BR102016023429A2 - NEW SPIRY [3H-INDOL-3,2? -PYROLIDIN] -2 (1H) -ON COMPOUNDS AND DERIVATIVES AS MDM2-P53 INHIBITORS - Google Patents

Abstract

The present invention encompasses compounds of formula (I) wherein the groups r1 to r4, r7, a, d, e, f, v, w, x, y, n, req are defined in claim 1, their use as inhibitors of mdm2-p53 interaction, pharmaceutical compositions containing such compounds, their use as medicines, especially as agents for the treatment and / or prevention of oncological diseases, and synthetic intermediates.

Description

(54) Title: NEW SPIRAL COMPOUNDS [3H-INDOL-3,2? -PIRROUDIN] -2 (1H) -ONAE DERIVED AS MDM2P53 INHIBITORS (51) Int. Cl .: C07D 487/14; A61K 31/40; A61P 35/00 (73) Holder (s): BOEHRINGER INGELHEIM INTERNATIONAL GMBH (72) Inventor (s): ANDREAS GOLLNER; JOACHIM BROEKER; NINA KERRES; CHRISTIANE KOFINK; JUERGEN RAMHARTER; HARALD WEINSTABL; ANNIKA GILLE; STEFAN GOEPPER; MANUEL HENRY; GÜNTHER HUCHLER (74) Attorney (s): FLÁVIA SALIM LOPES (57) Abstract: The present invention encompasses compounds of formula (I) in which the groups RI to R4, R7, A, D, E, F, V, W, X, Y, n, req are defined in claim 1, their use as inhibitors of the MDM2-p53 interaction, pharmaceutical compositions containing compounds of this type, their use as drugs, especially as agents for the treatment and / or prevention of oncological diseases, and synthetic intermediates.

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NEW SPIRAL COMPOUNDS [3H-INDOL-3,2'-PIRROLIDIN] -2 (1H) ONA AND DERIVATIVES AS MDM2-P53 INHIBITORS [001] The present invention relates to new [3H-indol-3, spiro compounds 2'-pyrrolidin] -2 (1H) -one and derivatives of formula (I)

(D in which the groups R ¹ to R ⁴ , R ⁷ , A, D, E, F, V, W, X, Y, n, req have the meanings presented in the claims and descriptive report, their use as inhibitors of interaction MDM2-p53, pharmaceutical compositions containing compounds of this type, their use as medicines, especially as agents for the treatment and / or prevention of oncological diseases, and synthetic intermediates.

Background to the invention [002] The tumor suppressor protein p53 is a sequence-specific transcription factor and plays a central role in the regulation of several cellular processes, including cell cycle and growth arrest, apoptosis, DNA repair, senescence, angiogenesis and immunity innate. Mouse Double Minute 2 (MDM2) protein (or its human counterpart, also known as HDM2) acts to down-regulate p53 activity in a way

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2/422 self-regulatory, and under normal cellular conditions (absence of stress), the MDM2 protein serves to maintain p53 activity at low levels. MDM2 directly inhibits the p53 transactivation function, exports p53 out of the nucleus and promotes p53 proteasome-mediated degradation through its ubiquitin ligase E3 activity.

[003] The deregulation of the MDM2 / p53 balance by overexpression of MDM2 or by mutation or loss of p53 leads to the malignant transformation of normal cells. Currently p53 is known to play a crucial role in virtually all types of human cancers, and the 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 is amplified by 7% of human cancers and that overexpression of MDM2 by amplification and p53 mutations is largely mutually exclusive (Momand et al., Nucleic Res. (1998) 26: 3,453-3,459).

[004] Because of the powerful tumor suppressor function of p53, reactivation of p53 has long been sought as a potentially unprecedented therapeutic strategy for cancer. In the tumor harboring wild type p53, MDM2 is the primary cell inhibitor of p53 activity, and MDM2 overexpression has been found in many human tumors. To the extent that MDM2 inhibits p53 through a direct protein-protein interaction, blocking this interaction using small molecules has been sought in many academic and industrial pharmaceutical laboratories in the past decade. Several small molecule compounds from

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3/422 drug-like, non-peptide such as imidazole compounds (eg Nutlins or RG7112), benzodiazepinedione compounds, spirooxindol compounds (eg MI-219), substituted piperidines, pyrrolidinone compounds (eg example, PXN820-dl) and modifications thereof were selected and designed to block the MDM2 / p53 interaction as a means to reactivate p53 in cells (Vassilev et al, Science (2004) 303: 844-848;

Grasberger et al, J. Med. Chem. (2005) 48: 909-912; Parks et al, Bioorg. Med. Chem. Lett. (2005) 15: 765; Ding et al., J. Am. Soc. (2005) 127: 10.130-10.131; WO 2010/028862, U.S. Patent 7,884,107, WO 2008/119741). Several potent MDM2 / p53 inhibitors have been evaluated in animal models of human cancer for their antitumor activity (Vassilev et al., Science (2004) 303: 844-848; Tovar et al., Cancer Res. (2013) 73 (8 ): 2,587-2,597; Ding et al, Journal of Medicinal Chemistry (2013) 56 (14):

5,979-5,983; Rew et al , Journal of Medicinal Chemistry (2012) 55: 4,936-4,954; Sun et al, Journal of Medicinal

Chemistry (2014) 57 (4): 1,454-1,472).

[005] In the pediatric pre-clinical testing program (PPTP) of the NCI, initial evidence regarding the high level antiproliferative activity of RG7112, an inhibitor of the MDM2-p53 interaction, could be seen in vitro and in vivo. In particular, RG-7112 showed cytotoxic activity with lower median IC50 values for wild type vs. p53. mutant cell lines for p53 (Carol et al., Pediatric Blood and Cancer (2013) 60 (4): 633641). In addition, RG-7112 induced inhibition of tumor growth in solid tumor xenograft models and was

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4/422 particularly effective in acute lymphoblastic leukemia (ALL) xenograft models with mixed lineage leukemia (MLL) rearrangement, (Carol et al., Pediatric Blood and Cancer (2013) 60 (4): 633-641). Additionally, the antiproliferative and pro-apoptotic activity of RG7112 was observed in models of human acute myeloid leukemia (AML) xenograft and human prostate tumor that harbor wild-type p53 (Tovar et al., Cancer Res. (2013) 73 ( 8): 2,587-2,597).

[006] Consequently, small molecule inhibitors of MDM2 protein interactions offer an important approach towards cancer therapy, either as a single agent or in combination with a wide variety of antitumor therapies, and therefore there is a need for inhibitors additional MDM2 that may be useful in the treatment of cancer.

[007] The following documents of the established technique reveal spiro oxindole compounds as inhibitors of the MDM2-p53 interaction:

WO 2007/104664; WO 2007/104714; WO 2008/141917; WO 2008/141975; WO 2009/077357; WO 2009/080488; WO 2010/084097; WO 2010/121995; WO 2011/067185; WO 2011/101297; WO 2011/134925; WO 2012/038307; WO 2012/022707; WO 2012/116989; WO 2006/091646; WO 2008/036168; WO 2011/060049; WO 2012/065022; WO 2012/155066; WO 2010/028862; WO 2011/153509, WO 2012/121361, WO 2015/155332, WO 2016/001376 and WO 2016/026937.

[008] The purpose of the present invention is to provide new compounds that can be used for the prevention and / or

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5/422 treatment of a disease and / or condition characterized by excessive or abnormal cell proliferation, especially a disease and / or condition in which the inhibition of the interaction between MDM2 and p53 is of therapeutic benefit.

[009] The compounds according to the invention are characterized by a powerful inhibitory effect on the interaction between MDM2 and p53 and, in turn, a high in vitro efficacy against tumor cells, for example, osteosarcoma, ALL etc., which is mediated by inhibiting the interaction between MDM2 and p53 and is the prerequisite for corresponding efficacy in in vivo models and future patients. In addition to the inhibitory effect and cell potency, the compounds exhibit good PK properties and selectivity against p53 mutant cell lines. In addition, they have good metabolic stability, which is a fundamental requirement for an active pharmaceutical ingredient to reach its place of action and allows long-term effectiveness. Finally, and in contrast to many compounds known in the established art, the compounds have good chemical stability, that is, they have, for example, less tendency to epimerization, a problem identified by many known representatives of spiro oxindols in the established technique (see, for example, Zhao et al J. Am. Chem. Soc. 2013, 135, 7.223-7.234; Shu et al Org.

Process Res. Dev. 2013, 17, 247-256; WO 2012/065022).

It is also emphasized that the construction of the composite frameworks (I) itself, that is, the frameworks of each subgroup (Ia), (Ib) and (Ic) is unprecedented and needs highly sophisticated synthetic approaches to obtain these complex compounds high structural.

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Detailed description of the invention [010] It has now surprisingly been found that compounds of formula (I), in which the groups R ¹ to R ⁴ , R ⁷ , A, D, E, F, V, W, X, Y, n, req have the meanings presented later, they act as inhibitors of the interaction of specific proteins that are involved in the control of cell proliferation. Thus, the compounds according to the invention can be used, for example, for the treatment of diseases connected with this protein-protein interaction and characterized by excessive or abnormal cell proliferation.

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

(I) where:

[TO]

R ¹ is a group optionally substituted by one or more R ^bl and / or R ^cl identical or different, selected from Cl - ₆ alkyl, C2 -6 alkenyl, C2 -6 alkynyl, C ₆ haloalkyl, C3-7 cycloalkyl , C4-7 cycloalkenyl, C ₆ -io aryl, 510 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^bl is independently selected from -0R ^cl , 15/452

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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 (Cx-4 alkyl) C (O) R ^c1 and the divalent substituent = O, while = O can only be a substituent in non-aromatic ring systems;

each R ^c1 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^d1 and / or R ^e1 , selected from 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, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^d1 is 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 (Cx-4 alkyl) C (O) R ^e1 and the bivalent substituent = O, while = O can only be one substituent on non-aromatic ring systems;

each R ^e1 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^f1 and / or R ^g1 , selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1- 6 haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^f1 is 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 _X -4 alkyl) C (O) R ^g1 and the divalent substituent = O, while = O can only be a substituent on non-aromatic ring systems;

each R ^g1 is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

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8/422 [B0]

R and R, each independently, are selected from hydrogen, C _6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein said C _6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are optionally substituted by one or more identical or different R ^b2 and / or R ^c2 ;

each R ^b2 is 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 (C1-4 alkyl) C (O) R ^c2 and the divalent substituent = O, while = O can only be one substituent on non-aromatic ring systems;

each R ^c2 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^d2 and / or R ^e2 , selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1- 6 haloalkyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^d2 is 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 (C1- ₄ alkyl) C (O) R ^e2 and the divalent substituent = O, while = O can only be one substituent on non-aromatic ring systems;

each R ^e2 , independently of one another, represents hydrogen or a group selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, C6-10 aryl , 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

[C0]

A is selected from 5-6 membered phenyl and heteroaryl

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9/422 if F is carbon or

A is 5-6 membered heteroaryl containing nitrogen if F

it is nitrogen; each R ⁴ is independently selected from R ^a4 and R ^b4 ; each R ^a4 , independently of each other, is a group optionally replaced by one or more R ^b4 and / or R ^c4

identical or different, selected from 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, heteroaryl 5-10 members and 3-10 members heterocyclyl;

each R ^b4 is 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) ₂ NR ^c4 R ^c4 , -NHSO2R ^c4 , -N (C1-4 alkyl) SO ₂ R ^c4 , -NHC (O) R ^c4 , -N (C1-4 alkyl) C (O) R ^c4 it's the substitute divalent = O, while = O can only be a

substituent on non-aromatic ring systems;

each R ^c4 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^d4 and / or R ^e4 , selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1 -6 haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^d4 is 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 (C1-4 alkyl) C (O) R ^e4 and the bivalent substituent = O, while = O can only be a substituent in non-aromatic ring systems;

each R ^e4 , independently of one another, represents hydrogen or a group optionally substituted by one or

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10/422 plus identical or different R ^f4 and / or R ^g4 , selected from 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, 510 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^f4 is 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 ^g4 and the substituent bivalent = O, while = O can only be a substituent in non-aromatic ring systems;

each R ^g4 is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

r represents the number 0, 1, 2 or 3; [D0] n represents the number 1, 2 or 3; [E0] ₇ each R ⁷ is selected independently between halogen, C _1-4 alkyl, -CN, C ₁ . -4 haloalkyl, -OC _1-4 alkyl and -OC1-4 haloalkyl; q represents the number 0, 1, 2 or 3; [F0] W, X and Y are selected, each independently, in -N = and -CH = since the hydrogen in each -CH = can be

. . 7 replaced by a substituent R, if present, and that a maximum of two of W, X and Y can be -N =;

[G0]

V is oxygen or sulfur;

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11/422 [HO]

D is nitrogen, E is carbon and F is carbon; or D is carbon, E is nitrogen and F is carbon; or D is carbon, E is carbon and F is nitrogen;

or a salt like this.

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

(fa) or a salt like this.

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

or a salt like this.

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12/422 [014] In one aspect, composed of formula (Ic) the invention is related to a

or a salt like this.

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

or a salt like this.

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

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or a salt like this.

[017] In one aspect, the invention is related to a compound of formula (Ic *)

[018] It should be understood that compounds (Ia), (Ib) and (Ic) are each a subset of compounds (I) and that whenever the term compound (s) (1) is used, this too includes compound (s) (Ia), (Ib) and (Ic), unless otherwise stated.

[019] It should be understood that the compounds (Ia *), (Ib *) and (Ic *) are each a subset of compounds

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14/422 (la), (Ib) and (Ic), respectively, and that whenever (Ia), (lb) or (Ic) is used, this also includes the compound (s) (Ia *) , (Ib *) and (Ic *), respectively, unless otherwise stated.

[020] In another aspect [A1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

R ¹ is a group optionally substituted by one or more identical or different R ^b1 and / or R ^c1 , selected from 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, 510-membered heteroaryl and 3-10-membered heterocyclyl;

each R ^b1 is 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 (C1-4 alkyl) C (O) R ^c1 ;

each R ^c1 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^d1 and / or R ^e1 , selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1- 6 haloalkyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^d1 is 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 ) 2Re1, -S (O) 2NR ^e1 R ^e1 , -NHC (O) R ^e1 and -N (C1-4 alkyl) C (O) R ^e1 ;

each R ^e1 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^f1 and / or R ^g1 , selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1- 6 haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

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15/422 each R ^f1 is 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 _X -4 alkyl) C (O) R ^g1 ;

each R ^g1 is 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 , 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

or a salt like this.

[021] In another aspect [A2], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

R ¹ is a group optionally substituted by one or more identical or different R ^b1 and / or R ^c1 , selected from C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl and C3-7 cycloalkyl;

each R ^b1 is 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 (Cx-4 alkyl) C (O) R ^c1 ;

each R ^c1 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^d1 and / or R ^e1 , selected from C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, heteroaryl of 5-10 members and 3-10 members heterocyclyl;

each R ^d1 is 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 (Cx-4 alkyl) C (O) R ^e1 ;

each R ^e1 , independently of each other, is selected from hydrogen, C1-6 alkyl, C1-6 alkyl-O-C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and heterocyclyl 3-10 members;

or a salt like this.

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16/422 [022] In another aspect [A3], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

R ¹ is a group optionally substituted by one or more identical or different R ^b1 and / or R ^c1 , selected from C _1-6 alkyl, C _2-6 alkenyl, C _1-6 haloalkyl and C _3-7 cycloalkyl;

each R ^b1 is independently selected from -OR ^c1 , halogen and -S (O) ₂ R ^c1 ;

each R ^c1 , independently of one another, is a group optionally substituted by one or more identical or different R ^d1 and / or R ^e1 , selected from C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl and 3- 10 members;

each R ^d1 is independently selected from -OR ^e1 , CN and halogen;

each R ^e1 , independently of one another, is C1-6 alkyl or C1-6 alkyl-O-C1-6 alkyl;

or a salt like this.

[023] In another aspect [A4], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

R ¹ is a group optionally substituted by one or more identical or different R ^b1 and / or R ^c1 , selected from C1-6 alkyl, C2-6 alkenyl and C1-6 haloalkyl;

each R ^b1 is independently selected from -OR ^c1 and -S (O) 2R ^c1 ;

each R ^c1 , independently of one another, is a group optionally substituted by one or more identical or different R ^d1 and / or R ^e1 , selected from C1-6 alkyl, C3-7 cycloalkyl and C6-10 aryl;

each R ^d1 is independently selected from -OR ^e1, 25/452

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CN and halogen;

each R ^e1 , independently of one another, is C _1-6 alkyl or C _1-6 alkyl-OC _1-6 alkyl;

or a salt like this.

[024] In another aspect [A5], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

R ¹ is a group optionally substituted by one or more identical or different R ^b1 and / or R ^c1 , selected from C1-6 alkyl, C2-6 alkenyl and C1-6 haloalkyl;

each R ^b1 is independently selected from -OR ^c1 and -S (O) 2R ^c1 ;

each R ^c1 , independently of one another, is a group optionally substituted by one or more identical or different R ^d1 and / or R ^e1 , selected from C _1-6 alkyl, C _3-7 cycloalkyl and phenyl;

each R ^d1 is independently selected from -OR ^e1 , CN and halogen;

each R ^e1 , independently of one another, is C1-6 alkyl or C1-6 alkyl-O-C1-6 alkyl;

or a salt like this.

[025] In another aspect [A6], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

R ¹ is selected from C1-6 alkyl, C3-7 cycloalkyl-C1-6 alkyl and C2-6 alkenyl;

or a salt like this.

[026] In another aspect [A7], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

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R ¹ is C3-7 cycloalkyl-C _1-6 alkyl; or a salt like this.

[027] In another aspect [A8], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

R ¹ is cyclopropylmethyl; or a salt like this.

[028] In another aspect [B1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

R and R, each independently, are selected from hydrogen, C _6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein said C6-10 aryl, 5-10 membered heteroaryl and heterocyclyl 3-10 members are optionally replaced by one or more identical or different R ^b2 and / or R ^c2 ;

each R ^b2 is 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 _X -4 alkyl) C (O) R ^c2 ;

each R ^c2 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^d2 and / or R ^e2 , selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1- 6 haloalkyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^d2 is 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 (Cx-4 alkyl) C (O) R ^e2 ;

each R ^e2 , independently of one another, represents hydrogen or a group selected from C1-6 alkyl, C2-6

27/452

19/422 alkenyl, C ₂ - ₆ alkynyl, C ₁ - ₆ haloalkyl, C ₃ -6 cycloalkyl, C ₄ -6 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

or a salt like this.

[029] In another aspect [B2], the invention is related to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), where: one of R ² and R ³ is hydrogen and the other is selected between phenyl and heteroaryl of 5-6 members, where referred and 5-6 heteroaryl members are optionally replaced by one or more R ^b2 and / or R ^c2 identical or

many different;

each R ^b2 is 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 (C1-4 alkyl) C (O) R ^c2 ;

each R ^c2 , independently of one another, represents hydrogen or a group selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, phenyl, heteroaryl 5-6 members and 3-7 members heterocyclyl;

or a salt like this.

[030] In another aspect [B3], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

one of R ² and R ³ is hydrogen and the other is selected from phenyl and 5-6 membered heteroaryl, wherein said and 5-6 membered heteroaryl are optionally substituted by one or more identical or different substituents selected from -OC1 -6 alkyl, halogen, C1-6 alkyl and C1-6 haloalkyl;

28/452

20/422 or a salt thereof.

[031] In another aspect [B4], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

one of R ² and R ³ is hydrogen and the other is selected from phenyl, thienyl and pyridyl, wherein said phenyl, thienyl and pyridyl are optionally substituted by one or more identical or different substituents selected from -OC _1-6 alkyl, halogen, C _1-6 alkyl and C _1-6 haloalkyl;

or a salt like this.

[032] In another aspect [B5], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

one of R ² and R ³ is hydrogen and the other is selected from 3-chlorophenyl, 3-chloro-2-fluorophenyl and 3-bromo-2fluorphenyl;

or a salt like this.

[033] In additional aspects [B6], [B7], [B8], [B9], [B10] and [B11], the invention relates to a compound of formula (I), (Ia), (Ib) , (Ic), (Ia *), (Ib *) or (Ic *) with structural aspects [B0], [B1], [B2], [B3], [B4] and [B5], where:

R ³ is hydrogen; or a salt like this.

[034] In additional aspects [B12], [B13], [B14], [B15], [B16] and [B17], the invention relates to a compound of formula (I), (Ia), (Ib) , (Ic), (Ia *), (Ib *) or (Ic *) with structural aspects [B0], [B1], [B2], [B3], [B4] and [B5], where:

R ² is hydrogen;

29/452

21/422 or a salt thereof.

[035] In another aspect [C1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

A is selected from phenyl and 5-6 membered heteroaryl if F is carbon or

A is 5-6 membered heteroaryl containing nitrogen if F is nitrogen;

each R ⁴ is independently selected from R ^a4 and R ^b4 ; each R ^a4 , independently of one another, is a group optionally substituted by one or more identical or different R ^b4 and / or R ^c4 , selected from C1-6 alkyl, C2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} haloalkyl, C _3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^b4 is 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 (C1-4 alkyl) SO2R ^c4 , NHC (O) R ^c4 and N (C1- 4 alkyl) C (O) R ^c4 ;

each R ^c4 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^d4 and / or R ^e4 , selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1 -6 haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^d4 is 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 ) OR ^{e4 g4} NR, -S (O) 2 R ^e4, -S (O) 2NR R ^{e4 e4,} -NHC (O) R ^e4 and -N (C 1 -C ₄ alkyl) C (O) R ^e4;

each R ^e4 , independently of each other, represents

30/452

22/422 hydrogen or a group optionally substituted by one or more identical or different R ^f4 and / or R ^g4 , selected from 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, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^f4 is 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 (C1-4 alkyl) C (O) R ^g4 ;

each R ^g4 is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

r represents the number 0, 1, 2 or 3; or a salt like this.

[036] In another aspect [C2], the invention it is related to a compound of formula (I) , (Ia), (Ib), (Ia *) or (Ib *), in < what: A is phenyl and F is carbon; each R ⁴ is independently selected from R ^a4 and R ^b4 ; each R ^a4 , independently one of another, is one group optionally replaced for one or plus R ^b4 and / or R ^c4

identical or different, selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl and 3-10 membered heterocyclyl; each R ^b4 is 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 each other, represents hydrogen or a group optionally substituted by one or more identical or different R ^d4 and / or R ^e4 , selected

31/452

23/422 between C _1-6 alkyl, C- ₆ haloalkyl, C _3-7 cycloalkyl and 3-10 membered heterocyclyl;

each R ^d4 is independently selected from -OR ^e4 , NR ^e4 R ^e4 and -S (O) 2R ^e4 ;

each R ^e4 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^f4 and / or R ^g4 , selected from C _1-6 alkyl and 3-10 membered heterocyclyl;

each R ^f4 is -OR ^g4 ;

each R ^g4 is independently selected from hydrogen and C1-6 alkyl;

r represents the number 0, 1, 2 or 3; or a salt like this.

[037] In another aspect [C3], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

A is selected from phenyl and 5-6 membered heteroaryl if F is carbon or

A is 5-6 membered heteroaryl containing nitrogen if F is nitrogen;

each R ⁴ is independently selected from R ^a4 and R ^b4 ; each R ^a4 , independently of one another, is a group optionally substituted by one or more identical or different R ^b4 and / or R ^c4 , selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl , C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R ^b4 is 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 (C1-4

32/452

24/422 alkyl) SO2R ^c4 , -NHC (O) R ^c4 and -N (C1-4 alkyl) C (O) R ^c4 ;

each R ^c4 , independently of one another, is 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, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

r represents the number 0, 1, 2 or 3; or a salt like this.

[038] In another aspect [C4], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

A is selected from phenyl and pyridyl if F is carbon or

A is pyridyl if F is nitrogen;

each R ⁴ is independently selected from R ^a4 and R ^b4 ; each R ^a4 , independently of one another, is C _1-6 alkyl optionally substituted by one or more identical or different R ^b4 ;

each R ^b4 is 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 alkyl) SO2R ^c4 , NHC (O) R ^c4 and N (Cx-4 alkyl ) C (O) R ^c4 ;

each R ^c4 , independently of one another, is selected from hydrogen and C _1-6 alkyl;

r represents the number 0, 1, 2 or 3; or a salt like this.

[039] In another aspect [C5], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

A is selected from phenyl and pyridyl if F is carbon or

A is pyridyl if F is nitrogen;

33/452

25/422 each R ⁴ is independently selected from R ^a4 and R ^b4 ; each R ^a4, independently of one another, are Cl - ₆ alkyl optionally substituted by one or more identical or different R ^b4;

each R ^b4 is independently selected from -OR ^c4 , halogen, -CN, -C (O) OR ^c4 , -C (O) NR ^c4 R ^c4 and -S (O) 2R ^c4 ;

each R ^c4 , independently of one another, is selected from hydrogen and C _1-6 alkyl;

r represents the number 0, 1, 2 or 3; or a salt this. [040] In another aspect [C6] , a invention it is related to a compound of formula (I), (Ia), (Ib), (Ia *)

or (Ib *), where:

A is phenyl and F is carbon;

each R ⁴ is independently selected from R ^a4 and R ^b4 ; each R ^a4 , independently of one another, is C _1-6 alkyl optionally substituted by one or more identical or different R ^b4 ;

each R ^b4 is independently selected from -OR ^c4 , halogen, -CN, -C (O) OR ^c4 , -C (O) NR ^c4 R ^c4 and -S (O) 2R ^c4 ;

each R ^c4 , independently of one another, is selected from hydrogen and C1-6 alkyl;

r represents the number 0, 1, 2 or 3; or a salt like this.

[041] In additional aspects [C7], [C8], [C9], [C10], [C11], [C12] and [C13], the invention relates to a compound of formula (I), (Ia) , (Ib), (Ic), (Ia *), (Ib *) or (Ic *) with structural aspects [C0], [C1], [C2], [C3], [C4], [C5] and [C6], where:

r represents the number 1 or 2;

34/452

26/422 or a salt thereof.

[042] In another aspect [C14], the invention relates to a compound of formula (I), (Ia), (Ib), (Ia *) or (Ib *), in which:

A, together with the R ⁴ substituents, is

R ⁸ is selected from hydrogen, C ₆ alkyl, -0Ci- ₆ alkyl, halogen, -CN, -C (O) OH, -C (O) OCi_ ₆ alkyl, -C (O) NH _2, -C ( O) NHC- ₆ alkyl, -C (O) N (C- ₆ alkyl) ₂ and -S (O) ₂ C- ₆ alkyl;

R ⁹ is selected from hydrogen, C ₆ alkyl, -0Ci- ₆ alkyl, halogen, -CN, -C (O) OH, -C (O) OCi- ₆ alkyl, -C (O) NH _2, -C (O) NHC- ₆ alkyl, -C (O) N (C- ₆ alkyl) ₂ and -S (O) ₂ C- ₆ alkyl;

R ¹⁰ is selected from hydrogen, C ₆ alkyl, -0Ci- ₆ alkyl, halogen, -CN, -C (O) OH, -C (O) OCi- ₆ alkyl, -C (O) NH _2, -C (O) NHC- ₆ alkyl, -C (O) N (C- ₆ alkyl) ₂ and -S (O) ₂ C- ₆ alkyl;

provided that at least one of R to R, but not all of R to R ¹⁰ , is hydrogen;

or a salt like this.

[043] In another aspect [C15], the invention relates to a compound of formula (I), (Ia), (Ib), (Ia *) or (Ib *), in which:

A, together with the substituting R ⁴ , is

35/452

27/422

R ⁸ is -C (O) OH;

one of R ⁹ and R ¹⁰ is Cl - ₄ alkyl and the other is hydrogen; or a salt like this.

[044] In another aspect [Dl], the invention related to a compound of formula (I), (Ia), (Ib), (Ia *), (Ib *) or (Ic *), in which:

n represents the number 1 or 2; or a salt like this.

[045] In another aspect [D2], the invention related to a compound of formula (I), (Ia), (Ib), (Ia *), (Ib *) or (Ic *), where:

n is 1;

or a salt like this.

[046] In another aspect [D3], the invention related to a compound of formula (I), (Ia), (Ib), (Ia *), (Ib *) or (Ic *), in which:

n is 2;

or a salt like this.

[047] In another aspect [El], the invention related to a compound of formula (I), (Ia), (Ib), (Ia *), (Ib *) or (Ic *), in which:

each R ⁷ is independently halogen or -CN eq is or a salt thereof.

[048] In another aspect [E2], the invention is (Ic), is (Ic), is (Ic), is (Ic), or is

2;

36/452

28/422 related to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), where:

each R ⁷ is independently chlorine or fluorine and q is 1 or

2;

or a salt like this.

[049] In another aspect [Fl], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

W, X and Y are -CH =, provided that the hydrogen in each -CH = can be replaced by a substituent R ⁷ , if present;

or a salt like this.

[050] In another aspect [EF1], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

the 6-membered ring comprising W, X and Y, together with the Q ⁷ substituents R, has a substructure selected from (i) and (ii):

(Ii) or a salt thereof.

[051] In another aspect [Gl], the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *), on what:

V is oxygen;

or a salt like this.

[052] All structural aspects A1 to A8, BI to B17, Cl to C15, D1 to D3, El and E2, Fl, Gl and EF1 mentioned above are preferred modalities of aspects A0, B0, C0, D0, E0, F0 , EF0 and G0 corresponding, respectively, where EF0

37/452

29/422 (EF) represents the combination of EO (E) and FO (F). The structural aspects AO to A8, BO to B17, CO to C15, DO to D3, EO to E2, FO and Fl, EFO and EF1 and GO and G1 in relation to different molecular parts of compounds (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) and (Ic *) according to the invention, can be exchanged between them as desired in ABCDEFG combinations, in order to obtain preferred compounds (I), ( Ia), (Ib), (Ic), (Ia *), (Ib *) and (Ic *) (aspects E and F can be replaced by the combined aspect EF). Each ABCDEFG combination represents and defines individual modalities or generic subsets of compounds according to the invention.

[053] Modalities favorite invention with structure (Ia) are composed of example Ia-1 to Ia-57. [054] Modalities favorite invention with structure (Ib) are composed of example Ib-1 a Ib-254. [055] Modalities favorite invention with structure (Ic) are composed of example Ic-1 a Ic-38. [056] All synthetic intermediates generally

defined as well as specifically disclosed herein and their salts are also part of the invention.

[057] In a further aspect, the invention is also related to the synthetic intermediates of formula B-3 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ia) and (Ia *):

38/452

30/422 [058] The definitions of groups R ² , R ³ , R ⁷ , V, W, X, Y, qen in B-3 correspond to those given for compound (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, that is, [B0] for R ² / R ³ , [D0] for n, [E0] for R ⁷ / q, [F0 ] for W / X / Y and [G0] for V. R is a carboxyl protecting group, for example, C _1-6 alkyl or t-Bu.

[059] Preferred intermediates B-3 are those which lead to the preferred compounds (Ia) and (Ia *) according to the invention, that is, preferred modalities of B-3 have structural aspects selected from [B0] to [B17] for R ² / R ³ , [D0] to [D3] for n, [E0] to [E2] for R ⁷ / q, [F0] and [F1] for W / X / Y, [G0] and [G1 ] for V and [EF0] and [EF1] for

R ⁷ / q / W / X / Y together. These structural aspects (including definitions of R) can be exchanged with each other as desired in BDEFGR combinations, in order to obtain preferred intermediates B-3 (aspects E and F can be replaced by the combined aspect EF). Each BDEFGR combination represents and defines individual modalities or generic subsets of B-3 intermediates.

[060] In a further aspect, the invention is also related to the use of synthetic intermediates of formula B-3 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ia) and ( Ia *).

