)2NR g1 R g1 、-NHC(O)R g1 and-N(C 1-4 alkyl)C(O)R g1 ; Each R g1 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group; or a salt thereof.

5. A compound according to any one of the preceding claims, wherein R 2 With R 3 are each independently selected from hydrogen, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, wherein the C 6-10 Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups are optionally substituted with one or more identical or different R b2 and / or R c2 replace; Each R b2 Independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)R c2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-S(O)2R c2 、-S(O)2NR c2 R c2 、-NHC(O)R c2 and-N(C 1-4 alkyl)C(O)R c2 ; Each R c2 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d2 and / or R e2 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R d2 Independently selected from -OR e2 、-NR e2 R e2 , halogen, -CN, -C(O)R e2 、-C(O)OR e2 、-C(O)NR e2 R e2 、-S(O)2R e2 、-S(O)2NR e2 R e2 、-NHC(O)R e2 and-N(C 1-4 alkyl)C(O)R e2 ; Each R e2 independently represent hydrogen or selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; or a salt thereof.

6. A compound according to claim 5, wherein R 2 With R 3 One of them is hydrogen and the other is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are optionally substituted by one or more identical or different R b2 and / or R c2 replace; Each R b2 Independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)R c2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-S(O)2R c2 、-S(O)2NR c2 R c2 、-NHC(O)R c2 and-N(C 1-4 alkyl)C(O)R c2 ; Each R c2 independently represent hydrogen or selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Cycloalkenyl, phenyl, 5- to 6-membered heteroaryl and 3- to 7-membered heterocyclic groups; or a salt thereof.

7. A compound according to claim 6, wherein R 2 With R 3 One of them is hydrogen and the other is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are optionally substituted by one or more identical or different selected from -OC 1-6 Alkyl, halogen, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; or a salt thereof.

8. A compound according to any one of the preceding claims, wherein R 3 is hydrogen; or a salt thereof.

9. A compound according to any one of the preceding claims, wherein A is phenyl and F is carbon; Each R 4 Independently selected from R a4 and R b4 ; Each R a4 are independently of each other and are optionally substituted by one or more identical or different R b4 and / or R c4 The substituted 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3- to 10-membered heterocyclic groups; Each R b4 Independently selected from -OR c4 、-NR c4 R c4 , halogen, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-C(O)NR g4 OR c4 、-S(O)2R c4 and -NHC(O)R c4 ; Each R c4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R d4 and / or R e4 The substituted 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3- to 10-membered heterocyclic groups; Each R d4 Independently selected from -OR e4 、-NR e4 R e4 and -S(O)2R e4 ; Each R e4 independently of one another represent hydrogen or optionally substituted by one or more identical or different R f4 and / or R g4 The substituted 1-6 Alkyl and 3- to 10-membered heterocyclic groups; Each R f4 For-OR g4 ; Each R g4 are independently selected from hydrogen and C 1-6 alkyl; r represents a value of 0, 1, 2, or 3; or a salt thereof.

10. A compound according to any one of the preceding claims, wherein If F is carbon, then A is selected from phenyl and 5- to 6-membered heteroaryl, or If F is nitrogen, then A is a 5- to 6-membered nitrogen-containing heteroaryl group; Each R 4 are independently selected from R a4 and R b4 ; Each R a4 are independently selected from one or more identical or different R b4 and / or R c4 The substituted 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Each R b4 Independently selected from -OR c4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-C(O)NHOR c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHSO2R c4 、-N(C 1-4 Alkyl)SO2R c4 、-NHC(O)R c4 and-N(C 1-4 alkyl)C(O)R c4 ; Each R c4 independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 4-7 Cycloalkenyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group; r represents a value of 0, 1, 2, or 3; or a salt thereof.

Images