[061] In a further aspect, the invention is also related to the synthetic intermediates of formula B-4 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ia) and (Ia *):

39/452

31/422

[062] The Definitions of groups R ¹ , R ² , R ³ , R ⁷ , v, W, X, Y, q and n in B-4 correspond to those given for the compound (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, or that is, [AO] to R ¹ , [B0] for R ² / R ³ , [DO] for N, [E0] for R ⁷ / q, [F0] for W / X / Y and [GO] for V. R is a group of

carboxyl protection, for example, CI_ ₆ alkyl or t-Bu.

[063] Preferred intermediates B-4 are those that lead to the preferred compounds (Ia) and (Ia *) according to the invention, that is, preferred modalities of B-4 have structural aspects selected from [AO] to [A8] for R ¹ , [B0] to [B17] for R ² / R ³ , [DO] to [D3] for η, [E0] to [E2] for R ⁷ / q, [F0] and [Fl] for W / X / Y, [GO] and [Gl] for V and [EFO] and [EF1] for R ⁷ / q / W / X / Y together. These structural aspects (including definitions of R) can be exchanged with each other as desired in ABDEFGR combinations, in order to obtain preferred intermediates B-4 (aspects E and F can be replaced by the combined aspect EF). Each ABDEFGR combination represents and defines individual modalities or generic subsets of B-4 intermediates.

[064] In a further aspect, the invention is also related to the use of synthetic intermediates of formula B-4 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ia)

40/452

32/422 and (1a *).

[065] In a further aspect, the invention is also related to the synthetic intermediates of formula B-7 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ia) and (Ia *):

[066] The definitions of groups R ¹ , R ² , R ³ , R ⁷ , V, W, X, Y, qen in B-7 correspond to those given for compound (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, that is, [AO] for R ¹ , [B0] for R ² / R ³ , [DO] for η, [E0] for

R ⁷ / q, [F0] for W / X / Y and [GO] for V.

[067] Preferred intermediates B-7 are those which lead to the preferred compounds (Ia) and (Ia *) according to the invention, that is, preferred embodiments of B-7 have structural aspects selected from [AO] to [A8] for R ¹ , [B0] to [B17] for R ² / R ³ , [DO] to [D3] for η, [E0] to [E2] for R ⁷ / q, [F0] and [Fl] for W / X / Y, [GO] and [Gl] for V and [EFO] and [EF1] for R ⁷ / q / W / X / Y together. These structural aspects can be exchanged with each other as desired in ABDEFG combinations, in order to obtain preferred intermediates B-7 (aspects E and F can be replaced by the combined aspect EF). Each ABDEFG combination represents and defines individual modalities or generic subsets of B-7 intermediates.

41/452

33/422 [068] In a further aspect, the invention is also related to the use of synthetic intermediates of formula B-7 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ia ) and (Ia *).

[069] In a further aspect, the invention is also related to the synthetic intermediates of formula B-6 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ia) and (Ia *):

[070] The definitions of groups R ² , R ³ , R ⁷ , V, W, X, Y, qen in B-6 correspond to those given for compound (I), (Ia), (Ib), (Ic) , (Ia *), (Ib *) or (Ic *) above, that is, [B0] for R ² / R ³ , [DO] for η, [E0] for R ⁷ / q, [F0] for W / X / Y and [GO] for V.

[071] Preferred intermediates B-6 are those which lead to the preferred compounds (Ia) and (Ia *) according to the invention, that is, preferred embodiments of B-6 have structural aspects selected from [B0] to [B17] for R ² / R ³ , [D0] to [D3] for η, [E0] to [E2] for R ⁷ / q, [F0] and [Fl] for W / X / Y, [G0] and [Gl ] for V and [EF0] and [EF1] for R ⁷ / q / W / X / Y together. These structural aspects can be exchanged with each other as desired in BDEFG combinations, in order to obtain preferred intermediates B-6 (aspects E and F can be replaced by the aspect

42/452

34/422 combined EF). Each BDEFG combination represents and defines individual modalities or generic subsets of B-6 intermediates.

[072] In a further aspect, the invention is also related to the use of synthetic intermediates of formula B-6 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ia) and ( Ia *).

[073] In a further aspect, the invention is also related to the synthetic intermediates of formula B-8 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ia) and (Ia *):

[074] The definitions of groups R ¹ , R ² , R ³ , R ⁷ , V, W, X,

Y, qen in B-8 correspond to those given for compound (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, that is, [AO ] for R ¹ , [B0] for R ² / R ³ , [DO] for η, [E0] for

R ⁷ / q, [F0] for W / X / Y and [GO] for V.

[075] Preferred intermediates B-8 are those which lead to the preferred compounds (Ia) and (Ia *) according to the invention, that is, preferred embodiments of B-8 have structural aspects selected from [AO] to [A8] for R ¹ , [B0] to [B17] for R ² / R ³ , [DO] to [D3] for η, [E0] to [E2] for R ⁷ / q, [F0] and [Fl] for W / X / Y, [GO] and [Gl] for V and

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35/422 [EFO] and [EF1] for R ⁷ / q / W / X / Y together. These structural aspects can be exchanged with each other as desired in ABDEFG combinations, in order to obtain preferred intermediates B-8 (aspects E and F can be replaced by the combined aspect EF). Each ABDEFG combination represents and defines individual modalities or generic subsets of B-8 intermediates.

[076] In a further aspect, the invention is also related to the use of synthetic intermediates of formula B-8 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ia) and ( Ia *).

[077] In a further aspect, the invention is also related to the synthetic intermediates of formula B-10 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ia) and (Ia *):

[078] The definitions of groups R ¹ , R ² , R ³ , R ⁴ , R ⁷ , A, V, W, X, Y, r, qen in B-10 correspond to those given for compound (I), ( Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, that is, [AO] for R ¹ , [B0] for R ² / R ³ , [CO] for A / R ⁴ / r, [DO] for η, [E0] for R ⁷ / q, [F0] for W / X / Y and [GO] for V.

[079] Preferred B-10 intermediaries are those that

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36/422 lead to the preferred compounds (Ia) and (Ia *) according to the invention, that is, preferred modalities of B-10 have structural aspects selected from [AO] to [A8] for R ¹ ,

[B0] a [B17] for R ² / R ³ , [CO] a [C15] for A / R ⁴ / r, [DO] a [D3] for N, [E0] to [E2] for R ⁷ / q, [F0] and [Fl] for W / X / Y, [GO] and [Gl] for V and [AND FO] and [EF1] for R ⁷ / q / W / X / Y in

set. These structural aspects can be exchanged with each other as desired in ABCDEFG combinations, in order to obtain preferred intermediates B-10 (aspects E and F can be replaced by the combined aspect EF). Each ABCDEFG combination represents and defines individual modalities or generic subsets of intermediates ΒΙΟ.

[080] In a further aspect, the invention is also related to the use of synthetic intermediates of formula B-10 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ia) and ( Ia *).

[081] In a further aspect, the invention is also related to the synthetic intermediates of formula B-ll and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ia) and (Ia *):

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37/422 [082] The definitions of groups R ¹ , R ² , R ³ , R ⁴ , R ⁷ , A, V, W, X, Y, r, qen in B-11 correspond to those given for the compound (I ), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, that is, [A0] for R ¹ , [B0] for R ² / R ³ , [C0] for A / R ⁴ / r, [D0] for n, [E0] for R ⁷ / q, [F0] for W / X / Y and [G0] for V.

[083] Preferred intermediates B-11 are those which lead to the preferred compounds (Ia) and (Ia *) according to the invention, that is, preferred embodiments of B-11 have structural aspects selected from [A0] to [A8] for R ¹ , [B0] to [B17] for R ² / R ³ , [C0] to [C15] for A / R ⁴ / r, [D0] to [D3] for n, [E0] to [E2] for R ⁷ / q, [F0] and [F1] for W / X / Y, [G0] and [G1] for V and [EF0] and [EF1] for R ⁷ / q / W / X / Y together . These structural aspects can be exchanged with each other as desired in ABCDEFG combinations, in order to obtain preferred intermediates B-11 (aspects E and F can be replaced by the combined aspect EF). Each ABCDEFG combination represents and defines individual modalities or generic subsets of B11 intermediates.

[084] In a further aspect, the invention is also related to the use of synthetic intermediates of formula B-11 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia *).

[085] In a further aspect, the invention is also related to the synthetic intermediates of formula B-12 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ia) and (Ia *):

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[086] The definitions of groups R ¹ , R ² , R ³ , R ⁴ , R ⁷ , A, V, W, X, Y, r, qen in B-12 correspond to those given for compound (I), ( Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, that is, [AO] for R ¹ , [B0] for R ² / R ³ , [CO] for A / R ⁴ / r, [DO] for η, [E0] for R ⁷ / q, [F0] for W / X / Y and [GO] for V.

[087] Preferred intermediates B-12 are those which lead to the preferred compounds (Ia) and (Ia *) according to the invention, that is, preferred modalities of B-12 have structural aspects selected from [AO] to [A8] for R ¹ , [B0] to [B17] for R ² / R ³ , [CO] to [C15] for A / R ⁴ / r, [DO] to [D3] for η, [E0] to [E2] for R ⁷ / q, [F0] and [Fl] for W / X / Y, [GO] and [Gl] for V and [EFO] and [EF1] for R ⁷ / q / W / X / Y together . These structural aspects can be exchanged with each other as desired in ABCDEFG combinations, in order to obtain preferred intermediates B-12 (aspects E and F can be replaced by the combined aspect EF). Each ABCDEFG combination represents and defines individual modalities or generic subsets of B12 intermediates.

[088] In an additional aspect, the invention is also

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39/422 related to the use of synthetic intermediates of formula B-12 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ia) and (Ia *).

[089] In a further aspect, the invention is also related to the synthetic intermediates of formula B-19 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ia) and (Ia *):

B-19 [090] The definitions of groups R ⁴ , R ⁷ , A, V, W, X, Y, req in B-19 correspond to those given for compound (I), (Ia), (Ib), ( Ic), (Ia *), (Ib *) or (Ic *) above, that is, [CO] for A / R ⁴ / r, [E0] for R ⁷ / q, [F0] for W / X / Y and [GO] for V.

[091] Preferred intermediates B-19 are those which lead to the preferred compounds (Ia) and (Ia *) according to the invention, that is, preferred embodiments of B-19 have structural aspects selected from [CO] to [C15] for A / R ⁴ / r, [E0] to [E2] for R ⁷ / q, [F0] and [Fl] for W / X / Y, [GO] and [Gl] for V and [EFO] and [ EF1] for R ⁷ / q / W / X / Y together. These structural aspects can be exchanged with each other as desired in CEFG combinations, in order to obtain

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40/422 preferred intermediates B-19 (aspects E and F can be replaced by the combined aspect EF). Each CEFG combination represents and defines individual modalities or generic subsets of B-19 intermediates.

[092] In a further aspect, the invention is also related to the use of synthetic intermediates of formula B-19 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ia) and ( Ia *).

[093] In a further aspect, the invention is also related to the synthetic intermediates of formula B-20 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ia) and (Ia *):

(R ^? L _q (R ⁴ l

[094] The definitions of groups R ² , R ³ , R ⁴ , R ⁷ , A, V, W, X, Y, req in B-20 correspond to those given for compound (I), (Ia), (Ib ), (Ic), (Ia *), (Ib *) or (Ic *) above, that is, [B0] for R ² / R ³ , [CO] for A / R ⁴ / r, [E0] for R ⁷ / q, [F0] for W / X / Y and [GO] for V.

[095] Preferred intermediates B-20 are those which lead to the preferred compounds (Ia) and (Ia *) according to

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41/422 invention, that is, preferred modalities of B-20 have structural aspects selected from [BO] to [B17] for R ² / R ³ , [CO] to [C15] for A / R ⁴ / r, [EO ] to [E2] for R ⁷ / q, [FO] and [Fl] for W / X / Y, [GO] and [Gl] for V and [EFO] and [EF1] for R ⁷ / q / W / X / Y together. These structural aspects can be exchanged with each other as desired in BCEFG combinations, in order to obtain preferred intermediates B-20 (aspects E and F can be replaced by the combined aspect EF). Each BCEFG combination represents and defines individual modalities or generic subsets of B-20 intermediates.

[096] In a further aspect, the invention is also related to the use of synthetic intermediates of formula B-20 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ia) and ( Ia *).

[097] In a further aspect, the invention is also related to a method for the synthesis of an intermediate of formula B-20 (R ⁴ ír

( ^R7 ) q B-20 which comprises the reaction of a compound B-2

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R ³ in ₂

B-2 with a B-19 imine

on what:

R ² , R ³ , R ⁴ , R ⁷ , A, V,

W, X, Y, r and q are as defined hereinbefore.

[098] In a further aspect, the invention is also related to the synthetic intermediates of formula B-21, B-22 and B-23 and their salts, which can also be used as key intermediates in the synthesis of compounds of formula (Ia ) and (Ia *). The definitions of the groups / substituents in B21, B-22 and B-23 correspond to those given for the compound (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above.

[099] Preferred intermediates B-21, B-22 and B-23 are those which lead to the preferred compounds (Ia) and (Ia *) according to the invention.

[100] In an additional aspect, the invention is also related to the use of synthetic intermediates of formula

B-21 and / or B-22 and / or B-23 or their salts (and the various modalities and subgroups as described and / or defined herein)

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43/422 in the synthesis of compounds (Ia) and (Ia *).

[101] In a further aspect, the invention is also related to the synthetic intermediates of formula A-12 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ib) and (Ib *):

[102] The definitions of groups R ² , R ³ , R ⁷ , V, W, X, Y, neq in A-12 correspond to those given for compound (I), (Ia), (Ib), (Ic) , (Ia *), (Ib *) or (Ic *) above, that is, [B0] for R ² / R ³ , [DO] for η, [E0] for R ⁷ / q, [F0] for W / X / Y and [GO] for V.

[103] Preferred intermediates A-12 are those which lead to the preferred compounds (Ib) and (Ib *) according to the invention, that is, preferred modalities of A-12 have structural aspects selected from [B0] to [B17] for R ² / R ³ , [DO] to [D3] for η, [E0] to [E2] for R ⁷ / q, [F0] and [Fl] for W / X / Y, [GO] and [Gl ] for V and [EFO] and [EF1] for R ⁷ / q / W / X / Y together. These structural aspects can be exchanged with each other as desired in BDEFG combinations, in order to obtain preferred intermediates A-12 (aspects E and F can be replaced by the combined aspect EF). Each BDEFG combination represents and defines individual modalities or generic subsets of A-12 intermediates.

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44/422 [104] In a further aspect, the invention is also related to the use of synthetic intermediates of formula A-12 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ib ) and (Ib *).

[105] In a further aspect, the invention is also related to the synthetic intermediates of formula A-13 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ib) and (Ib *):

[106] The definitions of groups R ² , R ³ , R ⁴ , R ⁷ , A, V, W,

X, Y, n, q and r in A-13 correspond to those given for compound (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, or that is, [B0] for R ² / R ³ , [CO] for A / R ⁴ / r, [DO] for η, [E0] for R ⁷ / q, [F0] for W / X / Y and [GO ] to V.

[107] Preferred intermediates A-13 are those which lead to the preferred compounds (Ib) and (Ib *) according to the invention, that is, preferred modalities of A-13 have structural aspects selected from [B0] to [B17] for R ² / R ³ , [CO] to [C15] for A / R ⁴ / r, [DO] to [D3] for η, [E0] to [E2] for R ⁷ / q, [F0] and [ Fl] for W / X / Y, [GO] and [Gl] for V

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45/422 and [EFO] and [EF1] for R ⁷ / q / W / X / Y together. These structural aspects can be exchanged with each other as desired in BCDEFG combinations, in order to obtain preferred intermediates A-13 (aspects E and F can be replaced by the combined aspect EF). Each BCDEFG combination represents and defines individual modalities or generic subsets of A-13 intermediates.

[108] In a further aspect, the invention is also related to the use of synthetic intermediates of formula A-13 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ib) and ( Ib *).

[109] In a further aspect, the invention is also related to the synthetic intermediates of formula A-14 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ib) and (Ib *):

A-14 [110] The definitions of groups R ² , R ³ , R ⁴ , R ⁷ , A, V, W, X, Y, n, q and r in A-15 correspond to those given for compound (I), ( Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, that is, [B0] for R ² / R ³ , [CO] for A / R ⁴ / r , [DO] for η, [E0] for R ⁷ / q, [F0] for W / X / Y and [GO] for V.

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46/422 [111] Preferred intermediates A-14 are those which lead to the preferred compounds (Ib) and (Ib *) according to the invention, that is, preferred modalities of A-14 have structural aspects selected from [BO] to [B17] for R ² / R ³ , [CO] to [C15] for A / R ⁴ / r, [DO] to [D3] for η, [EO] to [E2] for R ⁷ / q, [FO ] and [Fl] for W / X / Y, [GO] and [Gl] for V and [EFO] and [EF1] for R ⁷ / q / W / X / Y together. These structural aspects can be exchanged with each other as desired in BCDEFG combinations, in order to obtain preferred intermediates A-14 (aspects E and F can be replaced by the combined aspect EF). Each BCDEFG combination represents and defines individual modalities or generic subsets of A-14 intermediates.

[112] In a further aspect, the invention is also related to the use of synthetic intermediates of formula A-14 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ib) and ( Ib *).

[113] In a further aspect, the invention is also related to the synthetic intermediates of formula A-15 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ib) and (Ib *):

A-15

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47/422 [114] The definitions of groups R ² , R ³ , R ⁴ , R ⁷ , A, V, W,

X, Y, n, q and r in A-15 correspond to those given for compound (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, or that is, [B0] for R ² / R ³ , [C0] for A / R ⁴ / r, [D0] for n, [E0] for R ⁷ / q, [F0] for W / X / Y and [G0 ] to V.

[115] Preferred intermediates A-15 are those that lead to the preferred compounds (Ib) and (Ib *) according to the invention, that is, preferred modalities of A-15 have structural aspects selected from [B0] to [B17] for R ² / R ³ , [C0] to [C15] for A / R ⁴ / r, [D0] to [D3] for n, [E0] to [E2] for R ⁷ / q, [F0] and [ F1] for W / X / Y, [G0] and [G1] for V and [EF0] and [EF1] for R ⁷ / q / W / X / Y together. These structural aspects can be exchanged with each other as desired in BCDEFG combinations, in order to obtain preferred intermediates A-15 (aspects E and F can be replaced by the combined aspect EF). Each BCDEFG combination represents and defines individual modalities or generic subsets of A-15 intermediates.

[116] In a further aspect, the invention is also related to the use of synthetic intermediates of formula A-15 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ib) and ( Ib *).

[117] In a further aspect, the invention is also related to the synthetic intermediates of formula A-17 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ib) and (Ib *):

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[118] The definitions of groups R ² , R ³ , R ⁴ , A er in A-17 correspond to those given for compound (I), (Ia), (Ib), (Ic), (Ia *), ( Ib *) or (Ic *) above, that is, [BO] for R ² / R ³ and [CO] for A / R ⁴ / r.

[119] Preferred intermediates A-17 are those that lead to the preferred compounds (Ib) and (Ib *) according to the invention, that is, preferred modalities of A-17 have structural aspects selected from [BO] to [B17] for R ² / R ³ and [CO] to [C15] for A / R ⁴ / r. These structural aspects can be exchanged with one another as desired in BC combinations, in order to obtain preferred intermediates A-17. Each BC combination represents and defines individual modalities or generic subsets of A17 intermediates.

[120] In a further aspect, the invention is also related to the use of synthetic intermediates of formula A-17 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ib) and ( Ib *).

[121] In a further aspect, the invention is also related to the synthetic intermediates of formula A-18 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ib) and (Ib *):

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[122] The definitions of groups R ² , R ³ , R ⁴ , A er in A-18 correspond to those given for compound (I), (Ia), (Ib), (Ic), (Ia *), ( Ib *) or (Ic *) above, that is, [BO] for R ² / R ³ and [CO] for A / R ⁴ / r.

[123] Preferred intermediates A-18 are those that lead to the preferred compounds (Ib) and (Ib *) according to the invention, that is, preferred modalities of A-18 have structural aspects selected from [BO] to [B17] for R ² / R ³ and [CO] to [C15] for A / R ⁴ / r. These structural aspects can be exchanged with each other as desired in combinations BC, in order to obtain preferred intermediates A-18. Each BC combination represents and defines individual modalities or generic subsets of intermediates A18.

[124] In a further aspect, the invention is also related to the use of synthetic intermediates of formula A-18 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ib) and ( Ib *).

[125] In an additional aspect, the invention is also related to the synthetic intermediates of formula A-20 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ib) and (Ib *):

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[126] The definitions of groups R ² , R ³ , R ⁴ , A, ner in A20 correspond to those given for compound (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, that is, [B0] for

R ² / R ³ , [CO] for A / R ⁴ / re [DO] for n.

[127] Preferred intermediates A-20 are those that lead to the preferred compounds (Ib) and (Ib *) according to the invention, that is, preferred modalities of A-20 have structural aspects selected from [B0] to [B17] for R ² / R ³ , [CO] to [C15] for A / R ⁴ / re [DO] to [D3] for n. These structural aspects can be exchanged with each other as desired in BCD combinations, in order to obtain preferred intermediates A-20. Each BCD combination represents and defines individual modalities or generic subsets of A-20 intermediates.

[128] In a further aspect, the invention is also related to the use of synthetic intermediates of formula A-20 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ib) and ( Ib *).

[129] In a further aspect, the invention is also related to the synthetic intermediates of formula A-21 and their salts, which can be used as key intermediates in the synthesis of compounds of formula (Ib) and (Ib *):

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[130] The definitions of groups R ² , R ³ , R ⁴ , A, ner in A21 correspond to those given for compound (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) above, that is, [B0] for

R ² / R ³ , [CO] for A / R ⁴ / re [DO] for n.

[131] Preferred intermediates A-21 are those that lead to the preferred compounds (Ib) and (Ib *) according to the invention, that is, preferred modalities of A-21 have structural aspects selected from [B0] to [B17] for R ² / R ³ , [CO] to [C15] for A / R ⁴ / re [DO] to [D3] for n. These structural aspects can be exchanged with each other as desired in BCD combinations, in order to obtain preferred intermediates A-21. Each BCD combination represents and defines individual modalities or generic subsets of A-21 intermediates.

[132] In a further aspect, the invention is also related to the use of synthetic intermediates of formula A-21 or their salts (and to the various modalities and subgroups as described and / or defined herein) in the synthesis of compounds (Ib) and ( Ib *).

[133] The present invention is also related to hydrates, solvates, polymorphs, metabolites, derivatives, isomers and prodrugs of a compound of formula (I), (Ia), (Ib), (Ic), (Ia *) , (Ib *) or (Ic *).

[134] Compounds of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) which, for example, harbor groups

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52/422 ester, are potential prodrugs of the ester being cleaved under physiological conditions.

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

[136] The present invention further relates to a cocrystal, preferably a pharmaceutically acceptable cocrystal, of a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *).

[137] In one aspect compounds (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) according to the invention are in amorphous form.

[138] The present invention also relates to a pharmaceutically acceptable salt of a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) with inorganic or organic acids or bases.

[139] The present invention is directed to compounds of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) which are useful in preventing and / or treatment of a disease and / or condition in which inhibiting the interaction between MDM2 and p53 is of therapeutic benefit, including, without limitation, cancer treatment and / or prevention.

[140] In another aspect, the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) - or a salt pharmaceutically acceptable product for use as a medicine.

[141] In another aspect, the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) - or a salt pharmaceutically acceptable product for use in a method for treating the human body or

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53/422 animal.

[142] In another aspect, the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) - or a salt pharmaceutically acceptable product for use in the treatment and / or prevention of a disease and / or condition in which the inhibition of the interaction between MDM2 and p53 is of therapeutic benefit.

[143] In another aspect, the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) - or a salt pharmaceutically acceptable product for use in the treatment and / or prevention of cancer, infections, inflammation or autoimmune diseases.

[144] In another aspect, the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) - or a salt pharmaceutically acceptable form thereof for use in a method for treating and / or preventing cancer, infections, inflammation or autoimmune diseases in the human and animal body.

[145] In another aspect, the 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, infections, inflammations or autoimmune diseases.

[146] In another aspect, the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) - or a salt pharmaceutically acceptable product for use in the treatment and / or prevention of cancer.

[147] In another aspect, the invention relates to the use of a compound of formula (I), (Ia), (Ib), (Ic), (Ia *),

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54/422 (Ib *) or (Ic *) - or a pharmaceutically acceptable salt thereof - for the preparation of a pharmaceutical composition for the treatment and / or prevention of cancer.

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

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

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

[151] In another aspect, the 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 acute myeloid leukemia (AML), prostate cancer or lung cancer, where

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55/422 cancer cells have functional p53, preferably wherein the cancer cells are wild type p53.

[152] In another aspect, the 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 acute myeloid leukemia (AML), prostate cancer or lung cancer, wherein the cancer cells preferably have functional p53, more preferably in which cancer cells are wild type p53.

[153] In another aspect, the invention relates to a method for the treatment and / or prevention of a disease and / or condition in which the inhibition of the interaction between MDM2 and p53 is of therapeutic benefit, which comprises the administration of a quantity therapeutically effective use of a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) - or a pharmaceutically acceptable salt thereof - to a human.

[154] In another aspect, the invention relates to a method for the treatment and / or prevention of cancer, which comprises administering a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) - or a pharmaceutically acceptable salt thereof - to a human.

[155] In another aspect, the 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.

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56/422 [156] In another aspect, the invention relates to a pharmaceutical preparation 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.

[157] In another aspect, the invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) - or a salt pharmaceutically acceptable thereto for use in the treatment and / or prevention of cancer, infections, inflammations or autoimmune diseases, wherein said compound is administered before, after or together with at least one other cytostatic or cytotoxic active substance.

[158] In another aspect, the 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, infections, inflammations or autoimmune diseases, wherein said compound is administered before, after or together with at least one other cytostatic active substance or cytotoxic.

[159] In another aspect, the invention relates to a cytostatic or cytotoxic active substance prepared to be administered before, after or together with 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 cancer, infections, inflammations or autoimmune diseases.

[160] In another aspect, the invention relates to a method for the treatment and / or prevention of cancer, infections, inflammations or autoimmune diseases, which

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57/422 comprises administering to a patient in need of 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.

Definitions [161] Terms not specifically defined herein should be given the meanings that would be given to them by those skilled in the art in the light of revelation and context. As used in the specification, however, unless otherwise specified, the following terms have the indicated meaning and the following conventions adhered to:

[162] The use of the prefix C _x - _y , where each x and y represents a natural number (x <y), indicates that the chain or ring structure or combination of chain and ring structure as a whole, specified and mentioned in direct association, can consist of a maximum of y and a minimum of x carbon atoms.

[163] Indication of the number of members in groups containing one or more heteroatoms (for example, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl) is related to the total number of atoms of all ring members or members of the chain or the total of all members of the ring and chain.

[164] Indication of the number of carbon atoms in groups consisting of a combination of carbon chain and carbon ring structure (eg, cycloalkylalkyl, arylalkyl) is related to the number

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58/422 total carbon atoms of all members of the carbon ring and carbon chain. Obviously, a ring structure has at least three members.

[165] In general, for groups comprising two or more subgroups (for example, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, arylalkyl) the last subgroup mentioned is the point of adhesion of the radical, for example, the substituent of a r1 -C1- 6 alkyl means an aryl group that is attached to a C 1-6 alkyl group, the latter of which is attached to the nucleus or group to which the substituent is attached.

[166] Alkyl represents saturated, monovalent hydrocarbon chains, which can be present in both linear (unbranched) and branched form. If an alkyl is substituted, the substitution can occur independently of the other, by mono- or polysubstitution in each case, in all carbon atoms that carry hydrogen.

[167] The term "C _1-5 alkyl includes, for example, H ₃ C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH (CH3) -, H3C-CH2-CH2-CH2-, H3C-CH2CH (CH3) -, H3C-CH (CH3) -CH2-, H3C-C (CH3) 2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH (CH3) -, H3C-CH2-CH (CH3) -CH2-, H3C-CH (CH3) -CH2CH2-, H3C-CH2-C (CH3) 2-, H3C-C (CH3) 2-CH2-, H3C-CH (CH3) -CH (CH3) - and H3C-CH2-CH (CH2CH3) -.

[168] Additional examples of alkyl are methyl (Me; CH ₃ ), ethyl (Et; -CH ₂ CH ₃ ), 1-propyl (n-propyl; nPr; -CH ₂ CH ₂ CH ₃ ), 2-propyl ( i-Pr; iso-propyl; -CH (CH ₃ ) ₂ ), 1butyl (n-butyl; n-Bu; -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (isobutyl; i- Bu; -CH ₂ CH (CH ₃ ) ₂ ), 2-butyl (sec-butyl; sec-Bu; CH (CH ₃ ) CH ₂ CH ₃ ), 2-methyl-2-propyl (tert-butyl; t- Bu; 67/452

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C (CH ₃ ) ₃ ), 1-pentyl (n-pentyl; -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH2CH ₃ ) 2), 3-methyl-1-butyl (iso-pentyl; -CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-2-butyl (-C (CH3) 2CH2CH3), dimethyl-1- propyl (-CH2CH (CH3) CH2CH3)

3-methyl-2-butyl (-CH (CH3) CH (CH3) 2), 2,2 (neo-pentyl; -CH ₂ C (CH ₃ ) ₃ ), 2-methyl-1-butyl, 1-hexyl (n-hexyl; -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ),

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 (CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH (CH ₃ ) C (CH ₃ ) 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 ( CH ₃ ) ₃ ), 2-methyl-1-pentyl (-CH ₂ CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3-methyl-1-pentyl (-CH ₂ CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ), 1-heptyl (n-heptyl), 2-methyl-1hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl,

2.3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl ( n-octyl), 1-nonyl (n-nonyl); 1-decile (n-decile) etc.

[169] By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further definition they mean saturated hydrocarbon groups with the corresponding number of carbon atoms, in which all isomeric forms are included.

[170] The above definition for alkyl also applies if alkyl is a part of another (combined) group such as, for example, Cx-y alkylamino or Cx-y alkyloxy.

[171] The term alkylene can also be derived from

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60/422 alkyl. Alkylene is divalent, unlike alkyl, and requires two bonding partners. Formally, the second valence is produced by removing a hydrogen atom in an alkyl. Corresponding groups are, for example, -CH3 and -CH2-, -CH2CH3 and -CH2CH2- or> CHCH etc.

[172] The term C _1-4 alkylene "includes for example, (CH2) -, - (CH2-CH2) -, - (CH (CHs)) -, - (CH2-CH2-CH2) -, - (C (CHs) 2), - (CH (CH2CH3)) -, - (CH (CH3) -CH2) -, - (CH2-CH (CH3)), - (CH2-CH2-CH2-CH2) -, - ( CH2-CH2-CH (CH3)) -, - (CH (CH3) -CH2CH2) -, - (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) -.

[173] Other examples of alkylene are methylene, ethylene, propylene, 1-methylethylene, butylene,

1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene etc.

[174] By the generic terms propylene, butylene, pentylene, hexylene, etc. without any further definition mean all conceivable isomeric forms with the corresponding number of carbon atoms, that is, propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

[175] The above definition for alkylene also applies if alkylene is part of another (combined) group such as, for example, in HO-C _xy amino alkylene or H ₂ NC _xy alkyleneoxy.

[176] Unlike alkyl, alkenyl consists of at least two carbon atoms, where at least two

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61/422 adjacent carbon atoms are joined together by a C-C double bond and a carbon atom can only be part of a C-C double bond. If in an alkyl, as defined above, which has at least two carbon atoms, two hydrogen atoms in adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding alkenyl is formed.

[177] Examples of alkenyl are vinyl (ethylene), prop-1-enyl, ally (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2 -enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl, pent -3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, hex-1-enyl, hex-2 -enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylidene-3-methylbutyl , 2,3-dimethylbut-1-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, penta-1,4dienyl, penta-1,3-dienyl, buta-1,3-dienyl, 2 , 3-dimethylbut1,3-diene, etc.

[178] By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, etc. without any further definition mean all conceivable isomeric forms with the corresponding number of carbon atoms, ie propenyl includes prop-1-enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl etc.

[179] Alkenyl can optionally be present in cis or trans or E or Z orientation with respect to the bond (or

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62/422 connections) double.

[180] The above definition for alkenyl also applies when alkenyl is part of another (combined) group, for example, in Cx-y alkenylamino or Cx-y alkenyloxy.

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

[182] Examples of alkenylene are ethylene, propenylene, 1-methylethylene, butenylene, 1methylpropenylene, 1,1-dimethylethylene, 1,2dimethylethylene, pentenylene, 1,1-dimethylpropenylene, 2,2dimethylpropenylene, 1,2-dimethylpropenylene,

1,3-dimethylpropenylene, hexenylene etc.

[183] By the generic terms propenylene, butenylene, pentenylene, hexenylene etc. without any further definition mean all conceivable isomeric forms with the corresponding number of carbon atoms, that is, propenylene includes 1-methylethylene and butenylene includes 1methylpropenylene, 2-methylpropenylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

[184] Alkenylene can optionally be present in cis or trans or E or Z orientation with respect to the double bond (or bonds).

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63/422 [185] The above definition for alkenylene also applies when alkenylene is a part of another (combined) group such as, for example, in HO-C _xy alkenyleneamino or H2N-Cx-y alkenyleneoxy.

[186] Unlike alkyl, alkynyl consists of at least two carbon atoms, where at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkyl, as defined above, which has at least two carbon atoms, two hydrogen atoms in each case in adjacent carbon atoms are formally removed and the free valences are saturated to form two additional bonds, the corresponding alkynyl is formed.

[187] Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methylprop-2-ynyl, pent-1 -inyl, pent-2-inyl, pent-3-inyl, pent-4inyl, 3-methyl-but-1-inyl, hex-1-inyl, hex-2-inyl, hex-3inyl, hex-4-inyl , hex-5-inyl, etc.

[188] By the generic terms propynyl, butynyl, pentinyl, hexynyl, heptinyl, octinyl, noninyl, decinyl, etc. without any further definition mean all conceivable isomeric forms with the corresponding number of carbon atoms, that is, propynyl includes prop-1-inyl and prop-2-inyl, butinyl includes but-1-inyl, but-2-inyl, but-3inyl, 1-methyl-prop-1-inyl, 1-methyl-prop-2-inyl etc.

[189] If a hydrocarbon chain carries at least one double bond and also at least one triple bond, by definition it belongs to the alkynyl subgroup.

[190] The above definition for alkynyl also applies if alkynyl is part of another (combined) group such as,

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64/422 for example, in C _x - _y alkynylamino or C _x - _y alkynyloxy.

[191] Unlike alkylene, alkynylene consists of at least two carbon atoms, where at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkylene, as defined above, which has at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valences are saturated to form two additional bonds, the corresponding alkylene is formed.

[192] Examples of alkynylene are ethynylene, propynylene, 1-methylethylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2dimethylpropynylene, 1,2-dimethylpropynylene,

1,3-dimethylpropynylene, hexynylene etc.

[193] By the generic terms propynylene, butynylene, pentynylene, hexynylene etc. without any further definition mean all conceivable isomeric forms with the corresponding number of carbon atoms, that is, propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1dimethylethynylene and 1,2-dimethylethylene.

[194] The above definition for alkynylene also applies if alkynylene is part of another (combined) group such as, for example, in HO-Cx-y alkynyleneamino or H2N-Cx-y alkynyleneoxy.

[195] By heteroatoms means oxygen, nitrogen and sulfur atoms.

[196] Haloalkyl (haloalkenyl, haloalkynyl) is

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65/422 alkyl derivative (alkenyl, alkynyl) previously defined by exchanging one or more hydrogen atoms in the hydrocarbon chain independently of the other for halogen atoms, which can be identical or different. If a haloalkyl (haloalkenyl, haloalkynyl) has to be additionally substituted, substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all carbon atoms that carry hydrogen.

[197] Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH2, -CF = -CBr = CH2, -C C-CF- _{: J} -CHFCH2CH3, -CHFCH2CF3 etc.

[198] From haloalkyl (haloalkenyl, haloalkynyl) previously withered, the terms haloalkylene (haloalkenylene,

Haloalkylene (haloalkenylene, unlike haloalkyl (haloalkenyl, haloalkynyl), is bivalent and requires two bonding partners Formally, the second valence is formed by removing a hydrogen atom from a haloalkyl (haloalkenyl, haloalkynyl).

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

[200] The above definitions also apply if the corresponding halogen-containing groups are part of another (combined) group.

[201] Halogen is related to fluorine, chlorine, bromine and / or iodine atoms.

[202] Cycloalkyl consists of the haloalkynylene ring subgroups).

haloalkynylene),

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66/422 monocyclic hydrocarbons, bicyclic hydrocarbon rings and spirohydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings two rings are joined together, in such a way that they have at least two carbon atoms together. In spiro-hydrocarbon rings, a carbon atom (spiroatom) belongs to two rings together.

[203] If a cycloalkyl has to be replaced, substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all carbon atoms that carry hydrogen. Cycloalkyl itself can be attached as a substituent to the molecule through each suitable position of the ring system.

[204] Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycles [2.2.0] hexyl, bicycles [3.2.0] heptyl, bicycles [3.2.1] octyl, bicycles [2.2.2] octyl, bicycles [4.3.0] nonil (octahidroindenil), bicyclo [4.4.0] decil (decahidronaftil), bicyclo [2.2.1] heptil (norbornil), bicyclo [4.1.0] hepty (norcaranil), bicyclo [3.1.1] heptil (pinanil), spiro [2.5] octyl, spiro [3.3] heptyl etc.

[205] The above definition for cycloalkyl also applies if cycloalkyl is part of another (combined) group such as, for example, Cx-y cycloalkylamino, Cx-y cycloalkyloxy or Cx-y cycloalkylalkyl.

[206] If the free valence of a cycloalkyl is saturated, then an alicyclic group is obtained.

[207] The term cycloalkylene can therefore be derived from the previously defined cycloalkyl.

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Cycloalkylene, unlike cycloalkyl, is bivalent and requires two bonding partners. Formally, the second valence is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are, for example:

cyclohexyl and

or

(cycloliexilene).

[208] The above definition for cycloalkylene also applies if cycloalkylene is part of another (combined) group such as, for example, in HO-C _x _ _y cycloalkyleneamino or H ₂ NC _x - _y alkyl enooxy cycle.

[209] Cycloalkenyl also consists of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spirohydrocarbon rings. However, the systems are unsaturated, that is, there is at least one C-C double bond, but no aromatic system. If in a cycloalkyl, as defined above, two hydrogen atoms in adjacent cyclic carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding cycloalkenyl is obtained.

[210] If a cycloalkenyl is to be replaced, substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all carbon atoms that carry hydrogen. The cycloalkenyl itself can be attached as a substituent to the molecule through each suitable position of the ring system.

[211] Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl,

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68/422 cyclopent-l-enyl, cyclohex-1-enyl, cyclohept-1-enyl, cyclohept-4-enyl, cyclopent-3-enyl, c ic1ohex-3-eni1, cyclohept-3-enyl, cyclopenta-1, 4ciclopent-2-enyl, cyclohex-2-enyl, cyclohept-2-enyl, cyclobut-1,3-dienyl, dienyl, cyclopenta-1,3-dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3- dienyl, cyclohexa-1,5-dienyl, cyclohexa-2,4dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl, bicycle [2.2.1] hepta-2,5-dienyl (norborna-2, 5-dienyl), bicycles [2.2.1] hept-2-enyl (norbornenyl), spiro [4,5] dec-2enyl etc.

[212] The above definition for cycloalkenyl also applies when cycloalkenyl is part of another (combined) group such as, for example, in C _x _ _y cycloalkenylamino, C _x - _y cycloalkenyloxy or C _x _ _y cycloalkenylalkyl.

[213] If the free valence of a cycloalkenyl is saturated, then an unsaturated alicyclic group is obtained.

[214] The term cycloalkenylene can therefore be derived from the cycloalkenyl previously defined. Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires two bonding partners. Formally, the second valence is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are, for example:

cyclopentenyl and

[215] The above definition for cycloalkenylene also applies if cycloalkenylene is part of another (combined) group, for example, in HO-C _x _ _y

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69/422 cycloalkenyleneamino or H ₂ NC _xy cycloalkenyleneoxy.

[216] Aryl represents mono-, bi- or tricyclic carbocycles with at least one aromatic carbocycle. Preferably, it represents a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or a six-membered ring with a five-membered ring), where the second ring can also be aromatic or, however, it can also be partially saturated.

[217] If an aryl must be replaced, substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all carbon atoms that carry hydrogen. The aryl itself can be attached as a substituent to the molecule through each suitable position of the ring system.

[218] Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphyl (1,2-dihydronaphyl), fluorenyl, etc. .

[219] The above definition of aryl also applies if aryl is part of another (combined) group, for example, in arylamino, aryloxy or arylalkyl.

[220] If the free valence of an aryl is saturated, then an aromatic group is obtained.

[221] The term arylene can also be derived from the previously defined aryl. Arylene, unlike aryl, is divalent and needs two bonding partners. Formally, the second valence is formed by removing a hydrogen atom from an aryl. Corresponding groups are,

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70/422 for example:

phenyl and

[222] The above definition for arylene also applies if arylene is part of another (combined) group, for example, in HO-aryleneamino or H ₂ N-aryleneoxy.

[223] Heterocyclyl represents ring systems, which are derived from cycloalkyl, cycloalkenyl and aryl previously defined by exchanging one or more of the -CH ₂ groups independently of the other in the hydrocarbon rings for the -0-, -S- or -NH- groups or by exchanging one or more of the = CH- groups for the = N- group, where a total of a maximum of five hetero atoms can be present, at least one carbon atom must be present between two oxygen atoms and between two atoms sulfur or between an oxygen atom and a sulfur atom and the ring as a whole must have chemical stability. Hetero atoms can optionally be present in all possible oxidation stages (sulfur -> sulfoxide -S0-, sulfone -S0 ₂ ; nitrogen -> N-oxide). In a heterocyclyl there is no heteroaromatic ring, that is, no heteroatom is part of an aromatic system.

[224] A direct result of the derivation of cycloalkyl, cycloalkenyl and aryl is that heterocyclyl consists of

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71/422 monocyclic hetero-rings, bicyclic hetero-rings, tricyclic hetero-rings and spiro-hetero-rings, which can be present in saturated or unsaturated form.

[225] By unsaturated means that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In bicyclic hetero rings, two rings are linked together so that they have at least two (hetero) atoms in common. In spirohetero-rings, a carbon atom (spiroatom) belongs to two rings together.

[226] If a heterocyclyl is substitution, it can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all carbon and / or nitrogen atoms that carry hydrogen. The heterocyclyl itself can be attached as a substituent to the molecule through each suitable position of the ring system.

[227] Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, oxiranyl, aziridinyl, azetidinyl, 1,4dioxanil, azepanil, diazepanyl, morpholinyl, thiomorpholinyl, homomorfolinil, homopiperidinil, homopiperazinyl, homotiomorfolinil, thiomorpholinyl -S-oxide, thiomorpholinylS, S-dioxide, 1,3-dioxolanil, tetrahydropyranyl, tetrahydrothiopyranil, [1,4] -oxazepanil, tetrahydrothienyl, homothiomorpholinyl-S, S-dioxide, dihydropyrazolyl, dihydropyridyl, substituted dihydropyridyl, pyridine , imidazolinyl, piperazinyl, oxazolidinonyl, dihydropyrazinyl, dihydrofuril, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl80 / 452

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S, S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazet, 2Hpyrrolyl, 4H-pyranyl, 1,4-dihydropyridinyl, 8-azabicyclo [3.2.1] octyl, 8-aza-bicyclo [5.1.0] octyl, 2-oxa-5azabicyclo [2.2.1] heptyl, 8-oxa-3-aza-bicyclo [3.2.1] octyl,

3,8-diaza-bicycles [3.2.1] octy, 2,5-diaza1-aza-bicycles [2.2.2] octy, bicycles [2.2.1] hepty,

3,8-diaza-bicycles [3.2.1] octy,

3, 9-diazabiciclo [4.2.1] nonil, 2,6-diaza-bicyclo [3.2.2] nonil, 1,4dioxa-spiro [4.5] decile, 1-oxa-3,8-diaza-espiro [4.5] decile,

2.6- diaza-spiro [3.3] hepty, 2,7-diaza-spiro [4.4] nonil,

2.6- diaza-espiro [3.4] octy, 3,9-diaza-espiro [5.5] undecil, 2.8-diaza-espiro [4,5] decil etc.

[228] Additional examples are the structures illustrated below, which can be attached via each atom that carries hydrogen (exchanged for hydrogen):

D ° D ^s

D

O

II

H õ

O

II s = o

0.

o, .o 2nd

Hô

^ s = the u

O o

° <

G ^NH s = ol {

O

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Η

Η

0 ο fl ο 0 —Ν Η 0 II Ο Ν Η δ —Ν Η ο ο 0 ^s - 0 0 θ, -0 0 O ό O V Η Η Η Μ , Ν, IT Η Q ^ι ο ϋ. '0

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[229] Preferably, heterocyclics are 4-8 membered, monocyclic, and have one or two heteroatoms selected independently of oxygen, nitrogen and sulfur.

[230] Preferred heterocyclics are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl.

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

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76/422 [232] If the free valence of a heterocyclyl is saturated, then a heterocyclic group is obtained.

[233] The term heterocyclyl is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups are, for example:

piperidinyl and

HO-

OR

QU

2,3-dihydro-pyrrolyl and

ΙΨ

OR QTJ.

or

H

efc [234] The above definition of heterocyclylene also applies if heterocyclylene is part of another (combined) group such as, for example, in HO-heterocyclyl amine or H ₂ N-heterocyclyloxy.

[235] Heteroaryl represents monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring that, compared to the corresponding aryl or cycloalkyl (cycloalkenyl), contain, instead of one or more carbon atoms, one or more identical or different heteroatoms, selected , one independently of the other, between nitrogen, sulfur and oxygen, in which the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic system. If the heteroaryl has to be replaced,

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77/422 substitutions can occur independently of each other, in the form of mono- or polysubstitutions in each case, in all carbon and / or nitrogen atoms that carry hydrogen. The heteroaryl itself can be attached as a substituent to the molecule through each appropriate position of the ring system, both carbon and nitrogen.

[236] Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridinyl, pyridazinyl, pyridinyl, pyridazinyl, pyridinyl, pyridazinyl, pyridinyl, pyridazinyl, pyridinyl, pyridinyl, pyridazinyl. -N-oxide, pyrimidinylN-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N-oxide , thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzyl, benzyl, benzyl, benzyl, benzyl , benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazol-o-quinolinyl-oxy-quinolinyl-quinolinyl -N-oxide, phthalazinyl-Node oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide etc.

[237] Additional examples are the structures illustrated below, which can be attached via each atom that carries hydrogen (exchanged for hydrogen):

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79/422 [238] Preferably, heteroaris are 56-membered monocyclic or 9-10-membered bicyclics, each with 1 to 4 heteroatoms selected independently of oxygen, nitrogen and sulfur.

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

[240] If the free valence of a heteroaryl is saturated, a heteroaromatic group is obtained.

[241] The term heteroarylene is also derived from the heteroaryl defined previously. Heteroarylene, unlike heteroaryl, is bivalent and needs two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are, for example:

pyrrolyl and

N .1.

or '—efc.

[242] The above definition of heteroarylene also applies if heteroarylene is part of another (combined) group, for example, in HO-heteroaryleneamino or H ₂ N-heteroaryleneoxy.

[243] By substituted means that a hydrogen atom that is directly attached to the atom under consideration, is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms), mono- or polysubstitution can occur in an atom. The replacement

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80/422 with a particular substituent is only possible if the permissible valences of the substituent and the atom that has to be replaced correspond to each other and the substitution leads to a stable compound (ie, a compound that is not spontaneously converted, for example , by rearrangement, cycling or elimination).

[244] Bivalent substituents, such as = S, = NR, = NOR, = NNRR, = NN (R) C (O) NRR, = N ₂ or similar, can only be substituents on carbon atoms, where the bivalent substituent = O can also be a sulfur substituent. Generally, the substitution can be performed by a bivalent substituent only in ring systems and requires the replacement of two twin hydrogen atoms, that is, hydrogen atoms that are bonded to the same carbon atom that is saturated before the substitution. Substitution with a bivalent substituent is therefore only possible in the -CH2- or sulfur atoms (only = O) group of a ring system.

[245] Stereochemistry / solvates / hydrates: Unless specifically indicated, throughout the specification and attached claims, a certain formula or chemical name must encompass tautomers and all stereo, optical and geometric isomers (eg enantiomers, diastereomers, E / Z isomers etc.) and racemates thereof, in addition to mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the forms mentioned above in which these isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts of these and solvates of these, for example, hydrates that include

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81/422 solvates of the free compounds or solvates of a salt of the compound.

[246] Salts: The phrase pharmaceutically acceptable ”is used here to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of a solid medical evaluation, suitable for use in contact with the tissues of human beings. humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and compatible with a reasonable risk / benefit ratio.

[247] As used herein, the term pharmaceutically acceptable salts ”refers to derivatives of the disclosed compounds in which the parent compound is modified by producing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, without limitation, mineral or organic acid salts of basic residues such as, for example, amines; alkaline or organic salts of acid residues such as, for example, carboxylic acids; and the like.

[248] For example, these salts include ammonia salts,

L-arginine, betaine, benetamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2'iminobis (ethanol)), diethylamine, 2- (diethylamino) -ethanol, 2 (dimethylamino) -ethanol, 2-aminoethanol , ethylenediamine, Netyl-glucamine, hydrabamine, 1H-imidazole, lysine (Llisin), proline (L-proline), magnesium hydroxide, 4- (2hydroxyethyl) -morpholine, morpholine, piperazine, potassium hydroxide, 1- (2- hydroxyethyl) -pyrrolidine, 1- (2-hydroxyethyl) pyrrolidone, sodium hydroxide, triethanolamine (2,2 ', 2' nitrilotris (ethanol), tromethamine, zinc hydroxide, acetic acid, 2,2-dichloroacetic acid, adipic acid, acid

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82/422 alginic, ascorbic acid (L), L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-hydroxybenzoic acid, 4-acetamidobenzoic acid, (+) camphoric acid, (+) - camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid (capric acid), dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactic acid, gentisic acid, D-glycoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2oxoglutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid (capric acid), hypuric acid, hydrobromic acid, hydrochloric acid , isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-) - L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene- 2-sulfonic, acid 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid (caprylic acid), oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (- ) -L-pyroglutamic acid, salicylic acid, 4 aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.

[249] Salts include acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides / hydrobromides, Ca-edetates / edetates,

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83/422 fumarates, glutamates, sulfamides, tartrates, sulphates, theoclates, cansilates, carbonates, camphorsulfonate, chlorides / hydrochlorides, chloroteophyllinate, citrates, edisylates, ethanedisulfonates, stylates, gluceptates, gluconates, glucuronates, glycates, glycates, glycates, glycolates, glycolates, glycolates, glycolates hydrabamines, hydroximaleates, hydroxinaftoates, iodides, isethionates, isothionates, lactates, lactobionates, lauryl sulfates, malates, maleates, mandelates, methanesulfonates, mesylates, methylbromides, methylnitrates, methylsulfates, mucates, naphthates, oxates, nitrates, oxides, nacts pantothenates, phenylacetates, phosphates / diphosphates, polygalacturonates, propionates, salicylates, stearates subacetates, succinates, sulfosalicylates, tannins, toluenesulfonates, trietiodides, trifluoracetates, ammonium, benzathines, chloroprocaines, choline, diethanolamines, choline, diethanol.

[250] Additional pharmaceutically acceptable salts can be formed with cations of metals 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).

[251] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic portion by conventional chemical methods. Generally, these salts can be prepared by reacting the acid or free base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as,

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84/422 for example, ether, ethyl acetate, ethanol, isopropanol or acetonitrile, or a mixture thereof.

[252] Salts of acids other than those mentioned above which, for example, are useful for purification or isolation of the compounds of the present invention (for example, trifluoro acetate salts), also comprise a part of the invention.

[253] The present invention also includes the co-crystals of any compound according to the invention, that is, those crystalline forms composed of at least two components (one being a compound according to the invention, the other being cocrystal forming) which form a unique crystalline structure without, in contrast to crystalline salts, proton transfer from one component to the other. Potential cocrystal builders are acids and bases as listed above for salts / salt builders.

[254] In a representation such as, for example,

N or the letter A has the function of designating a ring in order to make it easier, for example, to indicate the adhesion of the ring in question to other rings.

[255] For bivalent groups in which it is crucial to determine which adjacent groups they link to and with which valence, the corresponding liaison partners are indicated in parentheses, when necessary, for clarification purposes, such as the following representations:

\ (R ¹ )

_or (R ² ) -C (O) NH- or (R ² ) -NHC (O) -;

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[256] Groups or substituents are often selected in between several groups / substituents alternatives with an designation of group corresponding

(for example, R ^a , R ^b, etc.). If such a group is used repeatedly to define a compound according to the invention in different parts of the molecule, it is emphasized that the various uses must be considered as totally independent from each other.

[257] By a therapeutically effective amount for the purposes of this invention means an amount of substance that is able to shorten the symptoms of illness or to prevent or alleviate those symptoms, or that prolongs the survival of a treated patient.

List of abbreviations

B.C Acetyl AcCN Acetonitrile ^a q. Watery, watery ATP Adenosine triphosphate Bn Benzyl Boc terc -butyloxycarbonyl Bu Butyl ç Concentration d Day (s) dba Dibenzylidenoacetone TLC Thin layer chromatography Davephos 2-Dimethylamino-2'- dicyclohexylaminophosphinobiphenyl DBA Dibenzylidenoacetone DCM Dichloromethane DEA Diethylamine

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DEAD Diethyl azodicarboxylate DIPEA N-ethyl-N, N-diisopropylamine (Hünig's base) DMAP 4-N, N-dimethylaminopyridine DME 1,2-Dimethoxyethane DMF N, N-dimethylformamide DMSO Dimethylsulfoxide DPPA Diphenylphosphorylazide going dppf 1,1'-Bis (diphenylphosphino) ferrocene EDTA Ethylenediaminetetraacetic acid EGTA Ethylene glycoltetraacetic acid eq Equivalent (s) ESI Electron spray ionization Et Ethyl Et2O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol H Hour HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' - tetramethyl-uronium hexafluorophosphate HPLC High performance liquid chromatography IBX 2-iodoxibenzoic acid i iso conc. Concentrated LC Liquid chromatography LiHMDS Lithium bis (trimethylsilyl) amide sln. Solution MCH Methyl cyclohexane Me Methyl MeOH Methanol

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min Minutes MPLC Medium pressure liquid chromatography MS Mass spectrometry MTBE Tert-butyl methyl ether NBS N-bromo-succinimide NIS N- iodine-succinimide NMM N-methylmorpholine NMP N-methylpyrrolidone NP Normal phase at. Not available PBS Phosphate buffered saline Ph Fenil Pr Propyl Py Pyridine rac Racemic red. Reduction Rf (Rf) Retention factor RP Reverse phase rt Room temperature SFC Supercritical fluid chromatography Sn Nucleophilic substitution TBAF Tetrabutylammonium fluoride TBDMS terc-butyldimethylsilyl TBME tert-butylmethylether TBTU O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyl- tetrafluorborate uronium tBu tert-butyl TEA Triethylamine temp. Temperature

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terc tertiary Tf Triflate TFA Trifluoroacetic acid THF Tetrahydrofuran TMS Trimethylsilil tRet Retention time (HPLC) TRIS Tris (hydroxymethyl) -aminomethane TsOH P-Toluenesulfonic acid UV Ultraviolet

[258] Characteristics and advantages of the present invention will be evident from the following detailed examples that illustrate the principles of the invention by way of examples, without restriction of its scope:

Preparation of the compounds according to the invention

General [259] Unless otherwise stated, all reactions are performed on commercially available devices using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and / or moisture are stored under protective gas and corresponding reactions and manipulations are carried out under protective gas (nitrogen or argon).

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

[261] Microwave reactions are carried out in an initiator / reactor made by Biotage or in an Explorer made

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89/422 by EMC or Synthos 3000 or Monowave 3000 made by Anton Paar in sealed containers (preferably 2, 5 or 20 ml), preferably with stirring.

Chromatography [262] Thin layer chromatography is performed on ready-made silica gel 60 TLC plates on glass (with fluorescence indicator F-254) made by Merck.

[263] Preparative high pressure chromatography (RP HPLC) of the example compounds according to the invention is performed on Agilent or Gilson systems with columns made by Waters (names: SunFire ™ Prep C18, OBD ™ 10 pm, 50 x 150 mm or SunFire ™ Prep C18 OBD ™ 5 pm, 30 x 50 mm or XBridge ™ Prep C18, OBD ™ 10 pm, 50 x 150 mm or XBridge ™ Prep C18, OBD ™ 5 pm, 30 x 150 mm or XBridge ™ Prep C18 , OBD ™ 5 pm, 30 x 50 mm) and YMC (names: Actus-Triart Prep C18, 5 pm, 30 x 50 mm).

[264] Gradients other than H ₂ O / acetonitrile are used to elute the compounds, while for Agilent systems, 5% acid modifier (20 ml HCOOH to 1 liter of H ₂ O / acetonitrile (1/1)) is added to the water (acidic conditions). For Gilson systems, 0.1% HCOOH is added to the water.

[265] For chromatography under basic conditions for Agilent systems, H ₂ O / acetonitrile gradients are also used, while water is made alkaline by adding a 5% basic modifier (50 g NH ₄ HCO ₃ + 50 ml NH ₃ (25% in H2O) to 1 liter with H2O). For Gilson systems, the water is made alkaline as follows: 5 ml of NH ₄ HCO _{3 solution} (158 g in 1 liter of H ₂ O) and 2 ml of NH ₃ (28% in H ₂ O) are supplied to 1 liter with H2O.

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90/422 [266] The supercritical fluid chromatography (SFC) of the intermediates and example compounds according to the invention is carried out on a JASCO SFC system with the following columns: Chiralcel OJ (250 x 20 mm, 5 pm) , Chiralpak AD (250 x 20 mm, 5 pm), Chiralpak AS (250 x 20 mm, 5 pm), Chiralpak IC (250 x 20 mm, 5 pm), Chiralpak IA (250 x 20 mm, 5 pm), Chiralcel OJ (250 x 20 mm, 5 pm), Chiralcel OD (250 x 20 mm, 5 pm), Phenomenex Lux C2 (250 x 20 mm, 5 pm).

[267] Analytical HPLC (reaction control) of intermediate and final compounds is performed using columns made by Waters (names: XBridge ™ C18, 2.5 pm,

2.1 x 20 mm or XBridge ™ C18, 2.5 pm, 2.1 x 30 mm or Aquity UPLC BEH C18, 1.7 pm, 2.1 x 50 mm) and YMC (names: Triart C18, 3, 0 pm, 2.0 x 30 mm) and Phenomenex (names: Luna C18, 5.0 pm, 2.0 x 30 mm). The analytical equipment is also equipped with a mass detector in each case.

HPLC-mass spectroscopy / UV-spectrometry [268] The retention times / MS-ESI + for characterization of the example compounds according to the invention are produced using an HPLC-MS (high performance liquid chromatography with mass detector) apparatus ). Compounds that elute at the peak of injection receive the retention time t _Ret = 0.00.

HPLC methods:

Method A

HPLC - Agilent 1100 Series

MS - Agilent LC / MSD SL

Speaker - Waters, XBridge ™ C18, 2.5 pm, 2.1 x 20 mm,

Numbered part 186003201

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Solvent

A: 20 mM NH ₄ HCO ₃ / NH ₃ pH 9 B: acetonitrile (HPLC grade)

Detection

MS: positive and negative

Mass range: 120 - 900 m / z Shredder: 120

Gain EMV: 1

Threshold: 150

Steps: 0.2

UV: 315 nm

Bandwidth: 170 nm Reference: off Amplitude: 230 - 400 nm Amplitude step: 1.00 nm Peak width: <0.01 min Slit: 1 nm

Injection - 5 μΐ

Flow - 1.00 ml / min

Column temperature - 60 ° C

Gradient

0.00 min B 10% 0.00 - 1, 50 min B 10% 95% 1.50 - 2.00 min B 95% 2.00 - 2.10 min B 95% 10%

Method B

HPLC - Agilent 1200 Series

MS - Agilent 6130 LC / MS Quadripole

Column - Waters, XBridge ™ C18, 2.5 μπι, 2.1 x 30 mm Solvent

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A: 20 mM NH ₄ HCO ₃ / NH ₃ in water; pH 9.3 B: acetonitrile (HPLC grade)

Detection

MS:

Polarity: positive

Ionizer: MM-ES + APCI

Mass range: 150 - 750 m / z

Values of the shredder:

Pasta Shredder 150 70 750 110

Gain EMV: 1.00

Threshold: 150

Steps: 0.2

UV:

254 nm: reference off 214 nm: reference off Amplitude: 190 - 400 nm Amplitude step: 2.00 nm Threshold: 1.00 mAU

Peak width: 0.0025 min (0.05 s)

Slot: 4 nm

Injection - 0.5 μΐ

Flow - 1,400 ml / min

Column temperature - 45 ° C

Gradient

0.00 - 1.00 min B 15% A · 95%

1.00 - 1.30 min B 95%

Method C

HPLC - Agilent 1200 Series

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MS - Agilent 6130 LC / MS Quadripole

Column - YMC, Triart C18, 3.0 pm, 2.0 x 30 mm, 12

Solvent

A: water + 0.1% HCOOH

B: acetonitrile + 0.1% HCOOH (HPLC grade)

Detection

MS:

Polarity: positive

Mass range: 150 - 750 m / z

Values of the shredder:

nm

Pasta Shredder 150 70 750 110

Gain EMV: 1.00

Threshold: 150

Steps: 0.20

UV:

254 nm: reference off 214 nm: reference off Amplitude: 190 - 400 nm Amplitude step: 4.00 nm Threshold: 1.00 mAU

Peak width: 0.005 min (0.1 s)

Slot: 4 nm

Injection - 0.5 μl

Flow - 1,400 ml / min

Column temperature - 45 ° C Gradient

0.00 - 1.00 min B 15% A · 100%

1.00 - 1.13 min B 100%

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Method D

HPLC - Agilent 1200 Series

MS - Agilent 6130 LC / MS Quadripole

Column - Waters, XBridge ™ C18, 2.5 pm, 2.1 x 30 Solvent

A: 20 mM NH ₄ HCO ₃ / NH ₃ in water; pH 9.3

B: acetonitrile (HPLC grade)

Detection

MS:

Polarity: positive + negative

Ionization: MM-ES

Mass range: 150 - 750 m / z

Values of the shredder:

mm

Pasta Shredder 150 70 750 110

Gain EMV: 1.00

Threshold: 150

Steps: 0.2

UV:

254 nm: reference off 214 nm: reference off Amplitude: 190 - 400 nm Amplitude step: 2.00 nm Threshold: 1.00 mAU

Peak width: 0.0025 min (0.05 s)

Slot: 4 nm

Injection - 0.5 pl

Flow - 1,400 ml / min

Column temperature - 45 ° C

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Gradient

0.00 - 1.00 min B 15% A 95%

1.00 - 1.30 min B 95%

Method E

HPLC - Agilent 1200 Series

MS - Agilent 6130 LC / MS Quadripole

Column - Waters, XBridge ™ C18, 2.5 pm, 2.1 x 3.0

XP column; Numbered part 186006028

Solvent

A: 20 mM NH ₄ HCO ₃ / NH ₃ in water; pH 9.3 B: acetonitrile (HPLC grade)

Detection

MS:

Polarity: positive + negative

Ionizer: API-ES

Mass range: 150 - 750 m / z

Values of the shredder:

mm

Pasta Shredder 150 70 750 110

Gain EMV: 1.00

Threshold: 150

Steps: 0.2

UV:

254 nm: reference off 214 nm: reference off Amplitude: 190 - 400 nm Amplitude step: 2.00 nm Threshold: 1.00 mAU

Peak width: 0.0025 min (0.05 s)

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Slot: 4 nm

Injection - 0.5 μΐ

Flow - 1,400 ml / min

Column temperature - 45 ° C

Gradient

0.00 - 1.00 min B 15% 95%

1.00 - 1.30 min B 95%

Method F

HPLC - Agilent 1200 Series

MS - Agilent 6130 LC / MS Quadripole

Column - YMC, Triart C18, 3.0 μιυ, 2.0 x 30 mm, 12 Solvent

A: water + 0.1% HCOOH

B: acetonitrile + 0.1% HCOOH (HPLC grade)

Detection

MS:

Polarity: positive + negative

Mass range: 150 - 750 m / z

Values of the shredder:

nm

Pasta Shredder 150 70 750 110

Gain EMV: 1.00

Threshold: 150

Steps: 0.20

UV:

254 nm: reference off 214 nm: reference off Amplitude: 190 - 400 nm Amplitude step: 4.00 nm

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Threshold: 1.00 mAU

Peak width: 0.0063 min (0.13 s)

Slot: 4 nm

Injection - 0.5 μΐ

Flow - 1,400 ml / min

Column temperature - 45 ° C

Gradient

0.00 - 1.00 min B 15% 100%

1.00 - 1.13 min B 100%

Method G

HPLC - Agilent 1200 Series

MS - Agilent 6130 LC / MS Quadripole

Column - YMC, Triart C18, 3.0 μιυ, 2.0 x 30 mm, 12 Solvent

A: water + 0.1% HCOOH

B: acetonitrile + 0.1% HCOOH (HPLC grade)

Detection

MS:

Polarity: positive + negative

Mass range: 150 - 750 m / z

Values of the shredder:

nm

Pasta Shredder 150 70 750 110

EMV of gain: 1.00 Threshold: 150 Steps: 0.20 UV: 254 nm: reference off 230 nm: reference off

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214 nm: reference off

Amplitude: 190 - 400 nm

Amplitude step: 4.00 nm

Threshold: 1.00 mAU

Peak width: 0.005 min (0.1 s)

Slot: 4 nm

Injection - 0.5 μΐ

Flow - 1,400 ml / min

Column temperature - 45 ° C

Gradient

0.00 - 1.00 min B 15% A 100%

1.00 - 1.13 min B 100%

Method H

HPLC - Agilent 1200 Series

MS - Agilent 6130 LC / MS Quadripole

Column - YMC, Triart C18, 3.0 μιυ, 2.0 x 30 mm, 12 Solvent

A: water + 0.1% HCOOH

B: acetonitrile + 0.1% HCOOH (HPLC grade)

Detection

MS:

Polarity: positive + negative

Mass range: 200 - 800 m / z

Shredder: 70

Gain: 1.00

Threshold: 150

Steps: 0.20

UV:

254 nm: reference off

230 nm: reference off nm

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Amplitude: 190 - 400 nm

Amplitude step: 2.00 nm Peak width:> 0.01 min (0.2 s) Slot: 4 nm

Injection - 1.0 μΐ

Flow - 1,000 ml / min

Column temperature - 45 ° C

Gradient

0.00 - 0, 10 min 5% B 0.10 - 1, 85 min B 5% A · B 95.0% 1.85 - 1.90 min B 95% 1.95 - 1, 92 min B 95% A · B 5.0%

Method I

HPLC - Agilent 1200 Series

MS - Agilent 6130 LC / MS Quadripole

Column - YMC, Triart C18, 3.0 μιυ, 2.0 x 30 mm, 12 Solvent

A: water + 0.1% HCOOH

B: acetonitrile + 0.1% HCOOH (HPLC grade)

Detection

MS:

Polarity: positive + negative

Mass range: 200 - 800 m / z

Shredder: 70

Gain: 1.00

Threshold: 150

Steps: 0.20

UV:

254 nm: reference off

230 nm: reference off nm

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100/422

Amplitude: 190 - 400 nm

Amplitude step: 2.00 nm Peak width:> 0.01 min (0.2 s) Slot: 4 nm

Injection - 1.0 μΐ

Flow - 1,000 ml / min

Column temperature - 45 ° C

Gradient

0.00 - 0, 10 min B 15% 0.10 - 1, 55 min B 15% B 95.0% 1.55 - 1.90 min B 95% 1.95 - 1, 92 min B 95% B 15.0%

Method J

HPLC - Agilent 1260 Series

MS - Agilent 6130 LC / MS Quadripole

Column - YMC, Triart C18, 3.0 μιυ, 2.0 x 30 mm, 12 Solvent

A: water + 0.1% HCOOH

B: acetonitrile (HPLC grade)

Detection

MS:

Polarity: positive + negative

Mass range: 100 - 800 m / z

Shredder: 70

Gain: 1.00

Threshold: 100

Steps: 0.15

UV:

254 nm: reference off

230 nm: reference off nm

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101/422

Amplitude: 190 - 400 nm

Amplitude step: 4.00 nm

Peak width:> 0.013 min (0.25 s) Slit: 4 nm Injection - 0.5 μΐ Flow - 1,400 ml / min

Temperature da co luna - 45 ° Gradient 0.00 - 1.00 min B 5% 100% 1.00 - 1.37 min B 100% 1.37 - 1.40 min B 100% 5% Method K

HPLC - Agilent 1260 Series

MS - Agilent 6130 LC / MS Quadripole

Column - Waters, XBridge ™ C18, 2.5 μπι, 2.1 x 30 Solvent

A: 5 mM NH ₄ HCO _3/19 mM _NH3 in water

B: acetonitrile (HPLC grade)

Detection

MS:

Polarity: positive + negative

Mass range: 100 - 800 m / z

Shredder: 70

Gain: 1.00

Threshold: 100

Steps: 0.15

UV:

254 nm: reference off

230 nm: reference off

Amplitude: 190 - 400 nm mm

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102/422

Amplitude step: 4.00 nm

Peak width:> 0.013 min (0.25 s)

Slot: 4 nm

Injection - 0.5 μΐ

Flow - 1,400 ml / min

Column temperature - 45 ° C

Gradient

0.00 - 0.01 min 5% B

0.01 - 1.00 min B 5% 100%

1.00 - 1.37 min B 100%

1.37 - 1.40 min B 100% 5%

Method L

HPLC / MS - Waters UPLC-micromass Triple quad Column - Aquity UPLC BEH C18, 1.7 μΜ, 2.1 x 50 Solvent

A: water + 0.1% HCOOH

B: acetonitrile (HPLC grade) + 0.1% HCOOH

Detection

MS:

ES / APCI positive and negative mode

Mass range: 100 - 1,000 m / z

Capillary voltage: 3,500 V

Cone voltage: 30 - 50 V

Desolvation gas: 600 l / h

Desolvation temperature: 300 ° C

UV:

Bandwidth: 190 nm

Amplitude: 210 - 400 nm

Resolution: 1.20 nm

Sample rate: 5 mm

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103/422

Injection - 0.5 μΐ

Flow - 0.400 ml / min Column temperature - 40 ° C

Gradient

0.00 - - 1, 80 min B 0% 1.80 - - 3.80 min B 0% A 75% 3.80 - - 4.50 min B 75% A 95% 4.50 - - 6.00 min B 95% 6.00 - - 6.01 min B 95% A 0%

Method M

HPLC / MS - Agilent 1200, 6120MS

Column - Luna C18 (2) 5 μιη, 3 0 x 2,0 mm Solvent

A: water + 0.037% TFA

B: acetonitrile + 0.018% TFA

Detection

MS: positive and negative mode

Mass range: 100 - 1,000 m / z Fragmenter: 70 gain EMV: 1

Threshold: 150

Steps: 0.1

UV: 220/254 nm

Bandwidth: 200 nm

Reference: Off

Amplitude: 200 - 400 nm

Amplitude step: 0.4 nm

Peak width:> 0.05 min

Slot: 4 nm

Injection - 0.5 μΐ

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104/422

Flow - 1.0 ml / min

Column temperature - 50 ° C

Gradient

0.00 - - 0, 30 min B 0% 0.30 - - 1.40 min B 0% A · 60 1.40 - - 1, 55 min B 60% 1.55 - - 1, 56 min B 60% A · 0 1.56 - - 2.00 min B 0%

[269] The compounds according to the invention are prepared by the synthesis methods described hereinafter, in which the substituents of the general formulas have the meanings presented here previously. These methods aim to illustrate the invention, without restricting its subject and the scope of the claimed compounds to these examples. When the preparation of starting compounds is not described, they can be obtained commercially or they can be prepared analogously to compounds known in the art or by methods described herein. The substances described in the literature are prepared according to the published synthetic methods.

Compounds (Ia)

General reaction scheme and summary of the synthesis pathway

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Layout 1

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Layout 2

B-10

(la) * The location of superoxidation / formation of N-oxide is not entirely clear. B-13 as described in scheme 2 seems likely.

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Layout 3

(la) B-23 n = 1 ^{11 = 1} B-22 [270] New structure compounds (Ia) can be prepared in stages starting with a synthesis pathway described in scheme 1 of S-l isatin derivatives by means of

of a 1,3-dipolar decarboxylative cycloaddition with an amino acid B-1 (method A) or B-5 (method D) and nitroethene B-2 to build spiro systems B-3 and B-6 as a

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108/422 potentially racemic mixture together with other regium- 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 synthesis. All other known means for the separation of enantiomers can also be applied here or after any subsequent synthetic step described herein, for example, 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).

[271] BL.3 and BL.6 can be reacted with aldehydes or ketones in a reductive amination reaction to generate BL.4 (method B) and BL.7 (method E). Alternatively, an alkylation, addition, acylation or sulfonylation reaction can be carried out with B-3 and B-6 to obtain intermediates B-4 and

B-7.

[272] Intermediate B-4 can be reduced with DIBAL or another reducing agent and will then generate intermediates B-7 (method C).

[273] The hydroxy group of intermediate B-7 is oxidized, for example, with Dess-Martin periodinane, IBX or an alternative oxidation reagent, to the corresponding carbonyl compound B-8 (method F, scheme 2), which can be further reacted with nucleophiles, especially organometallic reagents such as Grignard or organo-zinc reagents (which can be obtained from B-9 via a metal-halogen exchange reaction) in intermediate B-10 as a mixture of two diastereomers

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109/422 (method G). The diastereoisomers of B-10 intermediates are not separated and used as mixtures for further reactions.

[274] Intermediates B-10 can be oxidized to ketone intermediates B-11 using Dess-Martin periodinane, IBX or other oxidation methods (method H).

[275] The reduction of both nitro groups of B-11 intermediates and subsequent reductive cyclization is triggered by treatment of B-11 intermediates with hydrogen under Raney nickel catalysis, or with alternative reducing agents, and generates B-12 intermediates as a mixture of two diastereoisomers (method I). The diastereomers of B-12 intermediates are not separated and used as the mixture for further reactions.

[276] An oxidative cyclization of B-12 intermediates by treatment with OXONE® (potassium peroxymonosulfate) in a mixture of water and DCM, or by treatment with alternative oxidizing agents generates compounds (Ia) according to the invention (method J) . If superoxidation occurs when treated with OXONE®, the subsequent reduction of the crude mixture containing superoxidation product B-13 with bis (pinacolate) diborane or another reducing agent can be performed to generate compounds (Ia).

[277] Compounds (Ia) that are obtained initially from B-12 or B-13 can be derivatized in optional derivatization steps not explicitly described in the schemes in all residues, especially in R ⁴ , if they carry functional groups, which can also be modified, for example, halogen atoms, groups

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110/422 amino and hydroxy (including cyclic amines), carboxylic acid or ester functions, nitriles etc. in additional compounds (Ia) by well-established organic chemical transformations such as, for example, metal-catalyzed cross-coupling reactions, acylation, amidation, addition, reduction or (reductive) alkylation or cleavage of protecting groups. These additional steps are not described in the general schemes. Likewise, it is also possible to include these additional steps in the synthetic routes described in the general schemes, that is, to perform derivatization reactions with compound intermediates. In addition, it may also be possible that building blocks that house protection groups are used, that is, additional steps for unprotection are necessary.

[278] Alternatively, compounds (Ia) can also be prepared with the following reaction sequence:

[279] Starting from anilines or amino acids B-14, an amino function can be acetylated with acetic anhydride or other standardized acetylation methods to generate B-15 intermediates. B-15 intermediates are brominated with NBS, TsOH and Pd (OAc) 2 to generate B16 bromine intermediates. Coupling Sonogashira with Boc-prop-2-ynyl-amine under Pd and Cu catalysis generates B-17 intermediates, which can be hydrated under acidic conditions under Pd (OAc) 2 catalysis, followed by global deprotection under acidic conditions ( HCl) to generate B-18 amines. Modifications of intermediates thus obtained, for example, esterification of free carboxyl groups (if one of R ⁴ = COOH) with SOCl2 and MeOH or an alternative esterification method, generates additional B-18 intermediates. The formation of imine from

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111/422 intermediates B-18 with S-1 isatins generates imine intermediates B-19, which can then react in a 1,3dipolar cycloaddition with nitroethenes B-2 to generate racemic intermediates B-20 together with other regium- 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 synthesis, for example, when intermediate B-22 is reached. All other known means for the separation of enantiomers can also be applied here or after any subsequent synthetic step described herein, for example, 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). The reduction and cyclization of intermediate B-20 with H2 under Pt / C catalysis generates B-21 intermediates, which can be reduced subsequently by adding VO (acac) 2 to the reaction mixture and continued stirring under H2 pressure to generate intermediates B-22. An oxidative cyclization of B-22 intermediates with Na2WO4 and H2O2 dihydrate, or by treatment with alternative oxidizing agents generates B-23 intermediates that can be converted into compounds (Ia) by reactions with aldehydes or ketones in a reductive amination reaction. Alternatively, an alkylation, addition, acylation or sulfonylation reaction can be carried out with B-23 to obtain additional compounds (Ia).

[280] Compounds (Ia) were tested for activity to affect the MDM2-p53 interaction in its racemic form or, alternatively, as the enantiopure form (in

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112/422 (Ia *)). Each of the two enantiomers in a racemic mixture can have activity against MDM2, albeit with a different binding mode. Enantiopure compounds are marked with the label Chiral. Compounds listed in any table below that are labeled Chiral (both intermediates and compounds (Ib) according to the invention) can be separated by chiral SFC chromatography of their enantiomers or are synthesized from enantiopure starting material which is separated by chiral SFC .

Example:

ABC [281] Structure A defines the racemic mixture of compounds with structure B and C, that is, structure A encompasses two structures (compounds Be C), while structures B and C, respectively, are enantiopure and only define one compound specific. Thus, the formulas (Ia) and (Ia *)

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113/422 with a set of specific definitions for groups R ¹ to R ⁴ , R ⁷ , V, W, X, Y, n, req represent the racemic mixture of two enantiomers (->(Ia); structure A above is a specific example of such a racemic mixture) or a single enantiomer (-> (Ia *); structure B above is a specific enantiomer), unless there are additional stereocenters present in one or more of the substituents. The same definition applies to synthetic intermediates.

Synthesis of B-6 intermediates

Experimental procedure for «(method D) synthesis of B-6a

[282] 6-Chlorisatin S-la (31.5 g, 174 mmol), 1- (3-chloro-2-fluorophenyl) -2-nitroethene B-2a (35 g, 174 mmol) and L-homoserin B- 5a (20.7 g, 174 mmol) are refluxed in MeOH for 4 h. The reaction mixture is concentrated in vacuo and purified by crystallization or chromatography, if necessary.

[283] The following B-6 intermediates (Table 1) are available in an analogous manner starting from different S-1 ringed Hpirrol-2,3-diones, B-5 amino acids and B-2 nitroethenes.

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Table 1

# Structure tret [min] [M + H] ⁺ Method HPLC Cl (A- ^f in ^ ^oh B-6a CI ^^ N 1.21 440 THE | Jy ^F no _2. ^ ^Oh B-6b ^Cl H Quiral 1.21 440 THE N ^ j ^ ^F NO z ^{0H 1} B-6c CI ^^ N UI _H 1.09 441 THE N ⁱ ^ V ' ^F NO ^ z ° ^H B-6d it 1.09 441 THE

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115/422

# Structure tret [min] [M + H] ⁺ Method HPLC B-6e Cl roar Π 1.13 441 THE B-6f At ^f Cl ₂ / ^n-0H CIAA ° C Cl Chiral β 1.13 441 THE B-6g άιυ 1.17 422 THE B-6h | Xo ₂ lj, ° ^H ÍJ ^ Quitai 1.17 422 THE

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116/422

# Structure tret [min] [M + H] ⁺ Method HPLC B-6i Cl | ^ Y ^f no ₂ > ^0H 1.25 458 THE B-6j Cl i ^ V ^f no ^ ^oh ClW-N Chiral 1.25 458 THE

Synthesis of B-7 intermediates

Experimental procedure for (method E) the synthesis of

B-7a

B-6a B-7a [284] To a solution of cyclopropanecarbaldehyde (1.7 ml, 22.7 mmol) in AcOH (19.5 ml) is added intermediate B6a (1.60 g, 3.8 mmol) and the reaction mixture is stirred for 15 min. Sodium triacetoxyborohydride (1.34 g, 6.3 mmol) is added and the reaction mixture is stirred overnight. Water is added to the reaction mixture and it is extracted with EtOAc. The combined organic layer is dried

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117/422 (MgSO ₄ ), filtered, concentrated in vacuo and the crude product B-7a is purified by chromatography, if necessary.

[285] The following B-7 intermediates (table 2) are available in an analogous manner from different B-6 intermediates and aldehydes.

Table 2

# Structure tret [min] [M + H] ⁺ Method HPLC B-7a | Λ < ^Ρ ΝΟ ^ ^θΗ α-Μ'Ν 1.37 494 THE Cl / y ^F N0 ^ ^0H B-7b Chiral 1.37 494 THE B-7c Cl At ^f no ₂ ^ ^oh Cl ^ kjA-N ⁰ H Chiral 1.44 508 THE

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118/422

# Structure tret [min] [M + H] ⁺ Method HPLC B-7d CI ^^ N ^ ⁰ Chiral 1.43 496 THE B-7e UI | ^ V ^f in ^ ^oh Crsvv H Chiral 1.47 510 THE B-7f ΠΓΪΐδ ^Η χγ * - α'Ν, Α-Ν Chiral 1.37 482 THE B-7g Cl | Ât ^f no ^ ^oh CI-ÃíÃ-N Chiral 1.32 468 THE

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119/422

# Structure tret [min] [M + H] ⁺ Method HPLC B-7h CI ^^ N Chiral 1.28 498 THE B-7i ΑΛο, ει ^0H ^ 'Ν < 1.47 574 THE B-7j Cl | A | - ^F NO ₂ P ^H ci-ÃAn <Chiral 1.45 574 THE B-7k OH N [ ^N0 ^ —J 'CI ^^ N H 495 1.29 THE

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120/422

# Structure tret [min] [M + H] ⁺ Method HPLC Β-71 OH N ^N0 2 ^^ ix * '* CI ^^ N Chiral 495 1.29 THE B-7m oc ^^ ^OH ciAAn Quiral 1.29 495 THE Β-7η JL _ M OH Γ GO s-f ciAZn 1.37 476 THE Β-7ο Cl Aau ^ ^oh ítS-T pi ^ v ^ N H Chiral 1.37 476 THE

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121/422

# Structure tret [min] [M + H] ⁺ Method HPLC B-7p At ^f Cl ₂ / ^0H C, AAn ° 1.38 512 THE B-7q rT ^F ^ ^0H _CI & XZ _{N H} Chiral IU ° ^V 1.38 512 THE B-7r In Jy IU ^F ₂ ^0H hunt ° < 0.80 575 AND B-7s Cl At ^f no ^ ^oh PÇÍÇCin _cl AAr ° <Chiral 0.80 575 AND

Synthesis of B-3 intermediates

Experimental procedure for the synthesis of B-3a (method A)

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S-1a

B-3 to [286] 6-Chlorisatin S-la (5 g, 27.0 mmol), 1- (3-chloro2-fluoro-phenyl) -2-nitroethene B-2a (5.5 g, 27.0 mmol) and amino acid B-la (4.4 g, 27.0 mmol) are refluxed in MeOH for 4 h. The reaction mixture is concentrated in vacuo and purified by crystallization or chromatography, if necessary.

[287] The following B-3 intermediates (table 3) are available in an analogous manner starting from different S-1 ring-pyrrole-2,3-diones, B-1 amino acids and B-2 nitroethenes.

Table 3

# Structure tret [min] [M + H] ⁺ Method of HPLC B-3a H 1.42 482 THE

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123/422

# Structure tret [min] [M + H] ⁺ Method of HPLC B-3b CI ^^ N H Chiral 1.42 482 THE

Synthesis of B-4 intermediates

Experimental procedure for (method B) the synthesis of B-4a

MeCN, AcOH

[288] To a solution of cyclopropanecarbaldehyde (0.64 g, 8.9 mmol) in AcOH (0.5 ml) is added intermediate B-3a (2.68 g, 4.4 mmol) and the reaction mixture is stirred for 15 min. Sodium triacetoxyborohydride (2.8 g, 13.3 mmol) is added and the reaction mixture is stirred overnight. Water is added to the reaction mixture and it is extracted with EtOAc. The combined organic layer is dried (MgSO ₄ ), filtered, concentrated in vacuo and the crude product B-4a is purified by chromatography, if necessary.

[289] The following B-4 intermediates (table 4) are available in a similar way from different B-3 intermediates and different aldehydes.

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Table 4

# Structure tret [min] [M + H] ⁺ Method HPLC B-4a H 1.52 536 THE B-4b H Chiral 1.52 536 THE

Synthesis of additional intermediates B-7 Experimental procedure for the synthesis of (method C)

B-7t

DIBAL

[2 90] To a solution of B-4a (2.38 g, 4.0 mmol) in DCM is added DIBAL (18.0 ml, 18 mmol, 1.0 M in DCM) slowly at 0 ° C and at reaction mixture is stirred for 1 h. To the reaction mixture, water and saturated aqueous potassium sodium tartrate solution are added and the mixture is stirred overnight at room temperature. At

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125/422 phases are separated and the aqueous phase is extracted with DCM. The combined organic layer is dried (MgSO ₄ ), filtered, concentrated in vacuo and the crude product B-7t is purified by chromatography, if necessary.

[291] The following B-7 intermediates (table 5) are available in a similar way from different B-4 intermediates.

Table 5

# Structure tret [min] [M + H] ⁺ Method of HPLC B-7t NO ₂ ^F f / fr ~ ^0H £ H 1.52 508 THE B-7u IU IAR ^FNC w ^ ^0H H Chiral 1.52 508 THE

Synthesis of intermediates B-8 synthesis of

B-8b

Experimental procedure for (method F)

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126/422 [292] To a solution of intermediate B-7b (1 g, 2.02 mmol) in ACN (20 ml) is added NaHCO ₃ (0.34 g, 4.05 mmol) and stirred for 5 min before of DessMartin periodinane (1.72 g, 4.05 mmol) is added portionwise to the mixture. The reaction mixture is stirred for another 30 min before being diluted with H ₂ O, saturated NaHCO ₃ and EtOAc. The reaction mixture is extracted with EtOAc. The combined organic layer is dried (MgSO ₄ ), filtered, concentrated in vacuo and the crude product B-8b is purified by chromatography, if necessary.

[293] The following B-8 intermediates (table 6) are available in a similar way from different B-7 intermediates.

Table 6

# Structure tret [min] [M + H] ⁺ Method HPLC Cl Λ / νΟ. / ¹ B-8a CI ^^ N 1.45 492 THE rY ^F ^ ° ^ ° B-8b CI ^^ N Chiral 1.46 492 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B-8c Cl H Chiral 1.48 506 THE B-8d _CI W ° ui _H Chiral 1.50 494 THE B-8e Cl cS ^ Y Chiral 1.55 506 THE B-8f Cl j ^ V ^F n% ^ ⁰ CI ^^ N Chiral 1.46 480 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B-8g nr ^F ^ ° H Chiral 1.39 464 THE B-8h ι ^ γ ^ρ Νο, λ ° CI ^^ N Chiral 1.35 494 THE B-8i Cl iíYÔ ^ o _C | AjA-n Q H 0.91 572 B B-8j Chiral 1.53 572 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B-8k Ν ^ γ ^Ρ ΝΟ ₂ * ° ci ^ ÁAn 1.37 493 THE B-81 Cl Ν * Ύ ^Ρ ΝΟ ₂ * ° frS ^ o ^ Cl ^ si ^ N H Chiral 1.37 493 THE B- 8m i ^ V ^f no ₂ «P ÍtVo ^ Cl ^ lAfj Chiral 1.34 493 THE B-8n ΓΧαΧ ⁷ ' ⁰ CI ^^ N Π 1.42 506 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B-8th / ¾ ⁴ CI ^^ N Chiral 1.42 506 THE B-8p Cl A » _c. -A ^ -n H Chiral 1.46 474 THE B-8q Αγ ^Ρ ΝΟ ₂ Chiral 0.84 510 B B-8r Γ ¥ α> ^ ⁰ cÂAfj k Chiral n. The. n. The. n. The.

Synthesis of intermediates B-10

Experimental procedure for the synthesis of B-10a (method G)

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131/422 /

Ο c

B-8b

Cl

O \

H Chiral

B-10a [294] A solution of 4-iodo-3-nitro-benzoic acid methyl ester B-9a (2.60 g, 8.48 mmol) in THF (17 ml) is cooled to -50 ° C and chloride Phenylmagnesium (4.05 ml, 8.09 mmol, 2 M) is added dropwise and the reaction mixture is stirred for an additional 30 min at -50 ° C. A solution of intermediate B-8b (1.90 g, 3.85 mmol) in THF (7.7 ml) is added to the reaction mixture dropwise at -50 ° C and the reaction mixture is stirred for another 15 min at the same temperature. The reaction mixture is slowly warmed to room temperature and stirred for an additional 2 h before saturated aqueous solution of KHSO ₄ and EtOAc are added. The reaction mixture is extracted with EtOAc. The combined organic layer is dried (MgSO ₄ ), filtered, concentrated in vacuo and the crude product B-10a is purified by chromatography. B-10a is obtained as a mixture of two diastereomers which is used for the next step without separation.

[295] The following B-10 intermediates (table 7) are available in a similar way from different B-8 intermediates and different B-9 iodides.

Table 7

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# Structure tret [min] [M + H] ⁺ Method HPLC B-10a / 0 Ç ¹ O _? N— H Chiral 1.58 673 THE B-10b / 0 Ç ¹ ° 2 ^N_ CZy ^F in CI ^^ N H Chiral 1.63 687 THE B-lOc / 0 Ç ¹ ° 2 ^N- C_y ^F no 'DH n >> CI ^^ N Chiral 1.61 675 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC / 0 B-10d Ç ¹ o _? n- <7 <^ y ^F No ^X 3H Chiral 1.62 687 THE B-10e / 0 Ç ¹ ON-Ç? <^ y ^F NO, _ H Chiral 1.57 659 THE f 0 B-10f Ç ¹ ONf? ^ Ay ^F NO 'oh CI ^^ N H Chiral 1.53 647 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B-10g / 0 Ç ¹ o _? n-çA oh _CI XXG ° 'UI _H Chiral 1.49 675 THE B-10am / 0 Ϋ * _F OH cGpb-u Chiral 1.63 753 THE B-Hi / 0 Ç ¹ ON-ÇT— | ^ ^V jf ^ ^F NO \ _i - CI ^^ N H Chiral 1.61 687 THE

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135/422

# Structure tret [min] [M + H] ⁺ Method HPLC B-10j Z 0 Ç ¹ O _? N-Çp j ^ y ^F No {'3H Chiral 1.62 687 THE B-10k Z 0 Ç ¹ ο ₂ ν- ^ Λ-ο rV ^ ^FNO u (, '3H rfCv CI ^^ N Chiral 1.52 703 THE B-1O1 Z Z ° í / ° Ç ¹ OjN-f? py ° ^{C. S} 3H rX ^v CI ^^ N Π 1.58 709 THE

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136/422

# Structure tret [min] [M + H] ⁺ Method HPLC / f ° / ° B- 10m Ç ¹ ON-f? f ^ y ^F NCL% 7 CI ^^ N H Chiral 1.58 709 7 \ Ç ¹ o _? ⁿ - py ^F NQ ( ⁰ Β-1Οη CI ^^ N H Chiral 1.54 673 THE / 0 Ç ¹ O _? N ^ 2— B-lOo ΓιΓ ^Ρν % (/ jS> ° t H Chiral 1.66 698 THE

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137/422

# Structure tret [min] [M + H] ⁺ Method HPLC Β-10ρ Z 0 Chiral 1.62 767 THE B-10q Z 0 Ç ¹ ° 2 ^N “C / N | < ^F NO, (DH CI ^^ N 1.51 674 THE B-10r z 0 Ç ¹ ° 2 ^N “C ~ 7 V iT ^Fno ^ * ( ^X 3H XJ> ^ CI ^^ N H Chiral 1.51 674 THE

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138/422

# Structure tret [min] [M + H] ⁺ Method HPLC / 3 > 0 B-lOs O, N-f 7 y no ΛχΛγ oh THE 1.48 674 THE Chiral Çl ho ^ U, ^r nq / 0— 0 B-10 H n. The. n. The. Çl ₂ \> HC3) ™ ( 0— B-lO NO, / Y / jqSE CI ^^ N H 0 n. The. n. The. - Chiral

Synthesis of B-9 intermediates

Experimental procedure for de B-9b

AT THE,

NaNO ₂ , HCI, Kl

[296] To a solution of 4-amino2-methyl-3-nitro-benzoic acid methyl ester (2.4 g, 11.0 mmol) in HCI (25 ml)

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139/422 at 0 ° C sodium nitrite is slowly added and the mixture is stirred for 30 min at the same temperature. Potassium iodide (5.7 g, 34.0 mmol) is added in portions at 0 ° C and the mixture is stirred at room temperature for 1 h. To the reaction mixture, water and Et ₂ O are added. The phases are separated and the aqueous phase is extracted with Et ₂ O. The combined organic layer is dried (MgSO ₄ ), filtered, concentrated in vacuo and the crude product B-9b is purified by chromatography, if necessary.

Experimental procedure for the synthesis of B-9c

[297] To a solution of 2hydroxy-4-iodo-3-nitro-benzoic acid methyl ester (1.0 g, 3.1 mmol) are added potassium carbonate (1.3 g, 9.3 mmol) and methyl iodide (0.4 ml, 6.2 mmol) at room temperature. The reaction mixture is stirred at room temperature for 4 h. Water is added to the mixture and the solid formed is filtered and dried to generate intermediate B-9c.

Table 8

# Structure tret [min] [M + H] ⁺ Method HPLC ° γ ~ Ο B-9b go 1.25 n. The. THE n »> 1 ²

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# Structure tret [min] [M + H] ⁺ Method HPLC B-9c rw ₂ 1 ² 1.19 338 THE

Synthesis of Intermediates B-ll

Experimental procedure for the synthesis of B-lla

B-10a B-11a [298] To a solution of intermediate B-10a (1 g, 1.49 mmol) in THF (10 ml) is added NaHCO ₃ (0.34 g, 1.49 mmol) and stirred for 5 min before DessMartin periodinane (1.26 g, 2.97 mmol) is added portionwise to the mixture. The reaction mixture is stirred for an additional 2 h at room temperature before being diluted with H ₂ O, saturated NaHCO ₃ and EtOAc. The reaction mixture is extracted with EtOAc. The combined organic layer is dried (MgSO ₄ ), filtered, concentrated in vacuo and the crude product B-1la is purified by chromatography, if necessary.

[299] The following B-ll intermediates (table 9) are available in a similar way from different B-10 intermediates.

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Table 9

# Structure tret [min] [M + H] ⁺ Method HPLC B-lla / 0 Ç ¹ H Chiral 1.57 671 THE B-llb / 0 Ç ¹ γΊΓ ^ρ ν °> jO ^ q CI ^^ N H Chiral 1.66 685 THE B-llc / 0 Ç ¹ O _? N — Cy * l ^ y ^F No Cl * ^ N H Chiral 1.64 673 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B-lld / 0 Ç ¹ o _? n- <7 o. CI ^^ N Chiral 1.65 687 THE B-lle / 0 Ç ¹ CLN-Ç? CI ^^ N Chiral 1.60 659 THE B-llf / 0 Ç ¹ ο ₃ Ν-ςΛ py ^F N ° 'Quiral 1.56 645 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B-llg / 0 Ç ¹ ο _? ν- <Λ rY ^F SL ° w Chiral 1.50 675 THE B-llh / 0 Ç ¹ ° 2 ^N “^^ Chiral 1.63 751 THE B-lli / 0 Ç ¹ ON-f) - xx? ^ ⁷ H Chiral 1.63 685 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B-llj / 0 Ç ¹ O ₃ N-Ç $ CI ^^ N H Chiral 1.62 685 THE B-llk / 0 Ç ¹ ο ₂ ν- ^ Λ-ο ΓΙαΪ ^ '*' jOd ^> CI ^^ N H Quiral 1.57 701 THE B-lll / 0 Ç ¹ ° 2 ^N “\ _ ^ ^U H 1.54 701 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B- llm / 0 Ç ¹ CLN — C? rlf ^f n ° x Cl ^^ - N H Chiral 1.54 701 THE B-lln Ç ¹ γυ ^Ρν °. ⁰ CI ^^ N H 1.56 671 THE Chiral / 0 B-llo ° 2 ^M ~ ^ 7- xSv 'CI ^^ N H Chiral 1.70 687 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B-llp / 0 Ç ¹ O _? N- <V- Chiral 1.65 765 THE B-llq Z 0 Ç ¹ Ο ₂ Ν-ςΛ _C |> * vjí ^ N ^U H 1.55 672 THE B-llr Z 0 Ç ^{1 0} 2 ^N ~ Ç / Cl - ^^ N Chiral 1.55 672 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC / 0 > 0 Ç ¹ O ₂ Nf B-lls r ^ ^F z 0.89 672 J ci ^ n ^ n Chiral ϊ ° 3- < P- NO ZV l B-llt millstone Π 0.98 699 AND f O- < 0— B-llu no, zvJ CI ^^ N 0.98 699 AND Chiral

Synthesis of B-12 intermediates

Experimental procedure for the synthesis of B-12a (method I)

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B-12a [300] To a solution of intermediate B-lla (1.10 g, 1.60 mmol) in MeOH (6 ml) and DCM (9 ml) in an autoclave is added a catalytic amount of Raney nickel and the reaction mixture is stirred for 24 h under a hydrogen atmosphere (8 bar (0.8 MPa)). More Raney nickel is added and the reaction mixture is stirred for another 24 h under an atmosphere of hydrogen (8 bar (0.8 MPa)). The reaction mixture is filtered (Celite®) and the solvents are removed in vacuo. The residue is dissolved in EtOAc and saturated aqueous NaHCO ₃ solution is added. The reaction mixture is extracted with EtOAc. The combined organic layer is dried (MgSO ₄ ), filtered, concentrated in vacuo and the crude product B-12a is purified by chromatography, if necessary. Intermediate B-12a is obtained as a mixture of two diastereomers which is used for the next step without further separation.

[301] The following B-12 intermediates (table 10) are available in a similar way from different B-ll intermediates.

Table 10

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# Structure tret [min] [M + H] ⁺ Method HPLC Grandfather ΓΗ O B-12a Cl IF ^H U ^NH 2 1.52 595 THE c, XX .NX So V Chiral HI Grandfather j \ O ϋ 1 οχ UI T F ^NH 2 1.59 r r \ q D - -LZ U ciAAn H ba Chiral ouy 2-i Grandfather n Hi X B-12c Cl 'IFJ HLJ ^W _H nh ₂ Chiral 1.58 597 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B-12d P f ^NH 2 n§? - <H Chiral 1.62 611 THE B-12e ? ^F nh, Fl ^H B> Chiral 1.53 583 THE y ° s B-12f T ^F nh, rV ^H B> ΛΟ ~ H Chiral 1.48 568 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC S-A B-12g Jvh -Λ ' ^NH2 CI ^^ N H Chiral 1.40 599 THE <y ° ^ B-12h ^NH2 _C ^ TO ^ O '° - H Chiral 1.56 675 THE O B-12Í I ^F Nl-L rV ^H B> CI ^^ N H Chiral 1.55 609 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC B-12 j T ^F 7 ^ nh, laugh ^Η ΰ> CI ^^ N H Chiral 1.58 609 THE B-12k P 7 7 ^ nh, rV ^Η ΰ> CI ' ^A ^ ^U N Chiral 1.42 625 THE v ° ' B-121 P 7 7 ^ nh, ΓΙ ^H B> jQD = õV H 1.55 625 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC 'Grandfather ν— · υ 7 \ Π Λ-λ lj-1 I F 7 ΝΗ, π _ 1 ο τη laugh 1 RR <R 9 [R 7 \ -L! ί ^ Γ Λ CI ^^ N ^Ul Η Chiral 0 çi I F 7 ΝΗ, Β-12η ΓΗ 1.50 595 THE _c , jCq ^Μ Η Chiral Grandfather % 1-U ΓΜ O υι Τ F / ^ NH, Β-12ο Γϊ ^Η Ε ^ 1.63 611 THE VAs / ^ ο, ΧΧη tr ^Ul Η Chiral

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# Structure tret [min] [M + H] ⁺ Method HPLC Β-12ρ Ϊ ^F nh, n ^HÜ > UI _H Chiral 1.61 689 THE Ύλ Q B-12q jf J NH, hnA jQ>? v Cl ^^ - N H 1.48 596 THE Y ° s B-12r JL ^F J * 'NH, Ν' ^ γΗΝ'Χ CI ^^ N H Chiral 1.48 596 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Grandfather O R 1 Οσ Gl T F ^NH 2 1.44 c q r 7 \ fTS ci ^ n ^ n H N \ »0 K Chiral ° Ύ ° - ^ NH ₂ B-12t ^CI J HN 1.61 623 THE s UI _H NX = 0 ° Ύ ° ' V ^ ~ nh ₂ B-12u ^C \ 1 hn 'jÇ ·! « Chiral 1.61 623 THE

Synthesis of compounds (Ia) according to the invention Experimental procedure for the synthesis of Ia-1 (method J)

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[302] To a solution of intermediate B-12a (329 mg,

0.65 mmol) in DCM (7 ml) is added a solution of Oxone® (7 93 mg, 1.29 mmol) in H ₂ 0 (7 ml) at 0 ° C dropwise. The biphasic reaction mixture is stirred vigorously for 20 min at 0 ° C and for another 2 h at room temperature. The reaction mixture is diluted with H ₂ O and extracted with DCM. The combined organic layer is dried (MgSO ₄ ), filtered, concentrated in vacuo and the crude product is purified by chromatography, which generates compound Ia-1.

[303] The following compounds (Ia) (table 11) are available in an analogous manner from different B-12 intermediates.

Table 11

# Structure tret [min] [M + H] ⁺ Method HPLC 0¾ , 0 ^ CL Λ .. Ia-1 \ F Ν ' 1.60 591 THE CiXXÍ v ⁷ H Chiral

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# Structure tret [min] [M + H] ⁺ Method HPLC ικ Λ Ia-2 ci _f ⁿ \ νκΛ 1.67 605 THE _ci jCq ui _H :? □ Chiral , Ο-η. Ia-3 ci f < 1.64 593 THE / ¾ CI ^^ N H go Chiral 0¾ Ia-4 Cl / Λνζ 3 1.59 579 THE ο, υς Chiral

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-5 Cl Vz ^F ΝΛ CI ^^ N H Chiral 1.54 565 THE Ia-6 O- ⁰ 'Cl n / T CI ^^ N Chiral 1.49 595 THE Ia-7 ° ~ ° - Cl | XTf H Chiral 1.59 671 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-8 o ^ ⁰ - Cl fOÇ CI ^^ N Chiral 1.64 605 THE Ia-9 Cl JtJ n- \ CI ^^ N Chiral 1.63 605 THE Ia-10 o ~ ° - C _f ^N M (L ·! _H Chiral 1.50 621 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-11 ÃÃ ⁰ Cl Á-Í Cl ^^ - N 1.58 621 THE Ia-12 o ~ ° - Cl ρ ^Ν * ϊ H Chiral 1.58 621 THE Ia-13 d _f ⁿ \ I Cl ^^ - N H Chiral 1.59 591 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-14 Cl f ⁿ * Ã jw- H Chiral 1.69 685 THE Ia-15 ° τ ° Cl Ρ ^Ν · Χ CI '^^ N Chiral 1.67 607 THE Ia-16 0 ^ ° - C ΧΪ d ' ^A ^ ^! * 'N Chiral 1.66 607 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-17 Cl / Y v, ^F νΛ CI ^^ N H 1.48 592 THE Ia-18 Cl _f ⁿ DT ^ 1 _H Chiral 1.48 592 THE Ia-19 0 ^ 0- ci ι <Υ ci ^ n ^ n Chiral 1.48 592 THE

Synthesis of additional compounds (Ia) according to the invention

Experimental procedure for the synthesis of Ia-20 (method J + method K)

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Bis (pinacolato) 'diboro

MeCN

* The location of superoxidation / formation of N-oxide is not entirely clear. B-13a as revealed seems likely.

[304] To a solution of intermediate B-12j (417 mg,

0.68 mmol) in DCM (10 ml) is added a solution of Oxone® (841 mg, 1.37 mmol) in H ₂ 0 (7 ml) at 0 ° C dropwise. The biphasic reaction mixture is stirred vigorously for 20 min at 0 ° C and for another 6 h at room temperature. The reaction mixture is diluted with H ₂ O and extracted with DCM. The combined organic layer is dried (MgSO ₄ ), filtered, concentrated in vacuo, which generates a crude mixture of Ia-20 and an oxidized form B-13a (M + H = 621). This mixture is dissolved in

MeCN (4.2 ml) and bis (pinacolate) diborane (326 mg, 1.28 mmol) is added. The reaction mixture is heated under microwave irradiation to 100 ° C for 30 min. The reaction mixture is diluted with H ₂ O and extracted with DCM. The combined organic layer is dried (MgSO ₄ ), filtered, concentrated in vacuo and the crude product is purified by chromatography, which generates compound Ia-20.

[305] The following superoxidized compounds B-13 (table 12) are available in a similar way from different B-12 intermediates and can be reduced by

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Table 12

# Structure tret [min] [M + H] ⁺ Method HPLC B-13a ° Ύ ° ci f ⁿ * X Jt5ò ° 'CI ^ cA-n Chiral 0.96 621 Ç B-13b o ^ ⁰ - Cl _F ^N E) f CI ^^ N Chiral 0.89 565 Ç B-13c O- ⁰ 'Cl <1 iwF ci-ΆΑν Chiral 0.94 611 ç

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# Structure tret [min] [M + H] ⁺ Method HPLC S P B-13d ci ç On k, ϊ5 «· Π 0.95 635 AND B-13e ^{0 Cl} vj _b ft f 0.95 635 AND TrC, ⁰ 'CI ^^ N H Chiral

Table 13

# Structure tret [min] [M + H] ⁺ Method HPLC O ^ ⁰ '- Ia-20 ci f ⁿ * À 1.66 605 THE H Chiral

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-21 ^ο τ ^ο Cl _f ⁿ TT CI ^^ N Chiral 1.54 565 THE Ia-22 ci Zl Ν- \ CI ^^ N H Chiral 1.46 595 THE Ia-23 ^Cl Ç ^N -W ^> CI ^^ N 1.01 619 AND

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# Structure tret [min] [M + H] ⁺ Method HPLC 'J * O-\ Ia-24 1.01 619 AND H Chiral

Synthesis of additional compounds (Ia) by means of ester saponification

Experimental procedure for the synthesis of Ia-25

Ia-1 la-25 [306] Ia-1 (405 mg, 0.69 mmol) is dissolved in THF (30 ml) and aqueous NaOH solution (2 ml, 8 M) is added. The reaction mixture is stirred at 70 ° C for 8 h. After acidification with 2 M aqueous HCl and extraction with EtOAc the organic phase is dried with MgSO ₄ . Purification with reverse phase HPLC leads to pure la-25.

[307] The following compounds (Ia) (table 14) are available in an analogous manner starting from compounds (Ia)

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Table 14

# Structure tret [min] [M + H] ⁺ Method HPLC 0¾. OH Ia-25 Cl N ^Z LFN γΛ A 1, 04 577 THE C | AAn H Chiral OH Λ Ia-26 Cl N. 1 / N 1, 10 591 THE N ~ \ -0 □ Chiral OH Cl N ^Z Ia-27 1, 09 579 THE _C | AAn ' Cr Chiral

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-28 o ~ ^OH ci f ⁿ ^ X CI ^^ N H Chiral 1, 14 593 THE Ia-29 0 ^ ^0H Cl pH ^ T CI ^^ N H Chiral 1, 06 565 THE Ia-30 0 ^ ^0H Cl _C ^N 3 LJ ^N \ CI ^^ N Chiral 1, 00 551 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC OH Ia-31 Cl N. ' * T 0.95 581 THE -Ν'Χ-Ο Chiral the _x ^OH Ia-32 Cl nM v F 'μ ^Λ QULf 1, 11 657 THE í * ^ lS · ciAArj H Chiral What » , Oh Ia-33 ci _F <\ Kz 1, 07 591 THE α '- ^ - Ν Chiral

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# Structure tret [min] [M + H] ⁺ Method HPLC ο _ύ ^οη Ia-34 Cl LZ ΝΛ H Chiral 1.03 591 THE Ia-35 O ~ ^OH ci J <i G CI ^^ N Chiral 1, 04 607 THE O ^ ^OH Ia-36 Cl _F ^N Of 1, 04 607 THE ClA ^ N

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# Structure tret [min] [M + H] ⁺ Method HPLC 0 ^ OH ci X. Ia-37 V r M ί ^ ϊ 'Λ CI ^^ N X Chiral 1, 04 607 THE i-V ^ OH Ia-38 ci / fX / · 1.01 577 THE _Cl £ u UI _H Chiral 0¾ OH Cl X. Ia-39 V - N Ck / 1, 09 593 THE H kr Chiral

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-40 Ο _χ ^ΟΗ Cl XEW ⁰ '' - H Chiral 1, 13 671 THE Ia-41 0 ~ ^0H ci f ⁿ * X xSk CI ^^ N H 1.02 578 THE Ia-42 o ^ ^OH ci _i <J L / νΛ H Chiral 1.02 578 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-43 0 ^ ^0H Cl ci ^ n ^ n Chiral 1.02 578 THE Ia-44 Tx ^ ' CI ^^ N 1, 07 605 THE Ia-45 0 ^H0 V CI ^^ N H Chiral 1, 07 605 THE

Synthesis of additional compounds (Ia) by means of amidation

Experimental procedure for the synthesis of Ia-46

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la-46 [308] Ia-26 (10 mg, 0.02 mmol) is dissolved in anhydrous THF (1 ml) and HATU (8 mg, 0.02 mmol) is added at room temperature. After adding DIPEA (3.4 mg, 0.03 mmol) the reaction mixture is stirred at room temperature for 15 min. 1-Amino-2-methylpropan-2-ol (2 M in THF, 1.5 mg, 0.02 mmol) is added and the reaction is stirred for another 60 min. The crude reaction mixture is subjected to reverse phase column chromatography generating pure Ia-46.

[309] The following compounds (Ia) (Table 15) are available in an analogous manner starting from compounds (Ia) initially obtained.

Table 15

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# Structure tret [min] [M + H] ⁺ Method HPLC H V- Ta _À £ Cl _F ^NZ , Λ 1 J.7 £ £ 9 7 \ oA CI ^ Aj H ba Chiral _L ί 1J u u Ζι 0 H x ^{1 '57} Ia-47 Cl _p N 1.49 630 THE > 0 □ N H Chiral Ia-48 Cl _F ^{N z} , cx < Η _Λ ✓ 1.51 692 THE Chiral

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-49 H ci _f ⁿ TÇ CI ^^ N H Chiral 1.46 692 THE Ia-50 H 0 ^ ^N > Λ ^ ° ^H d _F <r H Chiral 1.22 594 THE Ia-51 ci f ⁿ * À jmb CI ^^ N H Chiral 1.35 621 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-52 Cl CI ^^ N H Chiral 1.50 618 THE Ia-53 ci f ⁿ ^ X CI ^ XN H Chiral 1.33 620 THE Ia-54 0 ^ Q <x ^N -f Cl f ^N -TC xêhr · '· H Chiral 1.52 740 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ia-55 0 ΗΝ-γθ ci f ⁿ * A H Chiral 1.51 728 THE Ia-56 HN ^ ç ⁰ Cl F ^N -Tf H Chiral 1.49 684 THE Ia-57 ci f ⁿ ^ X H Chiral 1.54 698 THE

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Synthesis of starting material S-l

Experimental procedure for the synthesis of S-lb

[310] 3,3-Dibromo-6-chloro-1,3-dihydro-pyrrolo [2,3b] pyridin-2-one (7.6 g, 23.3 mmol) is suspended in acetonitrile (500 ml) and water (25 ml). AgNO ₃ (8.9 g, 52.7 mmol) is added and the reaction mixture is stirred at room temperature for 1 h. Acetonitrile is removed under reduced pressure and EtOAc is added. The phases are separated and the organic layer is dried with MgSO ₄ . Removal of the solvents generates pure 6-chloro-li-pyrrolo [2,3-b] pyridine-2,3dione S-lb.

Synthesis of B-15 intermediates

Experimental procedure for the synthesis of B-15a

B-15a [311] To a solution of B-14a (87 g, 575 mmol) in toluene (240 ml) is added Ac ₂ 0 (58 ml, 604 mmol) dropwise at reflux and the mixture is stirred at reflux for another 10 min. By cooling to -10 ° C and adding MCH (240 ml) the product B-15a is crystallized out of the mixture.

[312] The following B-15 intermediates (table 15-1) are available in a similar way from

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Table 15-1

# Structure [M + H] ⁺ B-15a CO ₂ Me X A 194 B-15b CO ₂ Me X A 208 B-15c CO ₂ Me ^ 0 224 B-15d CO ₂ Me X 224 B-15e X ^^ 0 194

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# Structure [M + H] ⁺ ÇO ₂ Me íV B-15f HN ^ Ά ₀ 208

Synthesis of B-16 intermediates

Experimental procedure for the synthesis of B-16a

NBS

D « ^B ' ^16a

B-15a [313] To a solution of B-15a (93.2 g, 482.5 mmol) in

AcOH (300 ml) TsOH monohydrate (46 g, 241.8 mmol) and Pd (OAc) ₂ (3.25 g, 14.5 mmol) are added. The mixture is heated to 75-80 ° C and NBS (94.6 g, 531.5 mmol) is added in portions. After stirring at 75-80 ° C for 10 min, the solution is cooled to 40 ° C. By adding water and additional cooling to 5 ° C, the product B-16a crystallizes and can be isolated by filtration.

[314] The following B-16 intermediates (table 15-2) are available in a similar way from different B-15 acetamides.

Table 15-2

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# Structure [M + H] ⁺ B-16a ÇO ₂ Me 273 B-16b CO ₂ Me 287 B-16c Ç ₂ Me jrr ⁰ 'A _o 303 B-16d CO ₂ Me 303 B-16e ^^ CO ₂ Me <A _o Br 273 B-16f CO ₂ Me aJ 287

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Synthesis of B-17 intermediates

Experimental procedure for the synthesis of B-17a

Pd ₂ (dba) ₃ [(t-Bu) ₃ PH] BF ₄ Cul, DIPA, DMSO

[315] To a suspension of B-16a (111.3 g, 409 mmol) in

DMSO (350 ml) Boc-prop-2-ynyl-amine (82.5 g, 532 mmol), Cul (1.56 g, 8.2 mmol), Pd ₂ (dba) ₃ (3.75 g) are added ,

4.1 mmol), [(tBu) ₃ P] BF ₄ (4.75 g, 16.4 mmol) and DIPA (287 ml). The mixture is stirred at room temperature for 3 days. The product B-17a can be crystallized by cooling the suspension to 5 ° C and adding water (585 ml). If necessary, product B-17a can be further purified by crystallization from nBuOAc / MCH.

[316] The following B-17 intermediates (table 15-3) are available in a similar way from different bromine acetamides B-16.

Table 15-3

# Structure [M + H] ⁺ B-17a ÇCLMe γψ A _o || -pj ¹ H 347

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# Structure [M + H] ⁺ B-17b Ύ ¹ H ÇO ₂ Me II 361 B-17c í A> i 4AJ ¹ H O ^ Me Y ⁰ ' 377 B-17d ^ ° Y Jí ΗΚΓ ^ 0 • 4oÍn · ¹ H ÇO ₂ Me '' Ύχ II 377 B-17e P ΗΝ- ^ γ A) II 4.v ¹ H ^ CO ₂ Me 347

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Experimental procedure for the synthesis of B-18a

B-17a [317] To a solution of B-17a (62.4 g, 180 mmol) in AcOH (325 ml) is added Pd (OAc) ₂ (0.81 g, 3.6 mmol) and the mixture is stirred at room temperature until complete consumption of B-17a. Subsequently, water (130 ml) and concentrated HCl (235 ml) are added. After dividing the Boc group (decreasing the formation of CO ₂ ), the mixture is heated to 70 ° C and stirred at that temperature for 3 days. The product B-18a can be crystallized from the reaction mixture by cooling.

[318] The following B-18 intermediates (table 15-4) are available in a similar way from different phenyl alkynis B-17.

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Table 15-4

# Structure [M + H] ⁺ C ° ₂ H rii B-18a HCI 209 KlW HCI hX co ₂ h V B-18b HCI r ^ ° 223 hX HCI H _; KT Ç ° ₂ H B-18c HCI 239 η ₂ ιψ HCI Ç ° 2 ^H O \ rii HjN AJ B-18d HCI 1 * ° 239 Ηχ HCI

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B-18a

SOCI ₂

MeOH

HCI

HCI

[319] To a suspension of B-18a (102 g, 418 mmol) in

MeOH (1235 ml) is added SOC1 ₂ (91 ml, 1254 mmol) dropwise at 60 ° C and the mixture is stirred overnight at that temperature. After cooling to room temperature, the mixture is filtered over an activated carbon filter and the solvents are then removed under reduced pressure. The B-18g product can be crystallized from PrOH.

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189/422 [320] The following B-18 benzoic acid ester intermediates (table 15-5) are available in an analogous manner starting from the different B-18 benzoic acids initially obtained.

Table 15-5

# Structure [M + H] ⁺ B-18g ₂ Me Xj HCI L 1 ° hor HCI 223 B-18h CU ₂ Me ^H 2 ^N ^ f Hd A _o h ₂ n HCI 237 B-18Í CO ₂ Me rr ^H 2 ^N HCI Αθ H-tí HCI 253

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# Structure [M + H] ⁺ CO ₂ Me THE Η, ΙΨ V B-18j HCI '' x 253 HCI X ^ CO ₂ Me II ^H 2 ^N 1 B-18k HCI % 223 HJT HCI CO ₂ Me (Air h ₂ im ψ ¹ B-181 HCI 237 HN ^ HCI

Synthesis of B-19 intermediates

Experimental procedure for the synthesis of B-19a

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191/422 [321] To a suspension of B-18g (79.4 g, 307 mmol) in

MeOH (1900 ml) is added 6-chloroisatin S-la (61 g, 338 mmol), AcOH (43 ml, 737 mmol) and TEA (86 ml, 615 mmol). After 3 days of stirring at room temperature, product B-19a can be filtered.

[322] The following B-19 imine intermediates (table 15-6) are available in an analogous manner from different esters of benzoic acid B-18.

Table 15-6

# Structure [M + H] ⁺ B-19a CO ₂ Me Cl _H 387 B-19b CO ₂ Me ° ui _H 400

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# Structure [M + H] ⁺ CO ₂ Me h ₂ n-4? ' B-19C O 416 Cl ^x H j ° 2 ^Me h.nÁJ B-19d (θ 416 N Xx> ° cr H r ^ \ ^ co ₂ M _e! B-19e r ° 387 Jf Cl ^ 1 H

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# Structure [M + H] ⁺ CO ₂ Me H B-19f Γ 0 _c , jQG Cl _H 400

Synthesis of intermediates B-20

Experimental procedure for the synthesis of B-20a

[323] 1-Chlorine-2-fluorine-3- (E) - 2-nitro-vinyl) -benzene (4.7 g, 23.3 mmol) is suspended in toluene (60 ml) and water (12.5 ml) and heated. At 75 ° C, imine B-19a (8.1 g, 21.1 mmol) is added and the suspension is further heated to 80 ° C. Then, 1-methylpyrrolidine (4.4 ml, 42.3 mmol) is added and the mixture is heated to reflux (82 ° C). After 7 min, more 1-methylpyrrolidine (4.4 ml, 42.3 mmol) is added and the solution is stirred for an additional 30 min under reflux. The reaction is quenched at 0 ° C by the addition of AcOH (6 ml). The organic phase is washed with water and saline and is then added dropwise to nHep (140 ml). The product B-20a can be purified by crystallization from

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MeOH.

[324] If a chiral separation of the enantiomers from the racemic mixture of intermediate B-20a is desired, then crystallization with chiral acids such as (S, S) - (+) - 2,3-dibenzoyl-D- tartaric, (S, S) - (+) 2,3-p-toluyl-D-tartaric acid (IS) - (+) camphor-10sulfonic acid, (12?) - (-) camphor-10-sulfonic acid , (2?) - () -mandelic acid, L-pyroglutamic acid or (S, S) -D - (-) tartaric acid can be considered. The use of (12 ') - () camphor-10-sulfonic acid is preferred.

[325] The following B-20 intermediates (table 15-7) are available in a similar way from different B-19 imines.

Table 15-7

# Structure [M + H] ⁺ B-20a CO ₂ Me NOj jcÁ ° 587 B-20b \ CO ₂ Me C r \\ J xsè ° Cl N 601

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# Structure [M + H] ⁺ , C0 ₂ Me HN Cl c V 7 NO, ^ 0 f M \ B-20c -NH 0 617 CL _H ^ 0 , C0 ₂ Me HN Cl r L 7 NO, jj B-20d fV 617 -NH ^ 0 0 jOò Η N- Cl Γ V and ^F NO, C0 ₂ Me f VÂ / l B-20e NH = 0 0 587 XQ Cl _H CO ₂ Me Cl hLN- L · z ^F NO, v KZ z> í B-20f 0 601 jCo NH

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# Structure [M + H] ⁺ B-20g CO ₂ Me no ₂ ^ K> rvV ^H II JL ^ ⁼ θ Chiral CI - ^^ N 587 B-20h \ CO ₂ Me Cl _B ^H ^ ^N '< ^S Í \ __ f no ₂ Jvc ^H II JL Quiral CI - ^^ N 601 B-20Í CO ₂ Me Cl \\ V LJ '° ² jfx ^ ⁰ 1 _C | A ^ AN θ'—! H 617 B-20j ^ 0 \ CO ₂ Me V / no ₂ ^ w Tve ^H | teo Quiral 617

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# Structure [M + H] ⁺ h ₂ n—. AT THE ? V z / CO.Me rLA B-20k ç ) 587 Chiral H CO ₂ Me Η N- Cl c V z ^F NO, IA B-201 0 601 jm -NH ^ 0 Chiral

Synthesis of Intermediates B-22

Experimental procedure for the synthesis of B-22a

B-20g

B-21a

B-22 a

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198/422 [326] To a solution of B-20g (39 g, 66.5 mmol) in MeTHF (22 ml) is added water (4.4 ml) and Pt / C (6.7 g). The mixture is hydrogenated for 3 days at 30 ° C under 70 bar (7 MPa) of H ₂ pressure. After complete conversion to B-21a, VO (acac) 2 (2.0 g, 7.4 mmol) is added and the mixture is further hydrogenated at 30 ° C to 70 bar (7 MPa) for 2 days. The catalysts are removed by filtration and the solvent is removed under reduced pressure. The product B-22a is dissolved in toluene (500 ml) and by adding 2 M H2SO4 (37 ml, 74 mmol) the B-22a sulfate can be precipitated.

[327] The reaction sequence B-20 A B-21 A B-22 is also possible with racemic B-20 (if there is no chiral separation of B-20). In this case, chiral separation can also be carried out in the B-22 stage by crystallization with chiral acids such as (S, S) - (+) - 2,3dibenzoyl-D-tartaric acid, (S, S) - (+) - 2,3-p-toluyl-Dtartaric acid (1S) - (+) camphor-10-sulfonic acid (R) - () - mandelic, L-pyroglutamic acid, (S, S) -D - (-) tartaric acid (S) - (-) - L-malic acid or L- (+) -lactic acid ((S, S) - (+) - 2,3-p-toluyl -D-tartaric is preferred).

[328] The following B-21 and B-22 intermediates (table 15-8) are available in a similar way from different B-20 intermediates.

Table 15-8

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# Structure [M + H] ⁺ B-21a CO ₂ Me n ₂ ^N -O VA Cl Chiral 557 B-21b \ CO ₂ Me ^h ^ ⁿ ^ O Cl HO. fLy Chiral Π 571 B-21c CO ₂ Me ^Η * ^Ν “0- ^θ \ njy j $ o = ^H ° _c | N Chiral H 587

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# Structure [M + H] ⁺ -0 CO, Me \ _ ( ² B-21d h ₂ n- Cl HO, V> ^F N 'ΓχΛ 587 B UI _H NH = 0 Chiral B-21e h ₂ n-Í ÇCs-γ X5> ° CO ₂ Me Chiral 557 CO, Me _ / ² B-21f h ₂ n— Cl HO, V and ^F Ν 'cCb 571 jQ> ° Chiral H

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# Structure [M + H] ⁺ CO-Me _{_} _ ( ² B-22a h ₂ n Άα ^HN fXz í 541 xq Cl _H -NH ^ 0 Chiral í CO ₂ Me B-22b h ₂ n— Ύ / HN- cCa P 555 jCo = ° p 1 N t> ui r al H Eats B-22c h ₂ n- Ύα hn- ΛκΛ 571 Χ $ Λ 4 am = 0 Chiral

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Synthesis of B-23 intermediates

Experimental procedure for the synthesis of B-23a

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[329] To a suspension of B-22a (25.2 g, 39.5 mmol) in

CH ₂ C1 ₂ (2.05 ml) and water (52 ml) are added Na ₂ W0 ₄ dihydrate (0.13 g, 0.4 mmol) and H ₂ 0 _{2 solution} (30% in water, ml, 98.7 mmol) and the mixture is stirred under reflux (37 ° C) for 2 h. Then, a solution of K ₂ CO ₃ (11 g, 79.6 mmol) in water (103 ml) is added and the CH ₂ C _{1 2} is removed under reduced pressure. After adding MeOH (516 ml), the mixture is stirred at room temperature. The solid product B-23a precipitates overnight.

[330] The following B-23 intermediates (table 15-10) are available in a similar way from different B-22 intermediates.

Table 15-9

# Structure [M + H] ⁺ CO ₂ Me Ύ F Vk B-23a Chiral 537

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# Structure [M + H] ⁺ B-23b CO ₂ Me Cl _ρ Π Chiral 551 B-23C CO ₂ Me D _C i íèè Cl - ^^ N Chiral 567 B-23d CO ₂ Me Cl _F £ 5 $ ° Chiral 567

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# Structure [M + H] ⁺ B-23e _F ^N '^ 537 jOl5 = ° Chiral Ç ₂ Me ⁰¹ F ^N Ôk B-23f 551 xsi Chiral

Compounds (Ib)

General reaction scheme and summary of the synthesis path Scheme 3

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BocHN

BocHN

method A

A-1) n

A-6

NH

COOH

BOCHN

COOtBu '\ |) n

HN_O frog

R

A-3

method C

MeOH

S-1

A-2

COOH method D

O

(Ib) A-11 [331] New compounds of structure (Ib) can be prepared in stages by a synthetic route starting from protected amino acids A-1 (scheme 3). First, an acylation reaction using acrylic acid derivatives A-2 generates compounds of structure A-3 (method A). Acrylic acids that are not directly available can be obtained, for example, by a Wittig reaction (D-1, D-2, not described in scheme 3). 0 treatment of A-3 intermediates

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207/422 under acidic conditions, preferably with trifluoroacetic acid, forms derivatives of free unsaturated amino acids A-4 (method B). A decarboxylative 1,3-dipolar cicloaddition of A-4 and S-1 isatin derivatives generates A-5 cicloaducts as a mixture of diastereoisomers and builds the spiro system (method C). Diastereomers can be separated, for example, by HPLC or SFC. The racemic mixture that can be obtained can be resolved by chiral separation by SFC or at any later stage in the synthesis. All other known means for the separation of enantiomers can also be applied here or after any subsequent synthetic step described herein, for example, 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).

[332] Alternatively, the cycloadload A-5 can be prepared by a 1,3-dipolar cycloaddition of amine A-8 and S-1 isatin derivatives as a mixture of diastereoisomers (method E). Intermediates A-8 can be prepared in a pot from amines A-6 by an acylation reaction using acrylic acid derivatives A-2 and subsequent cleavage of the Boc protecting group by adding HCl (method D).

[333] Intermediates A-5 can be reacted with aldehydes or ketones in a reductive amination reaction to generate intermediates A-9 (introduction of R ¹ , method F). Alternatively, an alkylation, addition, acylation or sulfonylation reaction can be carried out with A-5 on additional intermediates of formula A-9. Submission of

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208/422 intermediates A-9 to metal-catalyzed cross-coupling reactions (eg Buchwald amidation) with substituted nitro (hetero) aryl halides A-20 generates intermediates A-11 (method G). A reductive cyclization of intermediates A-11 by treatment with iron powder in acetic acid, or alternative reducing agents generates compounds (Ib).

[334] Compounds (Ib) that are initially obtained can be derivatized in optional derivatization steps not explicitly described in the schemes in all residues, especially in R ⁴ , if they carry functional groups, which can still be modified, for example, atoms halogen, amino and hydroxy groups (including cyclic amines), carboxylic acid or ester functions, nitriles etc. in additional compounds (Ia) by well-established organic chemical transformations such as, for example, metal-catalyzed cross-coupling reactions, acylation, amidation, addition, reduction or (reductive) alkylation or cleavage of protecting groups. These additional steps are not described in the general schemes. Likewise, it is also possible to include these additional steps in the synthetic routes described in the general schemes, that is, to perform derivatization reactions with compound intermediates. In addition, it may also be possible that building blocks that house protection groups are used, that is, additional steps for deprotection are necessary.

Layout 4

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[335] Alternatively, new compounds of structure (Ib) can be prepared in stages by a synthesis route starting from intermediates A-5 (scheme 4). Intermediates A-5 are treated with acetic anhydride in formic acid to generate intermediates A-12 (method I). The submission of A-12 intermediates to metal-catalyzed cross-coupling reactions (eg Buchwald amidation) with substituted nitro (hetero) aryl halides A-20 generates A-13 intermediates (method G). A reductive cyclization of A-13 intermediates by treatment with iron powder in acetic acid, or alternative reducing agents, generates A-14 intermediates. Hydrochloric acid-mediated deformylation in MeOH generates intermediates A-15 (method J).

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Intermediates A-15 can be reacted with aldehydes or ketones in a reductive amination reaction to generate compounds (Ib) (introduction of R ¹ , methods K and L). Alternatively, an alkylation, addition, acylation or sulfonylation reaction can be carried out with A-15 for additional compounds of formula (Ib).

Layout 5

(ib) [336] Alternatively, new compounds of structure (Ib) can be prepared in stages by a synthesis route starting from diamino (hetero) aris A-16 (scheme 5). First, an acylation reaction using acrylic acid derivatives A-2 generates compounds of structure A-17 (method M).

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Acrylic acids that are not directly available can be obtained, for example, by a Wittig reaction (D-1, D-2, not described in scheme 5). Treatment of intermediates A-17 with hydrochloric acid generates condensed imidazole (eg benzimidazole) intermediates A-18 (method N). Alkylation of intermediate A-18 with bromides A-19, or alternative alkylating agents, generates intermediates A-20 (method O). The treatment of intermediates A-20 under acidic conditions, preferably with trifluoroacetic acid, forms free unsaturated amine derivatives A-21 (method P). A 1,3dipolar cicloaddition of A-21 and S-1 isatin derivatives generates A-15 cicloaducts as a mixture of diastereoisomers and builds the spiro system (method Q). Intermediates A-15, as described above, can be reacted with aldehydes or ketones in a reductive amination reaction to generate compounds (Ib) (introduction of R ¹ , methods K and L). Alternatively, an alkylation, addition, acylation or sulfonylation reaction can be carried out with A-15 on additional compounds of formula (Ib).

[337] Compounds (Ib) were tested for activity to affect the MDM2-p53 interaction in its racemic form or, alternatively, as the enantiopure form. Each of the two enantiomers in a racemic mixture can have activity against MDM2, albeit with a different binding mode. Enantiopure compounds are marked with the label Chiral. Compounds listed in any table below that are labeled Chiral (both intermediates and compounds (Ib) according to the invention) can be separated by chiral SFC chromatography of their enantiomers

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212/422 or are synthesized from enantiopure starting material which is separated by chiral SFC.

Example:

/ jCdU

H ^M _H

OH

Chiral

Chiral

ABC [338] Structure A defines the racemic mixture of compounds with structure B and C, that is, structure A encompasses two structures (compounds Be C), while structures B and C, respectively, are enantiopure and only define one compound specific. Thus, the formulas (Ib) and (Ib *)

(Ib) (Ib *) with a set of specific definitions for groups R ¹ to R ⁴ , R ⁷ , V, W, X, Y, n, req represent the racemic mixture of two enantiomers (- »(Ib); structure A above is a specific example of such a racemic mixture) or a single enantiomer (-> (Ib *); structure B above is a

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213/422 specific enantiomer), unless additional stereocenters are present in one or more of the substituents. The same definition applies to synthetic intermediates.

Synthesis of Intermediates A-2

Experimental procedure for the synthesis of A-2a

NaOH

OH

A-2a [339] 2-Chlorine-3-fluorine-pyridine-4-carbaldehyde D-la (1 g,

6.3 mmol) is dissolved in anhydrous MTBE (10 ml) under an argon atmosphere. Methyl (triphenylphosphoranilidene) acetate (2.1 g, 6.3 mmol) is added in one portion and the reaction mixture is stirred at room temperature for 1 h. Water and EtOAc are added and the phases are separated. The organic phase is dried over MgSO ₄ , filtered, and the solvent is removed under reduced pressure. The residue is purified by reverse phase column chromatography generating pure (E) -3- (2-chloro-3-fluoro-pyridin-4-yl) -acrylic acid methyl ester D-2a.

[340] D-2a (780 mg, 3.6 mmol) is dissolved in THF (3 ml) and 2 M NaOH is added (3.6 ml, 7.2 mmol). The reaction mixture is stirred at 60 ° C for 1 h before it is quenched by the addition of 2 M HCI. Extraction with EtOAc and subsequent drying of the organic phase using MgSO ₄ generates crude A-2a by removing the solvents under reduced pressure. Reverse phase column chromatography generates (E) -3222/452 acid

214/422 (2-chloro-3-fluoro-pyridin-4-yl) -acrylic A-2a pure.

[341] Additional building blocks A-2 are available in a similar way from different D-1 carbaldehydes.

Table 16

# Structure tret [min] [M + H] ⁺ Method HPLC A-2a 0 Cl 0.0 202 THE

Synthesis of intermediates A-3 (method A)

Experimental procedure for the synthesis of A-3a

[342] 3-Chloro-2-fluorine cinnamic acid A-2b (10.3 g, 50.67 mmol) is suspended in anhydrous DMF (300 ml) at 0 ° C and DIPEA (19.5 ml, 120.65 mmol) and HATU (20.39 g, 53.09 mmol) are added to the reaction mixture. The reaction mixture is stirred at 0 ° C for 30 min. A solution of (S) -4-amino-2-tert-butoxycarbonylamino-butyric acid tert-butyl ester hydrochloride (15.0 g, 48, 26 mmol) in DMF (100 ml) is added dropwise over a period of 15 min. The reaction mixture is stirred for more

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0 min and saturated aqueous NH ₄ C1 solution is added. Deionized water is added and the mixture is extracted with a 1: 1 mixture of EtOAc and cyclohexane. The layers are separated and the organic phase is washed with deionized water and dried with MgSO ₄ . The solvents are removed under reduced pressure and (S) -2-tert-butoxycarbonylamino-4 - [(E) -3- (3-chloro-2-fluoro-phenyl) acryloylamino] -butyric acid tert-butyl ester is used without further purification.

[343] The following A-3 intermediates (Table 17) are available in an analogous manner starting from different A-2 acrylic acids and A-1 protected amino acids. Table 17

# Structure tret [min] [M + H] ⁺ Method HPLC A-3a 8 ppAj-Xy ⁰ Chiral Cl 1.56 [M + H-Boc] ⁺ 357 THE A-3b B ^H N-% τ ' ^f V? Cl í 1.56 [M + H-Boc] ⁺ 357 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A-3c ² oo 0.82 443 G A-3d ιΓΥ ^ η'τ ⁰ τ γ _ρ ^H hn ^ o «y Quiral 0.82 443 G A-3e θ 0 | ^ΗΝ γθ Br yS n. The. n. The. A-3f ΐΓΥ '^ Ν'Τ ^ ο'ν ^H HN 0 Br y Quiral n. The. n. The. A-3g ΜγΑ-F ^HN y ° ⁰¹ y 1.44 466 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A-3h ΝγΛρ ^H ΗΝ _γ Ο ^Cl and Quiral 1.44 466 THE A-3i o <, ^h Go h Y Cl J n. The. n. The. A-3 j § Cl V Chiral n. The. n. The.

Synthesis of intermediates A-4 (method B)

Experimental procedure for the synthesis of A-4a

[344] (S) -2-tert-butoxycarbonylamino-4 - [(E) -3- (3-chloro-2-fluoro-phenyl) tert-butyl ester 226/452

218/422 acryloylamino] -butyric A-3a (22.4 g, 48.9 mmol) is dissolved in DCM (150 ml). TFA (35 ml) is added at 0 ° C and the reaction mixture is slowly warmed up to room temperature. The reaction mixture is heated to reflux for 24 h. Before it is concentrated in vacuo, aqueous NaOH (4 M) is added at 0 ° C until a pH of 12 is reached. The addition of aqueous HCl (2 M) results in the formation of a precipitate at pH 6-7, which is removed by filtration. The solid residue (S) -2-amino-4- [(E) -3 (3-chloro-2-fluoro-phenyl) -acryloylamino] -butyric acid hydrochloride A-4a and washed with water and acetonitrile and dried at 50 ° C under reduced pressure.

[345] The following A-4 intermediates (table 18) are available in a similar way from different A-3 intermediates.

Table 18

# Structure tret [min] [M + H] ⁺ Method HPLC A-4a 0 OH Cl Chiral 0.91 301 THE A-4b o nh ₂ oh Cl 0.91 301 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A-4c γΝ ^NH 2 Cl 0.63 287 THE A-4d ^{0H H} NH, Cl Quiral 0.63 287 THE A-4e ιί'ν ^ ΰ'τ ° ^H ΝγΑ _ρ ^H NH ₂ Cl 0.21 288 THE A-4f ^H NH, Cl Quiral 0.21 288 THE A-4g Ϊ T * Η T Cl 1.40 302 M A-4h «Γλρ H T Chiral 1.40 302 M

Synthesis of intermediate A-5 (method C)

Experimental procedure for the synthesis of A-5a and A-5c

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[346] (S) -2-Amino-4 - [(E) -3- (3-chloro-2-fluorophenyl) -acryloylamino] -butyric acid A-4a (0.34 g, 1.13 mmol), 6 chloro-li- -indole-2,3-dione S-la (2.1 g, 1.13 mmol) and crushed 4 Á activated molecular sieves are suspended in anhydrous MeOH (15 ml) in a microwave flask. The reaction vessel is sealed with Teflon caps and irradiated for 30 min at a final temperature of 100 ° C. After cooling to room temperature, the crude mixture is filtered over a block of Celite® and the solvents are removed under reduced pressure. The crude reaction mixture is purified by reverse phase HPLC that generates diastereomers A-5a and A5c.

[347] The following A-5 intermediates (Table 19) are available in a similar way from different A-4 and S-1 intermediates.

Table 19

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# Structure tret [min] [M + H] ⁺ Method HPLC A-5a H 0.49 420 G A-5b H ^α χχ ^ _c , x ^to X ^ N H Chiral 0.49 420 G A-5c H _n JoY H 0.45 420 G A-5d xXp ^c, / oy ° H 0.53 512 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A-5e H H Chiral 0.53 512 G A-5f jqqp 0.93 421 THE A-5g H ^c 'YrCi H Chiral 0.93 421 THE A-5h jn ° A J T α - ^ 'ιΖ'Ν H 0.89 421 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Τ ' n ^H 1 λγ cr A- 5i X H 0.99 406 THE Cl 0 H 0? cr A- 5 j 0.99 406 THE J I> ° cr H Chiral the H s_ j) A? cr A> F. Y ^ NH A-5k Ji 0.99 406 THE ç JL H Chiral η H 1l = \ cr ^ Jvnh A-51 0.93 421 THE Γ> = □ Cl H D ^H j j. cr . A-NH F A- 5m 0.93 421 THE X> ° cr N H Chiral

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# Structure tret [min] [M + H] ⁺ Method HPLC A- 5n H 0.50 451 G A-5th "’ Χχδ H Chiral 0.50 451 G A-5p H H 0.91 421 THE A-5q jçX) H Chiral 0.91 421 THE

Synthesis of intermediates A-8 (method D)

Experimental procedure for the synthesis of A-8a

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A-6 to [348] (F) -3 - (4-Chloro-thiophen-2-yl) -acrylic acid A-2c (554 mg, 2.94 mmol) is suspended in anhydrous DMF (5 ml) at 0 ° C and DIPEA (1.14 g, 129.3 mmol) and HATU (1.34 g, 3.52 mmol) are added to the reaction mixture. The mixture is stirred at 0 ° C for 30 min. A solution of tert-butyl ester of (2-amino-ethyl) carbamic acid A-6a (470 mg, 2.94 mmol) in DMF (1 ml) is added dropwise over a period of 15 min. The reaction mixture is stirred for another 30 min. Concentrated HCl (2.89 g, 29.37 mmol) is added and the mixture is heated to 90 ° C and stirred for 90 min. Sodium hydroxide (8 N in H ₂ O) is added until a pH of 12 is reached and the mixture is extracted with EtOAc. The layers are separated and the organic phase is washed with deionized water and dried with MgSO ₄ . The solvents are removed under reduced pressure and the crude reaction mixture is purified by reverse phase HPLC, if necessary to obtain intermediate A-8a.

[349] The following A-8 intermediates (table 20) are available in an analogous manner starting from different A-2 acrylic acids and A-6 amines.

Table 20

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# Structure tret [min] [M + H] ⁺ Method HPLC A-8a O 0.28 231 G A-8b £ ρΑ ~ ^ΝΗ 'Cl 0.29 231 G A-8c n - NH ₂ çç «Cl 0.86 243 THE A-8d O Cl 0.86 257 THE

Synthesis of additional intermediates A-5 (method E) Experimental procedure for the synthesis of A-5r and A-5t

A-8a [350] (E) -N- (2-Amino-ethyl) -3- (4-chloro-thiophen-2yl) acrylamide A-8a (0.37 g, 1.60 mmol), 6-chlorine -lT-indole2,3-dione S-la (306 mg, 1.60 mmol) and triethylamine (162 mg, 1.60 mmol) are suspended in anhydrous NMP (12 ml) in a vial

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227/422 of microwave. The reaction vessel is sealed with a Teflon cap and irradiated for 30 min at a final temperature of 110 ° C. After cooling to room temperature, the solvents are removed under reduced pressure. The product is used crude for the next step or purified by reverse phase HPLC, generating diastereomers A-5r and A-5t.

[351] The following A-5 intermediates (table 21) are available in a similar way from different intermediates S-1 and A-8.

Table 21

# Structure tret [min] [M + H] ⁺ Method HPLC A- 5r ^CI V H 0.47 394 G A-5s ^CI V cv? H Chiral 0.47 394 G A-5t Cl O H H 0.47 394 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Cl ο H, A- 5u H Chiral 0.47 394 G A - 5v ° ^ ÍJ c-OÜç H 0.39 394 THE A - 5w o ^H _ ° ^ N _C | Jsíi _N ⁰ H Chiral 0.39 394 THE A - 5x The H xr * H 0.39 394 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A- 5y H Chiral 0.39 394 THE A- 5z ^c 'xxb H 0.99 406 THE A-5aa D ^H ΓΊΐ ^r > ^Cl x & H Chiral 0.99 406 THE A-5ab H 0.80 406 K

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# Structure tret [min] [M + H] ⁺ Method HPLC A-5ac H Chiral 0.80 406 K A-5ad ríp H 0.49 420 G A-5ae H ^ci ciAAn ° Chiral 0.49 420 G A-5af N “Xx§ CI ^ Yes ^ n H 0.45 420 G

Synthesis of intermediates A-9 (method F)

Experimental procedure for the synthesis of A-9a

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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 room temperature 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 before deionized water is added. EtOAc is added and the phases are separated. After washing with water, the organic phase is dried with MgSO ₄ and the solvents are removed under reduced pressure. If necessary, the product is purified using reverse phase HPLC, resulting in purified A-9a.

[353] The following A-9 intermediates (table 22) are available in a similar way from different A-5 intermediates.

Table 22

# Structure tret [min] [M + H] ⁺ Method HPLC A-9a _C | '^' N H 0.74 476 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A-9b rX) ci '^ ^x X ^ rj H Chiral 0.74 476 G A- 9c ^a / X / H 1.29 474 THE A-9d H Γί ° Τ ^ν Ί ^c 'lÉ> A H Chiral 1.29 474 THE A-9e riX I-W-n H 0.73 566 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A-9f H | · ΐίΐ ⁰ H Chiral n. The. n. The. A-9g XO? - ^cl ll / J '/' oAX ' ^-0 > H 1.38 554 THE A-9am H Γι'Ά c, XX> ⁰ > H Chiral 1.38 554 THE A-9i rôb ci ^ n ^ n H 1.19 475 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A- 9 j H CI ^ N ^ N laughs Chiral 1.19 475 THE A-9k Jl J> ° j ci ^ n n / H 1.28 555 THE A-91 _n ° f5 ^Cl Jl X> = ° J M Chiral 1.28 555 THE A- 9m H για? ^cl w? _α ΛΛ _Β ⁰ 1.20 475 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A- 9n H _C , ^ * X ^ N H Chiral 1.20 475 THE A-9o fvVo Cl ^ x ^ -N H 1.24 460 THE A- 9p Cl ^ xs ^ N H Chiral 1.23 460 THE A- 9q O ^{H Cl} yVsY c, AX ° 0.62 434 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A- 9r O ^H A ^r > Cl ^^ N H Chiral 0.62 434 G A- 9s CI ^ X ^ -N H 1.21 504 THE A-9t π H π v> Χϊ> ° H Chiral 1.21 504 THE A- 9u XXa? fx αΛ'Ύ'ΐ kA XTÍo H 1.47 540 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A- 9v O H / x,% -N XXa? YjXÓ cRX-n Chiral 1.47 540 THE A - 9w Q_ - IZ j (W ΊΓ ^Z “V ^ZI 1.19 448 THE A- 9x ^C \ 0 ^H çuQ _α / θΡι> VI _H Chiral 1.19 448 THE A- 9y Cl O ^H 1.14 448 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A- 9z Cl η H Chiral 1.14 448 THE A- 9aa H 1.19 448 THE A - 9ab π ^{H w} H Chiral 1.19 448 THE A- 9ac O ^H n>^> Cl ^p 1.14 448 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A- 9ad Π ^H _c , joA> ^w H Chiral 1.14 448 THE A- 9ae XXa? fx ^{Cl 0 <} CI ^ IT-N M 1.25 541 THE A- 9af XXâ? fx CI ^ N ^ Sí H Chiral 1.25 541 THE

Synthesis of A-11 intermediates (method G)

Experimental procedure for the synthesis of A-lla

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240/422 [354] Intermediate A-9a (400 mg, 0.84 mmol), methyl 4-bromo-3-nitro-benzoic acid ester (A-20a, 334 mg,

0.126 mol), cesium carbonate (410 mg, 1.26 mmol), Xantphos (97.2 mg, 0.17 mmol) and palladium trifluoracetate (Pd (TFA) ₂ ; 28 mg, 0.08 mmol) are suspended in 1,4-dioxane (8 ml) in a microwave vial. The reaction is sealed and stirred at 130 ° C for 5 h. After consumption of the starting material, the reaction is diluted with acetonitrile and filtered through a plug of silica. The solvents are removed under reduced pressure, generating crude A-1la, which is purified by reverse phase column chromatography, if necessary.

[355] The following intermediates A-ll (table 23) are available in a similar way from different intermediates A-9 and A-10.

Table 23

# Structure tret [min] [M + H] ⁺ Method HPLC A-lla C ^ Xno ₂ XO) Xx *> - 1.00 655 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llb Chiral όγ> rçQ ^W H 0.93 655 D A-llc \ D XÀ-NCÇ H 0.88 653 G A-lld Chiral όγ> VÃ-NOj XO-? ^C 'X? A ^Vl H 0.90 653 D

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# Structure tret [min] [M + H] ⁺ Method HPLC A-lle Chiral V λ VjA-NO ₂ IJ / r> 0.90 653 D A-llf 'o V ^ in ₂ Λ ° 0.91 733 G A-llg Chiral ^ ^ ° Vr ^ -NOj X0-? 3c $ - ° ^ Λ » 0.91 733 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llh Chiral όγ ³ VAnOj _£ , χφ 0¾ Λ ° 0.91 733 G A-lli '°' i ι> r% r h 0.80 644 G A-llj Chiral Ò ^ ° KíAno ₂ XW ^c 'Í0 $ X H 0.80 644 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llk “JcA H 1.53 653 THE A-lll Chiral z X ^M H 1.53 653 THE A- llm Chiral IQno, jÇtò 0.95 667 D

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral \ o ° Ύ \ V> Year ₂ A- lln 0.85 683 G αΛ í IL H Chiral <0 A-llo ^F Y F ° ^f V ^ no ₂ 0.97 751 G Cl $ 5 A H Chiral <0 0 ^ ^u A- llp kA-nOj 0.97 681 D Cl Ιί / yz H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 ° l \ ZONE ₂ A- llq 0.90 667 G Cl-V cX 11 Λ * ». Η Chiral \ Ο X A- llr 0.91 681 G Cl H Chiral Xf ^z lJXno, A-lls 0.96 695 G Cl '·?' F> cr 1 | 1 Λ-τ__ _t C H

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llt Chiral ^W H 0.96 685 D A- llu Chiral X ^o F Ύ ^F χχρ / OH 0.92 721 G A- llv Λ KXno ₂ “x $ u H 0.89 693 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A- llw Chiral Λ ^w H 0.89 693 G A- llx 0 γ ^ ° ύ ^ν Λ = Ά-γΐ _cl ^F -oy /> H 0.91 695 G A- lly Chiral 0.91 695 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A- llz 0 ^ V / 0 VBnOj ^α / χχΒ Η 0.85 667 G A-llaa Chiral 0 ' 5th H 0.85 667 G A-llab cL ° ^c 'ÍoSy 0.55 640 AND

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llac Chiral O ^ ° / Mr ΓΪ 0.55 640 AND A-llad 1 Q VJ ~ -NO, X £ r? 0.89 734 F A-llae Chiral Ò ^ ° ΓΊι ° ^Ύ ^ éXv ° b- «L · 0.89 734 F

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llaf ViÀ-NOj ^Cl / «x H 0.86 668 G A-llag Chiral Ò-γθ VXnOj X £ õ 0.86 668 G A-llah Q ^no , ^c '/ a> X H 0.87 639 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A-liai Chiral ° yo ç> ' 0.88 639 G A-llaj Chiral -A ° U _cl ÁA? ° t> H 0.88 639 G A-llak 0 ^no > ^Cl H 0.89 639 F

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llal Chiral 0 X xo / ^N0 ' ^w H 0.89 639 F A-liam Chiral V ^o X “/ éSx H 0.93 677 G A-llan Vo V ^N °> ^Cl / a $ k ^Cl H 0.89 653 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llao Chiral çr ^M H 0.89 653 G A-llap X ^no > ci XVr cr ^ N 0.87 627 G A-llaq Chiral ° Vo Q ^no > ^F W 0.87 627 G

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# Structure tret [min] [M + H] ⁺ Method HPLC ^CF > A-liar % -rí ^N °> 1 ί h ' 0.92 707 G ci-V F Αν _λ X ^v ° V H Chiral O O z fy ^cF , By the way ^NO > II A ---_ 0.92 707 G Clan- Άι Cl ^ 1> H ^f A ° ' _S ° U ^N °> A-llat Π = \ 0.92 707 G Cl Λ e / j ύΑ H

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llau Chiral ^{,, c} A ° '% -N ^ «O, ^c ' / oÀ ^w H 0.92 707 G A-llav Chiral Vo ^FjCO / A ^x ^ o _r Ç _N o ₂ ^c, / éÃ> ^w H 0.96 737 G A-llaw ° ZO q ^ VnÇ no, jur ^Cl H 0.89 683 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llax Chiral Grandfather Q Wu 0.89 683 G A-llay Grandfather c, 9 ' V ‘V.N <Ql,> H 0.87 627 G A-llaz Chiral c, 5 ' ^c v vÇ ^{NOí M} H 0.87 627 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llba Vo Q ° ^ N ^N0 > _c , 3a> H 0.88 627 G A-llbb Chiral ° N-0 Q ° _V N ^N ° ₂ ^{c, _} ^ X _s Ãy ⁱ _c , J3a> ^U H 0.88 627 G A-llbc n-S '° ^c ' / a5u ^Cl H 0.80 673 G

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llbd Chiral k-0 ⁰ K jOOÓ ^M H 0.81 673 G A-llbe ° ₂ n VIA-NO; = / 0¾ _C l> x ^ NP H 1.50 640 THE A-llbf Chiral o ₂ n C ^ NO, jQÇp 1.50 640 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A-llbg Chiral ^ci / éK H 0.91 667 AND A-llbh Chiral 0.93 667 AND A-llbi Chiral ° / qk 0.92 667 AND

Synthesis of compounds (Ib) according to the invention

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261/422 (method Η)

Experimental procedure for the synthesis of Ib-1

Cl

Cl

Fe, AcOH

A-11a

Ç.

oCl

N

H lb-1 [356] A1-1 (533 mg, 0.8 mmol) is dissolved in acetic acid (10 ml) and iron powder (469 mg, 8.4 mmol) is added. The suspension is heated to 130 ° C overnight. After adding EtOAc and saturated aqueous Na ₂ CO _{3 solution} , the phases are separated and the organic phase is dried by adding MgSO ₄ . The removal of the solvents generates crude Ib-1, which is of sufficient purity for subsequent derivatization or purified by reverse phase column chromatography.

[357] The following compounds (Ib) according to the invention (table 24) are available in a similar way from different intermediates A-11.

Table 24

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-1 o- · « ^ci jo $ r H 0.86 607 G Ib-2 Chiral _ 0— 7a ^W H 0.92 607 B Ib-3 O- THE "Joyu H 1.52 605 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral o- ^0- h Ib-4 ^C, / SX> ^w H 1.52 605 THE Chiral Ib-5 ^F ií ^ r < ^N > f T f = o K. 1.52 605 THE Ib-6 ^Cl 0.54 685 D

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 \ 0 \ Ib-7 Clan- 0.1 ^ N H s 0 O 0.54 685 D Chiral Ç O- \ Ib-8 cX F> cr Xck xp H 0 X 0.54 685 D \ 0 X Ib-9 ^> ^N V ^N ' Λ 0.74 596 G cr SK H

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-10 Chiral ú Cl / λ i H 0.74 596 G Ib-11 0. ^z ° ^C, / 0 $ X H 0.81 605 G Ib-12 Chiral i ° 'UI _H 0.81 605 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral THE Ib-13 0.97 619 D Cl A · ” cX Ax H Chiral 0 ' O- § Ib-14 0.73 635 G Cl-V / X H Chiral ç ζ F ίσ Ib-15 0.97 703 G Clan Jjí H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 = $ 5 Ib-16 & 0.87 633 G Cl '?' THE H Chiral 0 = H Ib-17 rd ^ν ύν 0.85 619 G F X Cl ^ Ύ VoV H Chiral 0 X Ib-18 | <X 0.83 633 G here F Cl i L Λ A 'γ ^Ν >ύ> oV H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 Q Ib-19 n 0.89 647 G Clan Mr H Chiral 0 = <7 O Ib-20 r \. ί ^ν ^ Ί 0.96 685 D cr 7 Mr H Chiral p'L ^F 0 = \H Q Ib-21 LOL 0.92 673 G cr V 7 Mr H

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-22 rfü ^CI / O $ X H 0.81 645 G Ib-23 Chiral 0 xó / ^C '/ S> x H 0.81 645 G Ib-24 0 The X $? ^C '/ S> x H 0.80 647 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-25 Chiral B H 0.80 647 G Ib-26 0 To O BB H 0.73 619 G Ib-27 Chiral 0 Ao O XCÇ ¹ “BB H 0.73 619 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-28 ( 0 1} ci ^ n ^ n Π n. The. n. The. n. The. Ib-29 Chiral V n ^N ü, Cl ίΠ> θ ciAj n n. The. n. The. n. The. Ib-30 r ^ ^N ^ ^N h = Λ% υ> ^f jO> ° ci ^ n ^ n Π n. The. n. The. n. The.

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-31 Chiral 4 » CI ^ N ^ N n. The. n. The. n. The. Ib-32 0- V X0 ~ / ^c 'jSb> 0.84 620 G Ib-33 Chiral 4 jçÇÇ / GB 0.84 620 G

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# Structure tret [min] [M + H] ⁺ Method HPLC O Ib-34 XX X H 0.84 591 G Chiral O Ib-35 ^w H 0.84 591 G Chiral t ° ~ ° Ib-36 l Jl> = ^the n dX ^ NP * 0.84 591 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-37 and'· H 0.89 591 AND Ib-38 Chiral .7 ' ^C, / SA ^w H 0.89 591 AND Ib-39 Chiral o ^ ⁰ - ⁷ V ΧΦ 0.90 619 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-40 í UI _H 0.87 605 G Ib-41 Chiral 0 ^ ° - H 0.87 605 G Ib-42 ^Cl w CK ^ N 0.83 579 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-43 Chiral X 0.83 579 G Ib-44 o ^ ^u - F k ^f Vq jClí? 7, XT&Y CI - ^^ N 0.92 659 G Ib-45 Chiral 0 ^ ° 'FT ^f Vq ΧΦ ^c ' / o $ x 0.92 659 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-46 ° x ° If s UI _H 0.90 659 G Ib-47 Chiral O ^ z ° F f- Ç ^c 'x $ u ^W H 0.90 659 G Ib-48 Chiral fí ° ^CFJ fVO ^c ,; o $ ú> ^w H 0.97 689 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-49 ° Ύ ° O 1.60 671 THE Ib-50 Chiral ° Ύ ° Πι Ά ^C 'UXVa < _C , ÀA ° <Ηχ 1.60 671 THE Ib-51 CW ° - π A xua H 0.87 637 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 <v ° G Ib-52 saw 0.87 637 G THE % $ °%> H O Ib-53 Cl ^N Çí Σ 0.84 579 G c-y-N> H Chiral 0 ~ ° - Ib-54 Cl ^no xJ? 0.84 579 G s cX Ax> H

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# Structure tret [min] [M + H] ⁺ Method HPLC 0 Ib-55 H 0.85 579 G Chiral ° Y ° O Ib-56 0.85 579 G ° B Ib-57 ci- ^ A-n l> 1.40 625 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral / 0 > ° d- Ib-61 r \,> ^N v Λ 0.90 619 AND ci- ^ x | [x ^ z X / X H Chiral / ° x ° -d Ib-62 0.93 619 AND Clan Sx H Chiral O Q Ib-63 ^ν ύ ^ν λ 0.92 619 AND Ç 1 II K ^ .Z ¹ Ϊ0> ^Ν Υ _CI A> _Ü > H

Synthesis of A-12 intermediates (method I)

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Experimental procedure for the synthesis of A-12a

A-5a A-12a [358] Intermediate A-5a (2.0 g, 4.8 mmol) is dissolved in formic acid (10 ml) and acetic anhydride is added (3.5 ml, 38.1 mmol). The reaction mixture is stirred at 50 ° C for 16 h and subsequently quenched by the addition of water. Purification by reverse phase column chromatography generates intermediate A-12a.

[359] The following A-12 intermediates (Table 25) are available in a similar way from different A-5 intermediates.

Table 25

# Structure tret [min] [M + H] ⁺ Method HPLC H PA ^N> ) A-12a ^Cl yvX ° cAX ⁰ 0.99 448 THE A-12b Chiral Xí * 7,, 0 C | GA ⁰ 0.99 448 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC The ^H A-12c c | L7-N ° H 0.49 434 G A-12d Chiral O ^H JpT> 0 0.49 434 G

Synthesis of intermediates A-13 (method G)

Synthesis of A-13a

A-13a [360] 0 Intermediate A-13 can be synthesized from intermediate A-12 in analogy with the synthesis of intermediate A-ll from intermediate A-9 (method G, see above).

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Table 26

# Structure tret [min] [M + H] ⁺ Method of HPLC A-13a ci '/' / '! í Ϊ Vo ° 0.70 627 G Chiral X A-13b (y _NOí ^Cl υΧ \ ^Ν Λι ΓΣ.Υ ° ^Ο 0.70 627 G A-13c X ° _V Ã ⁿ ° ₂ Cl yw 0.70 613 G

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# Structure tret [min] [M + H] ⁺ Method of HPLC Chiral Q A-13d ^N ° 2 1 0.70 613 G cr cX H

Synthesis of intermediate A-14 (method H)

Synthesis of A-14a

A-13a A-14a [361] 0 Intermediate A-14 can be synthesized from intermediate A-13 in analogy with the synthesis of compounds (Ib) according to the invention from intermediate A-11 (method H, look above).

Table 27

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# Structure tret [min] [M + H] ⁺ Method HPLC 0- The ^z io A-14a r \. 1 ^N X Λ 0.65 579 G CI-X- | 1> -t-_ _t C 3 7 = 0 H Chiral O- 0 A-14b m 0.65 579 G Clan F / - cr ' 1L x ^ OV ⁰ X> 0 H 0 ~ ° - O A-14c hz X ...... z / = 0.66 565 G Clan Eh 3vn% ° Ύ? -O ν ^ -Ν H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral ^Ο Ύ ° O A-14d saw 0.66 565 G Cl x Λ Kl 0 F i ** · ¹ X | > 0 cr ’ N H

Synthesis of A-15 intermediates (method J)

Experimental procedure for the synthesis of A-15a

A-14 to A-15a [362] A-14a (840 mg, 1.45 mmol) is dissolved in MeOH (2 ml) and concentrated HCl (37%, 500 μΐ) is added. The reaction mixture is heated to 100 ° C for 30 min. The reaction is quenched by the addition of saturated aqueous NaHCO ₃ and subsequently extracted with EtOAc. The phases are separated and the organic phase is dried with MgSO ₄ . The solvents are removed under reduced pressure. Reverse phase column chromatography generates pure A-15a.

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289/422 [363] The following compounds A-15 (table 28) are available in a similar way from different compounds A-14.

Table 28

# Structure tret [min] [M + H] ⁺ Method HPLC A-15a o- • r Λ ^Cl _c , ÀAn ⁰ 0.67 551 G A-15b Chiral • r rW ^c, ax? ^nh ° 0.67 551 G A-15c ^M H 0.68 537 G

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Procedure ^ ^h Gh “

H ₂ N 1 A-16a

[364] 3-Chloro-2-fluoro-cinnamic acid A-2b (3.0 g, 14.81 mmol) is suspended in anhydrous DMF (25 ml) at 0 ° C and DIPEA (3.6 ml, 22, 21 mmol) and HATU (5.6 g, 14.73 mmol) are added to the reaction mixture. The reaction mixture is stirred at 0 ° C for 30 min. A solution of 3,4-diaminobenzoic acid methyl ester A-16a (2.95 g, 17.77 mmol) in DMF (5 ml) is added dropwise over a period of 15 min. The reaction mixture is stirred for an additional 3 h and an aqueous solution of K ₂ CO ₃ (8 ml, 2 N) is added. Deionized water is added and the mixture is extracted with DCM. The layers are

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291/422 separated and the organic phase is washed with deionized water and dried with MgSO ₄ . The solvents are removed under reduced pressure and the mixture is used without further purification or is purified by reverse phase column chromatography to generate A-17a.

[365] The following A-17 intermediates (Table 29) are available in a similar way from different A-2 and A-16 intermediates.

Table 29

# Structure tret [min] [M + H] ⁺ Method HPLC A-17a ^Cl “Λ A / = \ An / oh 1, 16 349 THE

Synthesis of intermediate A-18 (method N)

Experimental procedure for the synthesis of A-18a

HCI

[366] Intermediate A-17a (839 mg, 2.4 mmol) is dissolved in dioxane (5 ml) and concentrated HCI (1.76 g) and MeOH (24 ml) are added. The resulting mixture is stirred for 15 h at 7CPC. The mixture is diluted with EtOAc and aqueous NaOH (4 N) is added until a pH of 10 is reached. Concentrated HCI is added and the resulting solid is collected by filtration. Intermediate A-18a is used without further purification for the following steps.

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292/422 [367] The following A-18 intermediaries (table 30) are available in a similar way from different A-17 intermediaries.

Table 30

# Structure tret [min] [M + H] ⁺ Method HPLC A-18a llY ^ N / 1.22 331 THE Cl

Synthesis of intermediate A-20 (method 0)

Experimental procedure for the synthesis of A-20a and A20b

[368] Intermediate A-18a (100 mg, 0.30 mmol) is dissolved in NMP (3 ml) and NaH (38 mg, 1.51 mmol) is added at room temperature. The resulting mixture is

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293/422 stirred for 5 min and A-19a is added. The reaction mixture is stirred at 70 ° C for 15 h. Deionized water is added and the mixture is extracted with EtOAc. The layers are separated and the organic phase is washed with deionized water and dried with MgSO ₄ . The solvents are removed under reduced pressure and the mixture is purified by reverse phase column chromatography to generate A-20a and A-20b.

[369] The following A-20 intermediates (table 31) are available in a similar way from different A-18 and / or A-19 intermediates.

Table 31

# Structure tret [min] [M + H] ⁺ Method HPLC A-20a Cl 1.38 474 THE A-20b JV ° N θ Cl 1.38 474 THE

Synthesis of intermediate A-21 (method P)

Experimental procedure for the synthesis of A-21a

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A-20a

TFA

[370] Intermediate A-20a (50 mg, 0.05 mmol) is dissolved in DCM (1 ml). TFA (40 μΐ) is added at 0 ° C and the reaction mixture is slowly warmed up to room temperature. The reaction mixture is heated to reflux for 24 h and concentrated in vacuo. The residue is dissolved in EtOAc and water and aqueous NaOH (4 M) is added until a pH of 12 is reached. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are dried with MgSO ₄ . The solvents are removed under reduced pressure and the mixture is purified by reverse phase column chromatography to generate A-21a.

[371] The following A-21 intermediates (Table 32) are available in a similar way from different A-20 intermediates.

Table 32

# Structure tret [min] [M + H] ⁺ Method HPLC A-21a h ₂ n [Γ2ΐΓ ^^ ^{Ν z} Cl 1.14 374 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A-21b N Ãb n-v Cl 1.14 374 THE

Synthesis of additional intermediates A-15 (method Q)

Experimental procedure for the synthesis of A-15c (alternative synthesis, see also method J)

A-15c [372] Intermediate A-21a (20 mg, 0.027 mmol), 6-chlorolith-indole-2,3-dione S-la (5 mg, 0.027 mmol) and triethylamine (17 μΐ, 0.13 mmol) are suspended in anhydrous NMP (500 μΐ) in a microwave flask. The reaction vessel is sealed with a Teflon cap and irradiated for 45 min at a final temperature of 100 ° C. After cooling to room temperature, the solvents are removed under reduced pressure. The product is purified by reverse phase HPLC, generating intermediate A-15c.

[373] The following A-15 intermediaries (table 33)

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296/422 are available in a similar way from different intermediates A-21 and / or S-1.

Table 33

# Structure tret [min] [M + H] ⁺ Method HPLC A-15C H 1.26 537 THE Chiral όγ 0 A-15d ÍL f ^Cl 1.26 537 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC A-15e A Λ ^c 'xí $ ° H 1.26 537 THE A-15f Chiral H 1.26 537 THE

additional according to

Synthesis of compounds (Ib) invention (method K)

A-15a lb-64

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298/422 [374] A-15a (0.030 g, 0.054 mmol) and 3-methylbutyraldehyde (0.14 mg, 0.163 mmol) are dissolved in acetic acid (1 ml) and sodium triacetoxyborohydride (0.06 g, 0.272 mmol) ) is added. The reaction mixture is stirred at room temperature for 1 h before it is quenched by the careful addition of saturated aqueous NaHC0 ₃ solution at 0 ° C. Deionized water and EtOAc are added and the phases are separated. After washing with saturated aqueous NaHCO ₃ and water, the organic phase is dried with MgSO ₄ and the solvent is removed under reduced pressure. Reverse phase column chromatography generates pure Ib-64.

[375] The following compounds (Ib) (table 34) are available in a similar way from different A-15 intermediates.

Table 34

# Structure tret [min] [M + H] ⁺ Method HPLC Ib-64 O- Έ 0.90 621 G ^CI / 8A H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral O- 0 Ib-65 0.90 621 G Clan- X li 'YCN-v \ H O- 0 = Ib-66 ⁿ v ⁿ > 1.55 619 THE Cl A F / CK 11 H Chiral O- 0 H Ib-67 ΓΎ% ^N v X 1.55 619 THE Cl A F cr ^ AA H

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# Structure tret [min] [M + H] ⁺ Method HPLC 0 1/ Ib-68 X laugh. Grandma 0.78 579 G cr> II H Chiral 0- CF Ib-69 r \. Xv Λ 0.78 579 G Cl ^> F cr ji λ / ^ Τ ^ι, \ \ H 0- Ib-70 ^ν ύ ^ν ί 0.83 593 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral \ 0 0 Ib-71 r \, 0.83 593 G Clan F : and·' H O- 0 Ib-72 frog. 0.87 607 G Cl '? ·' Ύ5 ^ An H Chiral O- 0 ' Ib-73 fA 0.87 607 G Clan cX JL k / A-n H

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-74 O- ü 0.90 621 G Ib-75 Chiral ° í / ^F nV ^ H 0.90 621 G Ib-76 7) XXp 0.88 619 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral CX 0 = B Ib-77 fbb 0.88 619 G Cl-V F X Cl ^ 1L x. H 7 \ 0 0 Ib-78 , <G ^Ni r Ί n. The. n. The. n. The. ci- \ THE H -O \ Chiral cx 0 B Ib-79 X. χχ II n. The. n. The. n. The. Clan H ^ 0

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# Structure tret [min] [M + H] ⁺ Method HPLC 0 0 B Ib-80 0.81 637 G ClB H -O Λ Chiral Cl · \ 0 B Ib-81 > ^ν ύ ^ν Λ 0.81 637 G Cl ^ F cr ^ II ΒΜλ > = o ' H -O Λ 0- Ib-82 Cl-V F x Cl ^ ^Ν Ύ ^Ν η A / v \ ⁿ b H '0 À ~ 0.88 651 G

313/452

305/422

# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 ^ 0 ^ B Ib-83 ΤΑίλ α-'Α ^ '- Ν Η -O Λ ~ 0.88 651 G 0 Ib-84 CI- ^ Z F - cr ll L / > 0 H CF? - 0 0.67 671 G Chiral O- O- Ib-85 cAV / X THE ) GO > ~ N H Cps- 0 0.67 671 G

314/452

306/422

# Structure tret [min] [M + H] ⁺ Method HPLC 0 ic Ib-86 ) < fl 1.) 0.93 633 G cr χ F s X cr X ° b H Chiral \ 0 O ^: Ib-87 χ- m _v ⁿ ^ 0.93 633 G C | -> X H O- 0 = ic Ib-88 X x _M 0.95 647 G Cl '?' ex Xb

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307/422

# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 O- Q Ib-89 n jCÍ? 0.95 647 G Cl 0 0- íp Ib-90 r \. 0.81 647 G Cl-V F í Cl · '’’ ’ K / V ff í> 0 ^h H Chiral 0 O- Q Ib-91 ⁿ v ⁿ ^ 0.81 647 G Cl H

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-92 · /, C, AAn ⁰ 0.88 685 D Ib-93 Chiral L ^{C1 F n} ciAAfi 0.88 685 D Ib-94 d ΧΥ ^Ύ Ί ^ei 7Fd'rO ° α'-νΖ-'Ν H 0.87 685 G

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral O- 0 = H Ib-95 -X Cl? ' cX yi IL X ^Vo H 0 3 0.87 685 G ° Ύ ° O Ib-96 n'7 \ VN il> 1.11 671 K Cl Λ / J II Sv °> H \ = Λ \ 0 Chiral 0 ^ ° O Ib-97 > M Π 7 \ l 1.11 671 K Cl ^ z F cr IL ^ Α ^ν λ I voV (f H \ = y \ 0

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# Structure tret [min] [M + H] ⁺ Method HPLC 0 o- O Ib-98 1.13 671 K Clan OJ ^ 0 1 Chiral O Ib-99 b-N 1.13 671 K Clan F Cl ’ H

Synthesis of additional compounds (Ib) according to the invention (method L)

O-

A-15 to

HO

O-

1. AcOH, IBX

lb-100 [376] (3,3-difluorcyclobutyl) methanol (100 mg, 0.819

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311/422 mmol) is dissolved in acetic acid (500 μΐ) and IBX (298 mg, 1.065 mmol) is added. The reaction mixture is stirred at 40 ° C for 3 h before being filtered through a plug of Celite®. To the filtrate, a solution of A-15a (30 mg, 0.054 mmol) in acetic acid (500 μΐ) is added at room temperature. Sodium triacetoxyborohydride (58 mg, 0.272 mmol) is added in one portion to the reaction mixture and the reaction is stirred at room temperature for 30 min before being quenched by the careful addition of saturated aqueous NaHC0 ₃ solution at 0 ° C. Deionized water and EtOAc are added and the phases are separated. After washing with saturated aqueous NaHCO ₃ and water, the organic phase is dried with MgSO ₄ and the solvent is removed under reduced pressure. Reverse phase column chromatography generates pure Ib-100.

[377] The following compounds (Ib) (table 35) are available in an analogous manner starting from different A-15 intermediates and / or different alcohols.

Table 35

# Structure tret [min] [M + H] ⁺ Method HPLC 0 0 = Ib-100 OH, 0.82 655 G Clan- THE F

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-101 Chiral o- ^C, / Sr H 'F F 0.82 655 G Ib-102 0 ' PrVo cXn H 0.78 656 G Ib-103 Chiral o- X xy ^F n> ° _C P ^ N H 0.78 656 G

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# Structure tret [min] [M + H] ⁺ Method HPLC O- 0 ' B Ib-104 0.96 621 D Cl-V F Ji ci - > 0 íA-N H Chiral O- 0 Ib-105 0.96 621 D Cl- '?' F _r cr Νϊα  X H

Synthesis of additional compounds (Ib) by ester saponification

Experimental procedure for the synthesis of Ib-106

0 ^ OH

lb-3 lb-106

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314/422 [378] Ib-3 (484 mg, 0.8 mmol) is dissolved in MeOH (10 ml) and aqueous NaOH solution (2 ml, 4 M) is added. The reaction mixture is heated to reflux for 1 h. After acidification with 2 M aqueous HCl and extraction with EtOAc, the organic phase is dried with MgSO ₄ . Purification with reverse phase HPLC leads to pure Ib-106.

[379] The following compounds (Ib) (Table 36) are available in an analogous manner starting from compounds initially obtained (Ib).

Table 36

# Structure tret [min] [M + H] ⁺ Method HPLC Ib-106 OH '0 Cl _H 1.21 591 THE Ib-107 Chiral OH · « ^C / OF> H 1.03 591 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral OH CP H Ib-108 1.03 591 THE F x Cl ^ ' 11 / T ã ° \ H OH 0 ¾ Ib-109 ΓΆ. x ^N v Λ 1.12 593 THE Clan / 3 H Chiral OH 0 ^: H Ib-110 1.08 593 THE cr X ex H

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# Structure tret [min] [M + H] ⁺ Method HPLC OH 0 Ib-111 ^ ⁿ v ⁿ 1.01 565 THE II H Chiral OH 0 Ib-112 . ^N v ^N Λ 1.01 565 THE Cl A H OH 0 ' B Ib-113 Η, il 1.09 579 THE Cl-V F α-'Χ Xvn X 3n H lV 3-

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral OH 0 Ib-114 1.09 579 THE Clan F cr JL To H OH 0 Ib-115 Cl Τ 'F Jf cK jlJM ÍXa / [> 0-s Ά ^ ν H 1.11 593 THE Chiral OH 0 = * Ib-116 AA ^N A 1.11 593 THE ^Cl / RRfji ^F rj vVy ciAAn ⁰

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# Structure tret [min] [M + H] ⁺ Method HPLC OH 0 ^: Ib-117 X 'Λ') 1.14 607 THE Cl-V X5 = cX X ^ N H Chiral OH 0 Ib-118 X > ^N vb 1.14 607 THE Cl ^ x / 7 ll vJ 'X ^ N H OH 0 = B Ib-119 X- F X Cl ^ ί ^ν Υ ^ν Ί Η ί / X ^k N \ H 1.13 607 THE

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# Structure tret [min] [Μ + Η] ⁺ Method HPLC Chiral OH 0 1b Ib-120 1.13 607 THE C | A> Ιί Ky Xy λ Η ΟΗ Ο Ib-121 JüCO 1.10 605 THE \ H Chiral ΟΗ 0 H Ib-122 Y 'y _t y 1.10 605 THE Η

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-123 OH AVy f Λ ΟΙ'-Ο'-Ν ° O H 1.11 605 THE Ib-124 Chiral OH '/! ^F ~ \ Cl-X ^ N ° U 1.11 605 THE Ib-125 OH Ά ^c, / éSp H 7 ^ F F 1.06 641 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral OH 0 = y Ib-126 fA 1.06 641 THE Cl-V F χ here An Q H T ^ F F OH 0 B Ib-127 THE ..... <? Ί z 0.95 595 THE cr x ' / í 2> oA H Chiral OH 0 ’ H Ib-128 0.95 595 THE Clan cX a \ ⁿ a J> ° ^v o An \ H

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# Structure tret [min] [M + H] ⁺ Method HPLC 0 Ib Ib-129 Ϊλ? 1.05 623 THE Clan X H ^ 0 Λ- Chiral OH 0 = H Ib-130 rb ⁷ '' 1.05 623 THE ci A cX Αχ H -O Λ ' OH 0 = ¹ B Ib-131 £ Ι'ζ'λΓν ^f jXt5 = x ~ 0 λ- 1.09 637 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral OH 0 = s Ib-132 1.09 637 THE 01-¼ 7 ^ X ^N 0 \ .rN H -O A ~ OH 0 = B Ib-133 01¼ cX ⁿ v ⁿ > II x \ -Ν _Λ rN H 0-'§- 0 0.86 657 THE Chiral OH Ç Ib-134 γΎ ^Ν Χ 0.86 657 THE here F, cr II ^? V ^N ^ i 7 = 0 H O'§ ^_ 0

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# Structure tret [min] [M + H] ⁺ Method HPLC OH 0 X Ib-135 1.14 619 THE P Xp H Chiral 0 ^: X Ib-136 Shah 1.14 619 THE ciAr F x cr jí / ν ' TO H OH O- Ib-137 iXX 1.19 633 THE F χ Cl ^ h O

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral OH O Ib-138 HOLLOW 1.19 633 THE Mb OH 0 Ib-139 Cl A c, Z ? - '' AA vPn H 1.09 671 THE Chiral OH The ³ B / Ib-140 here F χ Cl ^ yx X n _v n ^ 0> 0 H 1.09 671 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-141 Chiral OH c-A ^ n 1.09 671 THE Ib-142 OH 'to, C | Vn ° 1.08 671 THE Ib-143 Chiral OH 'to, CI- ^ b ^ N H 1.08 671 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC OH 0 Ib-144 1 Λγ 0 1.12 671 THE CI ^A > X H í 5 Chiral OH 0 ' Ib-145 0 1.12 671 THE CI ^Z V cX X ^Vo H < ? OH Q Ib-146 frog AA 1.09 633 THE Cl ^ FF <X'v ^N • O> ^F H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral P ^H ° b Ib-147 ^W H 1.09 633 THE ONE ° b Ib-148 ClX ^ N 1.03 642 THE Chiral OH ° b Ib-149 XX _X ^N L0x ° _ci AAn 1.03 642 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC OH 0 Ib-150 1.15 607 THE ci ·? · '· F x cK ^ XbA ? = o • ^ N H Chiral OH 0 B Ib-151 Λ 1.15 607 THE Cl ^> 4 BB H OH 0 = íp Ib-152 Νγ B 0.97 582 THE C | Ak bb H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral UH 0 = Ib-153 jlO 0.97 582 THE Cl A- d Air H 0 VOH d Ib-154 ..... <? Ί z 1.03 591 THE F x CK JL OV ⁿ a X ^Vo t> H Chiral o _x VOH y Ib-155 - Ν _ν Νη 1.05 591 THE αΊ · F cr ll r / 0 H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral „OH ÇH Ib-156 ί ^ν Β 0.97 591 THE cB Ç X xB H Chiral ç OH Q Ib-157 J \ xBB 1.09 621 THE Cl t? LL / -f ' [> H Chiral O ^: OH f _F <o4 ^F B ^F Ib-158 AB 1.16 675 THE CI ^ X F / Cl '^ H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 OH 9 Ib-159 1.08 605 THE Cl F x cr ii? A H Chiral 0- OH B Ib-160 THE 1.05 605 THE Clan- XV H Chiral 0 OH x / THE Ib-161 V 1.08 619 THE Cl X v> H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral / ^0H \ _ 0 ^: Ib-162 1.14 633 THE Cl A- H Chiral The ⁷ OH THE/ O Ib-163 X 1.05 609 THE cr V r H Chiral 0 ^: OHF Ib-164 X ji ^N T / 1.12 659 THE Clan F x C | - Wn-, A ^Vo t> H

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-165 0 no H 1.11 631 THE Ib-166 Chiral 0 bUlVA ciAA / y ΎχΧθ \> H 1.11 631 THE Ib-167 0 \ ΛθΗ THE niU 3 ζχχΧ H 1.11 633 THE

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# Structure tret [min] [Μ + Η] ⁺ Method HPLC Ib-168 Chiral 0 / OH X ‘Ίδχ Η 1.11 633 THE Ib-169 0 Λοη ο ° '/ oSb Η 1.05 605 THE Ib-170 Chiral 0 Λοη Υλ ; S? B Η 1.05 605 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-171 OH '« CK N 'N 1.02 592 THE Ib-172 Chiral OH · « ^{c | f} jTx5 = o cr% · n H 1.02 592 THE Ib-173 OH 'W RI ^ci''n;:' H n 1.08 672 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral OH 0 = 1b / Ib-174 .n ^ n QJ o X> ° N N 1.08 672 THE ο _ύ ^οη O Ib-175 . O ll i> 1.08 577 THE ci7 ; í H Chiral ο _ύ ^οη O Ib-176 ^C 'Ci-AX-N °> 1.01 577 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral ο _ύ ^οη Ib-177 Hi 1.01 577 THE ci -Τ '· F / cr I t 1 N H > 0 d OH Ib-178 cX N ΐ Vn X H > 0.99 577 THE Chiral 0 V ΌΗ Ib-179 ci - '' 'χ X 5 N ~ T Vn r> Λ ^ν λ H > 0.99 577 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral Ib-180 X ^N U 0.99 577 THE F x THE 5> X> H ο _ύ ^οη O \ Ib-181 Clan X ⁿ 3 <? Μ Q and H 1.13 657 THE Chiral ο _ύ ^οη O \ Ib-182 Clan X NX ⁰ A Ύ> = 0 H 1.13 657 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC oA ^H 0 Ib-183 Clan ex THE Jo 1.05 657 THE Chiral ο _ύ ^οη 0 Ib-184 THE T-N 1.05 657 THE ΟΙ '-' Ζ X 11 H \ = / \ 0 Chiral oA ^H 0 Ib-185 f x r 1.05 657 THE Clan F cr 0b _Jo

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# Structure tret [min] [M + H] ⁺ Method HPLC 0 ^ OH THE SEE ' ΙΨ kl VN Ib-186 | l T > 1.08 657 THE O- F x THE ι '°' Χ ^ν Λ / = cr ^{= 0} B ) H Chiral , UH Ib-187 N 1.08 657 THE VN ^ ClB ⁿ a / = O- t 'X B Cl ^ 0 J H Chiral o ^ ^OH P Ib-188 NB VN Ξ \ = x * ¹ 1.05 591 THE cr F ⁷ [VoV cr A C H >

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# Structure tret [min] [M + H] ⁺ Method HPLC n ^OH □ <z X) Ν 1 Vn Ib-189 il Ξ> 1.01 591 THE JL Cl x p X \ F s % | | > 0k ci ^{A k} N C> H Chiral o ^ ^OH V Ib-190 Vn 7? 1.02 591 THE t Ζ ^ γ Cl z bys H I ^ ° \ α ^{Λ a} n l> H o ^ ^OH k Ib-191 Ν Ϊ Vn => 0.99 565 THE Cl 7 1¾ ^F jf δ Cl ^ ^l n H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 ^ ° H X Ib-192 N> Vn I> 0.99 565 THE Cl A- X xb THE H F ο _ύ ^οη F 1 V Ib-193 bx -Z ^ ‘ ii ii i 1.03 645 THE ci A X X H Chiral F ο _ύ ^οη xp Ib-194 b ^ 1 II 1.03 645 THE Cl A F Cl ^ 'P- -THE N H

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# Structure tret [min] [M + H] ⁺ Method HPLC o ~ ° ^h f k / ^F The ^F Ib-195 X x ..... 1.08 645 THE JL Cl X Xx ^F X H W \ cX ^K X ^k N L> H Chiral O ^ F D ^F Ib-196 ⁿ CT 1.08 645 THE G X VN i> Cl X ΑΧ F ^ x í I Νθ \ CI ^A X ^k n L> H Chiral 0 _Ύ ^0Η L OCR 0 Ib-197 1l J0. 1.10 661 THE Cl ΪΧχ F | I CX X ^ N l> H

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# Structure tret [min] [M + H] ⁺ Method HPLC ο _ύ ^οη O Ib-198 n 'Jf 1.06 621 THE THE H Chiral 0 ° ^H O Ib-199 THE \ ⁿ Oj | 1 = 1.06 621 THE Br THE shah [> H 0 _Ύ ^ΟΗ O Ib-200 Cl ^N -XN Λ A 1.01 565 THE s Cl ^ THE H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral ü ° H O Cl N> Ib-201 VN IO 1.01 565 THE s Y \ \ j cX H O ~ ^OH O Ib-202 Cl jr II II 1.03 565 THE '1 s -YVn [Vo Y Cl ' H Chiral ο _ύ ^οη O Ib-203 ⁿ X 1.03 565 THE Cl YY X H T> ok Cl ' L> H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral HO THE Ib-204 n 1.01 605 THE X IL v? xV H Chiral HO 9th -9 Ib-205 Vi χ ^ν ύ X 1.02 605 THE CI- ^ Z X IL V ' XV H Chiral HO > ° θ ' Ib-206 3 ^Ν Υ ^Ν Λ 1.01 605 THE Cl? X Ιί w XV H

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# Structure tret [min] [M + H] ⁺ Method HPLC 0 ^: % Ib-207 there is 1.03 606 THE Cl 7 -ΟΥ 7 A ^Vo H Chiral Cr OH 7 7 Ib-208 /THE 1.03 606 THE Cl 7 THE Vnv T 7 = ° An H

Synthesis of additional (Ib) compounds by amidation Experimental procedure for the synthesis of Ib-209

357/452

349/422 [380] Ib-107 (52 mg, 0.09 mmol) is dissolved in anhydrous DMF (1 ml) and HATU (40 mg, 0.11 mmol) is added at room temperature. After adding DIPEA (44.7 μΐ, 0.26 mmol) the reaction mixture is stirred at room temperature for 15 min. Methyl amine (2 M in THF, 52.6 μΐ, 0.11 mmol) is added and the reaction is stirred for another 30 min. The crude reaction mixture is subjected to reverse phase column chromatography generating pure Ib-209.

[381] The following compounds (Ib) (table 37) are available in an analogous manner starting from compounds (Ib) initially obtained.

Table 37

# Structure tret [min] [M + H] ⁺ Method HPLC Chiral NH cr THE Ib-209 zsA % Y Λ 1.34 604 THE cA X F cr ^ Jl A-A Ύ U H Chiral NH, 0 = THE Ib-210 THE' ⁿ v ⁿ > 1.29 590 THE cXX F χ Cl ^ II A-N-A H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral \ N- 0 V Ib-211 1.39 618 THE Cl ^> F Cl ^ VVv H Chiral 0 Ib-212 vYb 1.36 630 THE Clan F y Cl II rZ ΑΥικ A> ° t> H Chiral ^0h (Ά 0 ^ B Ib-213 Va ^ν ύί 1.32 662 THE ^Cl bryQv C | XAn ⁰ >

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 ^ ^0H Nd hr / -OH O Ib-214 ^N X 1.22 664 THE ^Cl 'd ^z \ l | οι-'Α ^ ν Chiral 0 = H J V-OH u Ib-215 yx r \ K 1.25 634 THE THE N V \ here' cX Air H Chiral 0 N- \ Ar ° Ib-216 1.34 648 THE cX ll x / Air H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 0 Ib-220 iVg 1.35 660 THE Clx F x Cl ^ A ^Vo t> H Chiral / r ^N > 0 B Ib-221 1.34 673 THE 4 II br H Chiral The ^z H N- \ JV _N h ₂ n Ib-222 rb Ab 1.35 633 THE Clz 'F x cr ' 1L 5 ^ b> b> H

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-226 Chiral θ h Ν ' ⁷ 7í H 1.34 674 THE Ib-227 Chiral OH c X _Λ Nx ^N - ^ci / H exy 1.26 646 THE Ib-228 Chiral / 'N HN ⁷ 7> 1.33 659 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral HO \. Ib-229 0 χ hJv ° 1.27 676 THE Clx F x CI ^A Air. H Chiral HO N- Ib-230 X '' 1.34 620 THE cr X SHAH, H Chiral HO NH Ib-231 X Clan F. cr > ⁿ v ⁿ ík AH H 1.28 606 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral NH, 0 ^ Ib-232 1.32 592 THE Cl-V cX xX H Chiral H Ν ' 0 Ib-233 X ^N x ^N X 1.36 606 THE Clan cX P H Chiral 0 = O' B Ib-234 'THE, Ί X X 1.34 620 THE CI-V cX I ί xAx H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 \ NH <7- Q Ib-235 1.38 634 THE _c A 7 THE H Chiral 0 ' O Ib-236 THE 1.40 648 THE cr A F here | l a ysA An L> H Chiral NH 0 = < δ Ib-237 AA ^ν ύ ^ν ί 1.34 618 THE THE H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0 MNH ₂ d Ib-238 1.27 590 THE Clan X $ yx H Chiral Cy ^NH 2 O Ib-239 d '' ιιΙΙ ^ ί ^- 1.25 576 THE CIA F x ' Cl '^ ii The VoV An l> H Chiral H cw ^N - O Ib-240 ^ ^N \ 1.29 590 THE Clan $ 3 X H

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# Structure tret [min] [M + H] ⁺ Method HPLC o ^ ^NH 2 O ) N 7.0 χ ZN \ JL JL? v Ib-241 Ax Λ 1.36 656 THE Cl? F _r | To cr H Chiral O ^ ^NH 2 O \ Ib-242 Xn 9 1 U r 1.36 656 THE Ax. A / A \ α χ AAA ^ FZ í | So Cl ^ Z-N H Chiral O ^ ^NH 2 O ) Ib-243 THE A z 1.36 656 THE f H JL? Λ ) Cl> x F. (í SO cr A _n H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral H CpVoH O \ Ib-244 ..... * 1.33 672 THE Cl THE, <7, γΝ-Χ H 7 = 0 Cl ^ H

Synthesis of additional compounds (Ib) by reducing esters

Experimental procedure for the synthesis of Ib-245

lb-3 lb-245 [382] Ib-3 (30 mg, 0.05 mmol) is dissolved in anhydrous toluene (1 ml) and a solution of Red-Al® (60% in toluene, 48 μΐ) is added. The reaction mixture is heated to 90 ° C for 16 h. After that period of time, more Red-Al® (24 μΐ) is added and heating is continued for 1 h. The reaction is quenched by the addition of water and extracted with EtOAc. The organic layer is dried with MgSO ₄ and the solvents are

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362/422 removed under reduced pressure. Reverse phase column chromatography generates pure Ib-245.

[383] The following compounds (Ib) (table 38) are available in an analogous manner starting from compounds (Ib) initially obtained.

Experimental procedure for the synthesis of Ib-247

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[384] Ib-59 (55 mg, 0.09 mmol) is dissolved in MeOH (500 μΐ) and concentrated aqueous HCl (37%, 40 μΐ) is added. The reaction mixture is heated to 65 ° C for 3 h. The reaction is quenched by the addition of 4 M NaOH and EtOAc. The phases are separated and the organic phase is dried with MgSO ₄ . After removing solvents under reduced pressure, reverse phase column chromatography generates Ib-247.

[385] The following compounds (Ib) (table 39) are available in an analogous manner starting from compounds (Ib) initially obtained.

Table 39

# Structure tret [min] [M + H] ⁺ Method HPLC H, N O 1-247 laughs BB Η 1.35 562 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral H, N O 1-248 THE χρ 1.35 562 THE Cl F C | AAn ° l> ui _H

Synthesis of additional compounds (Ib) by reductive amination

Experimental procedure for the synthesis of Ib-249

lb-249 [386] Glutaraldehyde (25% in water, 20 μΐ, 0.055 mmol) is dissolved in DMF (600 μΐ) and Ib-247 (10 mg, 0.018 mmol) is added as a DMF solution (400 μΐ). The reaction mixture is treated with AcOH (5.1 μΐ, 0.05 mmol) and stirred at room temperature for 15 min. After that time, sodium triacetoxyborohydride (11.3 mg, 0.05 mmol) is added in one portion and the reaction mixture is stirred

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365/422 at room temperature for 2 h. The reaction is quenched by the addition of water, filtered through a syringe filter and purified by reverse phase column chromatography to generate Ib-249.

[387] The following compounds (Ib) (Table 40) are available in an analogous manner starting from different compounds (Ib).

Table 40

# Structure tret [min] [M + H] ⁺ Method HPLC Ib-249 O u 1.64 630 THE Ib-250 Chiral o ^c 'x $ x H 1.64 630 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ib-251 / —N u ^c, joA H 1.35 562 THE Ib-252 / -N xó ~? ^CI / SÁ H 1.35 562 THE

Synthesis of additional compounds (Ib) by amine divage

Experimental procedure for the synthesis of Ib-253

lb-247

lb-253 [388] lb-247 (12 mg, 0.021 mmol is added to a

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367/422 mixture of hypophosphorous acid (50% in water, 300 μΐ, 2.7 mmol), sulfuric acid (15 μΐ, 0.26 mmol), and copper (II) sulfate (3.75 mg, 0.023 mmol). The reaction mixture is stirred at room temperature for 5 min before sodium nitrite (6 mg, 0.085 mmol) and two drops of water are added. The reaction is stirred for 5 min. After extinction by the addition of diluted NaOH and extraction with EtOAc, the phases are separated and the organic phase is dried with MgSO ₄ . The solvents are removed under reduced pressure and reverse phase column chromatography generates pure Ib-253.

[389] The following compounds (Ib) (table 41) are available in an analogous manner starting from compounds initially obtained (Ib).

Table 41

# Structure tret [min] [M + H] ⁺ Method HPLC Ib-253 P ^Cl H 1.51 547 THE Ib-254 Chiral Q ^W H 1.51 547 THE

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Compounds (Ic)

General reaction scheme and summary of the synthesis path Scheme 6

(Ic) c-6 [390] New compounds of structure (Ic) can be prepared in stages with a synthesis route described in scheme 6 starting from (hetero) aryl amines Cl by means of a three-component coupling reaction catalyzed by copper with C-2 protected alkynylamines (for example, protected by bis- or mono-Boc) and an α, β-unsaturated C-3 aldehyde to build C-4 imidazo (eg, imidazopyrimidyl) ring systems (Angew. Chem. Int. Ed. 2010, 49, 2743). The C-4 protection group (or groups) can be removed by an appropriate method. In case of protection with mono- or di-Boc, acidic conditions such as, for example, TFA in dioxane, can be used to generate the intermediate C-5.

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C-6 intermediates can be obtained from C-5 intermediates and S-1 isatin derivatives by means of a 1,3-dipolar cycloaddition to build spiro systems as a potentially racemic mixture together with other regium- and / or diastereoisomers of C-6. The C-6 enantiomers can be separated at this stage by chiral SFC or, alternatively, the racemic mixture can be separated at any later stage of synthesis. All other known means for the separation of enantiomers can also be applied here or after any subsequent synthetic step described herein, for example, 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).

[391] C-6 can be reacted with aldehydes or ketones in a reductive amination reaction to generate compounds (Ic). Alternatively, an alkylation, addition, acylation or sulfonylation reaction can be carried out with C-6 to obtain additional compounds (Ic).

[392] Compounds (Ic) that are initially obtained from C-6 can be derivatized in optional derivatization steps not explicitly described in the schemes in all residues, especially in R ⁴ , if they carry functional groups, which can still be modified such as, for example, halogen atoms, amino and hydroxy groups (including cyclic amines), carboxylic acid or ester functions, nitriles etc. in additional (Ic) compounds by well-established organic chemical transformations such as, for example, coupling reactions

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370/422 cross catalyzed by metal, acylation, amidation, addition, reduction or alkylation (reductive) or divation of protection groups. These additional steps are not described in the general schemes. Likewise, it is also possible to include these additional steps in the synthetic routes described in the general schemes, that is, to perform derivatization reactions with compound intermediates. In addition, it may also be possible that building blocks that house protection groups are used, that is, additional steps for unprotection are necessary.

[393] Compounds (Ic) were tested for activity to affect the MDM2-p53 interaction in its racemic form or, alternatively, as the enantiopure form. Each of the two enantiomers in a racemic mixture can have activity against MDM2, albeit with a different binding mode. Enantiopure compounds are marked with the label Chiral. Compounds listed in any table below that are labeled Chiral (both intermediates and compounds (Ic) according to the invention) can be separated by chiral SFC chromatography of their enantiomers or are synthesized from enantiopure starting material which is separated by chiral SFC .

Example:

Cl

Cl

Oh naked

H

H

B c

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371/422 [394] Structure A defines the racemic mixture of compounds with structure B and C, that is, structure A comprises two structures (Be C compounds), while structures B and C, respectively, are enantiopure and only define a specific compound. Thus, the formulas (Ic) and (Ic *)

(Ic) (Ic *) with a set of specific definitions for groups R ¹ to R ⁷ , A, V, W, X, Y, n, req represent the racemic mixture of two enantiomers (- »(Ic); the structure The above is a specific example of such a racemic mixture) or a single enantiomer (-> (Ic *); structure B above is a specific enantiomer), unless additional stereocenters are present in one or more of the substituents. The same definition applies to synthetic intermediates.

Synthesis of C-3 intermediates

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372/422 [395] 2-Chloro-3-fluorine-pyridine-4-carbaldehyde D-la (1.00 g, 6.27 mmol) and (triphenylphosphoranilidene) acetaldehyde (1.91 g, 6.27 mmol) are dissolved in DMF and stirred at room temperature for 16 h. The mixture is poured into ice water and the precipitate is filtered. The crude product is purified by chromatography to release intermediate C-3a.

[396] The following C-3a intermediates (table 42) are available in a similar way from different D-1 aldehydes.

Table 42

# Structure tret [min] [M + H] ⁺ Method HPLC C-3a d 0.45 185 Ç

Synthesis of C-4 intermediates

Experimental procedure for the synthesis of C-4a (method A)

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373/422 [397] Cla 2-amino-isonicotinic acid methyl ester (1.00 g, 6.572 mmol), N-Boc prop-2-inylamine C-2a (1.12 g, 7.230 mmol), E-3 - (3-chloro-2-fluorophenyl) propenal 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) are dissolved in toluene under argon and stirred at 100 ° C for 20 h. The solvent is removed in vacuo and the crude product is purified by chromatography to release intermediate C-4a.

[398] The following C-4 intermediates (table 43) are available in a similar way from different C-1, C-2 and C-3 intermediates.

Table 43

# Structure tret [min] [M + H] ⁺ Method HPLC C-4a Ay NHBoc: 1.41 474 THE C-4b Ay NHBoc 1.52 488 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC C-4c X X ^ci O ^NHB0C 0.87 589 Ç C-4d Ay AlT N (Boc) ₂ 0.89 575 ç C-4e Ay yur ci-Y ^ ⁿ ( ^Boc > ₂ n. The. n. The. n. The.

Synthesis of C-5 intermediates

Experimental procedure for the synthesis of C-5a (method B)

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[399] Intermediate C-4a (1.00 g, 1.372 mmol) is dissolved in 1,4-dioxane and stirred at room temperature for 3 h. The solvent is removed in vacuo and the crude product is purified by chromatography, if necessary to release intermediate C-5a.

[400] The following C-5 intermediates (table 44) are available in a similar way from different C-4 intermediates.

Table 44

# Structure tret [min] [M + H] ⁺ Method HPLC λ C-5a AQ nh ₂ 1, 16 374 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC C-5b F 1.29 388 THE Cl · NH ,, X C-5c F 0.46 388 Ç Cl · · X NH, yoy OJ C-5d F 1.01 375 THE Cl · NH,

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# Structure tret [min] [M + H] ⁺ Method HPLC C-5e ΟγΟ Γ) 1, 12 389 THE C-5f & Cl-bj ^MH2 1, 06 389 THE

Synthesis of C-6 intermediates

Experimental procedure for (method C) the synthesis of C-6a

C-5a

C-6a

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378/422 [401] A solution of intermediate C-5a (735 mg, 1.792 mmol), 6-chlorisatin S-la (813 mg, 4.479 mmol) and Nmethylpyrrolidine (763 mg, 8.958 mmol) in MeOH (30 ml) is heated under microwave irradiation at 120 ° C for 20 min. The reaction mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO ₃ . The organic layer is separated and the solvents are removed in vacuo and the resulting crude product is purified by chromatography and reverse phase HPLC to release intermediate C-6a.

[402] The following C-6 intermediates (table 45) are available in a similar way from different C-5 and S-1 intermediates.

Table 45

# Structure tret [min] [M + H] ⁺ Method HPLC C-6a í -Γ'Ν ^Cl 0.677 537 Ç / 5¾ CI ^^ N H

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# Structure tret [min] [M + H] ⁺ Method HPLC Chiral 0¾ , 0 ^ C-6b O Cl 0.677 537 Ç J0D H • NH ^ 0 0 ^ 0 ^ C-6c ci f ⁿ vA fl Az n. The. n. The. í ^ l 'Λ H NH 0 Chiral 0¾ 0 ^ C-6d Ci3 ci f ^N vÀ n. The. n. The. QLz CI ^ A -NH ^ 0

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# Structure tret [min] [M + H] ⁺ Method HPLC C-6e Cl F ^N vA CI ^^ N H n. The. n. The. - C-6f Chiral _κ ΛΝ VI _H n. The. n. The. - C-6g ° £ ^ci aJi V 1.17 538 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC C-6h Chiral v N ci f ^N A 1.17 538 THE C-6i A ^c Vf ⁿ x νΑΑ CI ^^ N H 1.23 552 THE C-6j Chiral í _μ -γ · ν ci f ^N A H 1.23 552 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC C-6k AN ^CL AJI H 1.23 552 THE C-61 Chiral í Cl N Ϊ THE H 1.23 552 THE

Synthesis of compounds (Ic) according to the invention Experimental procedure for the synthesis of Ic-1 (method D)

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383/422 [403] To a solution of cyclopropanecarbaldehyde (2.7 mg, 0.039 mmol) in AcOH (1 ml) is added intermediate C-6a (18 mg, 0.033 mmol) and the reaction mixture is stirred for 15 min. Sodium triacetoxyborohydride (14.2 g, 0.065 mmol) is added and the reaction mixture is stirred overnight. Water is added to the reaction mixture and it is extracted with EtOAc. The combined organic layer is dried (MgSO ₄ ), filtered, concentrated in vacuo and the crude product is purified by chromatography to generate compound Ic-1.

[404] The following compounds (Ic) (table 46) are available in an analogous manner starting from different C-6 intermediates and different aldehydes.

Table 46

# Structure tret [min] [M + H] ⁺ Method HPLC X Ic-1 H 1.50 1.50 THE Chiral Ic-2 h ci F ^N vA 1.50 1.50 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ic-3 í An ci F ^N Ak n. The. n. The. - Ic-4 Chiral í ci jni> A H n. The. n. The. - Ic-5 “S ci F ^N v4, pnÍA ΟΙ '-' ^ 'Ν n. The. n. The. -

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# Structure tret [min] [M + H] ⁺ Method HPLC Ic-6 Chiral 'S H n. The. n. The. - Ic-7 Y qAAn H 1.44 592 THE Ic-8 Chiral í 'ci f ^N vA _C | AAn ° H 1.44 592 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ic-9 A Cl F ^N 'tfA _l ^N ίΤ> Ρ ^Cl H 1.44 592 THE Ic-10 Chiral í -Í> N ci f ^N v4 CI ^^ N H 1.44 592 THE Ic-11 A ci f ^N vA H n. The. n. The. -

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# Structure tret [min] [M + H] ⁺ Method HPLC Ic-12 Chiral Cl F ^N go α ' ^Λ ^ ^Α ' Ν H n. The. n. The. - Ic-13 ci f \ A ClAXn ⁰ 1.57 686 THE Ic-14 Chiral -in ci f ^N vX CI ^^ NX 1.57 686 THE

Synthesis of additional compounds (Ic) by ester saponification

Experimental procedure for the synthesis of Ic-15

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388/422 (method E)

lc-15 [405] Ic-1 (12 mg, 0.022 mmol) is dissolved in THF (0.5 ml) and water (1 ml) and NaOH (25 mg, 0.45 mmol) is added. The reaction mixture is stirred at 70 ° C for 8 h. After acidification with 2 M aqueous HCI and extraction with EtOAc, the organic phase is dried over MgSO ₄ . Purification with reverse phase HPLC leads to pure lc-15.

[406] The following compounds (Ic) (table 47) are available in an analogous manner starting from initially obtained compounds (Ic).

Table 47

# Structure tret [min] [M + H] ⁺ Method HPLC n ^OH X lc-15 O ci Xyw · H 577 1.05 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ic-16 Chiral oX ^H ò -ΓΝ ci f ^N vA ssx H 577 1.05 THE Ic-17 n ^0H X C | AXn ^Ul H n. The. n. The. - Ic-18 Chiral ΟΧ ” THE -ΓΝ GO fVM aAA n. The. n. The. -

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# Structure tret [min] [M + H] ⁺ Method HPLC 0¾ < ^0H n Cl F ^N vÀ ic-iy aj- CI ^^ N H • n / l * o at. at. Chiral ° Ί OH r Ic-20 í ci f ⁿ v Y N at. at. CXr H . V ν ^> Δ * 0 0 ^ , 0H O ci A-Jl Ic-21 O*/ ci- ^ Xn ΝΧΪ * 0 at. at.

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# Structure tret [min] [M + H] ⁺ Method HPLC Ic-22 Chiral ο ^ ^ΟΗ p Cl F ^N vÀ lAA CI ^^ N n. The. n. The. - Ic-23 Ο ~ ° ^{Η ci} xJí 0.99 592 THE Ic-24 Chiral o ^ ^OH 'P ci ci ^ An H 0.99 592 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ic-25 ο _ύ ^οη o O ci ci - ^ - Xn H n. The. n. The. - Ic-26 Chiral n ^0H ò ci f ^N vA CI ^ An H n. The. n. The. - Ic-27 o ^ ^OH -A -zN ci f ⁿ vA CI ^^ N <H 1, 06 672 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ic-28 Chiral O ~. ° ^H H 1, 06 672 THE

Synthesis of additional compounds (Ic) by amidation Experimental procedure for the synthesis of Ic-29 (method F)

lc-29 [407] Ic-23 (7 mg, 0.012 mmol) is dissolved in anhydrous THF (1 ml) and HATU (5 mg, 0.05 mmol) is added at room temperature. After adding DIPEA (5 mg, 0.05 mmol), the reaction mixture is stirred at room temperature for 15 min. Dimethylamine (4 mg, 0.035 mmol) is added, and the reaction is stirred for another 60 min. The crude reaction mixture is subjected to column chromatography

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394/422 reverse phase generating pure Ic-29.

[408] The following compounds (Ic) (table 48) are available in an analogous manner starting from initially obtained compounds (Ic).

Table 48

# Structure tret [min] [M + H] ⁺ Method HPLC Ic-29 ci CI ^ Xn 1.30 619 THE Ic-30 Chiral p ci _ρ Ν Ϊ _c , ÂAn 1.30 619 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ic-31 οφ Ω ⁰¹ f ^N vA CI ^^ N 0.63 646 Ç Ic-32 Chiral Q ci f ^N XÍ CI ^^ N H 0.63 646 Ç Ic-33 ojD ò Cl _F ^N Xl jYX H 0.70 644 ç

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# Structure tret [min] [M + H] ⁺ Method HPLC Ic-34 Chiral ojO 0 ci H 0.70 644 Ç Ic-35 0 „O > N Cl BvÀ Hv CI - ^^ N 1.45 659 THE Ic-36 Chiral CI ^^ N 1.45 659 THE

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# Structure tret [min] [M + H] ⁺ Method HPLC Ic-37 -THE 1.29 661 THE Ic-38 Chiral O Cl nríV H 1.29 661 THE

[409] The following Examples describe the biological activity of the compounds according to the invention, without restriction of the invention to those Examples.

[410] Compounds of formulas (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) and (Ic *) are characterized by their many possible applications in the therapeutic field. Particular mention should be made of those applications in which the inhibitory effect on the proliferation of cultured human tumor cells, but also on the proliferation of other

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Mdm2-p53 inhibition alphaScreen [411] This assay is used to determine whether the compounds inhibit the p53-MDM2 interaction and thereby restore the function of p53.

[412] 15 µl of compound in 20% DMSO (serial predilutions of compound are made in 100% DMSO) are pipetted into the wells of a white OptiPlate-96 (PerkinElmer). A mixture consisting of 20 nM of GST-MDM2 protein (aa 23117) and 20 nM of biotinylated wt p53 peptide (comprising aa 16-27 of human wt p53, QETFSDLWKLLP-Ttds-Lys-Biotin amino acid sequence, molecular weight 2132 , 56 g / mol) is 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); Tween 20 0.01%). Thirty pl of the mixture is added to the compound dilutions and incubated for 15 min at room temperature while gently shaking the plate at 300 revolutions per minute (rpm). Subsequently, 15 pl of AlphaLISA glutathione acceptor microspheres and PerkinElmer AlphaScreen streptavidin donor microspheres (in assay buffer at a concentration of 10 pg / ml each) are added and the samples are incubated for 30 min at room temperature dark environment (shaking at 300 rpm). The signal is then measured on a PerkinElmer Envision HTS Multilabel reader using the PerkinElmer AlphaScreen protocol.

[413] Each board contains negative controls on which

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399/422 biotinylated p53-peptide and GST-MDM2 are removed and replaced with assay buffer. Negative control values are entered as a low base value when using GraphPad Prism software for calculations. In addition, a positive control (DMSO 5% instead of test compound; with protein / peptide mixture) is pipetted. Determinations of IC ₅₀ values are performed using the GraphPad Prism 3.03 software (or its updates).

[414] Table 49 shows the IC ₅₀ values of example compounds determined using the assay above.

Table 49

# IC ₅₀ MDM2 [nM] Ia-20 23 Ia-25 2 Ia-26 4 Ia-27 2 Ia-29 2 Ia-30 2 Ia-31 3 Ia-32 2 Ia-33 3 Ia-34 2 Ia-35 2 Ia-36 5 Ia-38 2 Ia-39 4 Ia-40 2 Ia-41 3 Ia-43 2

# IC50 MDM2 [nM] Ia-46 8 Ia-47 9 Ia-48 10 Ia-49 6 Ia-50 4 Ia-51 7 Ia-52 69 Ia-53 7 Ia-54 13 Ia-55 6 Ia-56 5 Ia-57 13 Ib-49 5 Ib-57 12 Ib-58 7 Ib-59 15 Ib-66 166

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# IC ₅₀ MDM2 [nM] Ib-106 3 Ib-107 2 Ib-108 79 Ib-109 8 Ib-110 3 Ib-111 7 Ib-113 4 Ib-115 7 Ib-117 8 Ib-119 12 Ib-121 11 Ib-123 4 Ib-125 14 Ib-127 11 Ib-129 10 Ib-131 22 Ib-133 58 Ib-135 15 Ib-137 34 Ib-139 4 Ib-140 2 Ib-141 48 Ib-142 3 Ib-144 8 Ib-146 11 Ib-148 21 Ib-150 20

# IC50 MDM2 [nM] Ib-152 7 Ib-154 3 Ib-155 2 Ib-156 5 Ib-157 2 Ib-158 3 Ib-159 7 Ib-160 4 Ib-161 11 Ib-162 6 Ib-163 2 Ib-164 3 Ib-165 28 Ib-167 22 Ib-169 7 Ib-171 10 Ib-173 7 Ib-175 3 Ib-176 2 Ib-177 53 Ib-178 4 Ib-179 2 Ib-180 83 Ib-183 3 Ib-184 2 Ib-185 14 Ib-186 4

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# IC ₅₀ MDM2 [nM] Ib-188 3 Ib-189 3 Ib-190 2 Ib-191 6 Ib-193 3 Ib-195 6 Ib-197 2 Ib-198 4 Ib-200 3 Ib-202 7 Ib-204 2 Ib-205 3 Ib-206 4 Ib-207 8 Ib-209 3 Ib-210 4 Ib-211 11 Ib-212 5 Ib-213 7 Ib-214 3 Ib-215 4 Ib-216 7 Ib-217 4 Ib-218 6 Ib-219 5 Ib-220 10 Ib-221 10

# IC50 MDM2 [nM] Ib-222 9 Ib-223 5 Ib-224 4 Ib-225 5 Ib-226 5 Ib-227 4 Ib-228 5 Ib-229 4 Ib-230 10 Ib-231 4 Ib-232 3 Ib-233 4 Ib-234 2 Ib-235 3 Ib-236 5 Ib-237 10 Ib-238 6 Ib-239 3 Ib-240 3 Ib-241 4 Ib-242 2 Ib-243 99 Ib-244 3 Ib-245 20 Ib-247 27 Ib-249 240 Ib-251 68

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# IC ₅₀ MDM2 [nM] Ib-253 72 Ic-23 6 Ic-27 13

# IC50 MDM2 [nM] Ic-29 10 Ic-35 10 Ic-37 10

Cell proliferation assays [415] The Cell Titer Glo assay for, for example, SJSA-1, SKOV-3, RS4-11 and KG-1 cells:

[416] SJSA-1 cells (Osteosarcoma, wild-type p53, ATCC CRL-2098TM) are seeded in duplicates on day 1 in 96-well flat-bottomed microtiter plates (Packard View 96-well plate, Catalog No. 6005181) in 90 pl of RPMI medium, 10% fetal calf serum (FCS, for example, from JRH Biosciences # 12103500M, Lot: 3N0207) at a density of 2,500 cells / well. Any other compatible luminescence plate format is possible.

[417] Similarly, p53 mutant SKOV-3 cells (ovarian adenocarcinoma, ATCC HTB-77 ™) are seeded in duplicates in 96-well flat-bottomed microtiter plates in 90 pl of McCoy's medium, 10% FCS at a density 3,000 cells / well.

[418] On day 2, dilutions of 5 pl of the test compounds covering a concentration range between approximately 0.6 and 50,000 nM are added to the cells. The cells are incubated for three days in a humidified incubator, with controlled CO ₂ , at 37 ° C.

[419] RS4-11 cells with wild-type p53 (acute lymphoblastic leukemia, ATCC CRL-1873 ™):

[420] Day 1: RS4-11 cells are seeded on

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403/422 96-well flat-bottom microtiter (Packard View 96-well white plate, Catalog No. 6005181) in 90 pl of RPMI medium, 10% fetal calf serum (FCS, for example, from JRH Biosciences # 12103- 500M, Lot: 3N0207) at a density of 5,000 cells / well. Any other compatible luminescence plate format is possible.

[421] Day 2: 5 pl dilutions of the test compounds covering a concentration range between approximately 0.3 and 25,000 nM (alternative dilution schemes are possible) are added to the cells. The cells are incubated for three days in a humidified incubator, with controlled CO ₂ , at 37 ° C. The final DMSO concentration is 0.5%.

[422] KG-1 cells mutant for p53 (acute myelogenous leukemia, ATCC CCL-246):

[423] Day 1: KG-1 cells harboring a p53 mutation at the exon 6 / intron 6 splice donor site are seeded in flat-bottomed 96-well microtiter plates (96-well Packard View white plate, No. Catalog 6005181) in 90 pl of IMDM medium, 10% FCS (JRH Biosciences # 12103-500M, Lot: 3N0207) at a density of 10,000 cells / well. Any other compatible luminescence plate format is possible.

[424] Day 2: 5 pl dilutions of test compounds that cover a concentration range between approximately 0.3 and 25,000 nM (alternative dilution schemes are possible) are added to the cells. The cells are incubated for three days in a humidified incubator, with controlled CO ₂ , at 37 ° C. The final DMSO concentration is 0.5%.

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404/422 [425] The evaluation of all “Cell Titer Glo” assays is done on day 5 after sowing. On day 5, 95 μl of reagent “Cell Titer Glo” (“Cell titer Glo Luminescent”, Catalog No. G7571, Promega) are added to each well and incubated for another 10 min at room temperature (with shaking). Luminescence is measured on a Wallac Victor using a standardized luminescence reading. IC ₅₀ values are calculated using standardized Levenburg Marquard algorithms (GraphPad Prism).

[426] In addition, several other cancer cell lines from various tissue sources are sensitive to compounds (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) and (Ic *).

Examples include NCI-H460 (lung), Molp-8 (myeloma) and MV411 (AML).

[427] Based on their biological properties, the compounds of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) according to the invention, its tautomers, racemates, enantiomers, diastereomers, mixtures of these and salts of all the forms mentioned above, are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation.

[428] These diseases include, for example: viral infections (for example, HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (eg, colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; leukemias, lymphomas and solid tumors (for example, carcinomas and sarcomas), skin diseases (for example, psoriasis); hyperplasia-based diseases that are characterized by an increase in the number of cells (for example

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405/422 example, fibroblasts, hepatocytes, bone and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (for example, endometrial hyperplasia); bone diseases and cardiovascular diseases (for example, restenosis and hypertrophy). They are also suitable for the protection of proliferating cells (eg, hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and / or cytostatic treatment.

[429] For example, the following cancers / proliferative diseases can be treated with compounds according to the invention, without being restricted to them:

brain tumors such as acoustic neuroma, astrocytomas such as pilocytic astrocytomas, fibrillar astrocytoma, protoplasmic astrocytoma, gemistocytic astrocytoma, anaplastic astrocytoma and glioblastoma, glioma, brain lymphomas, such as brain metastases, tumor, brain tumor , tumor producing HGH (human growth hormone) and tumor producing ACTH (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningiomas and oligodendrogliomas; nervous tumors (neoplasms), such as tumors of the vegetative nervous system, such as sympathetic neuroblastoma, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and glomus-caroticum tumor, tumors in the peripheral nervous system, such as neuroma of amputation, neurofibroma, neurinoma (neurilemoma, Schwanoma) and malignant Schwanoma, as well as tumors of the central nervous system, such as brain and spinal tumors

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406/422 bone; intestinal cancer such as, for example, carcinoma of the rectum, carcinoma of the colon, colon-rectal carcinoma, anal carcinoma, carcinoma of the large intestine, tumors of the small intestine and duodenum; tumors of the eyelids, such as basalioma or basal cell carcinoma; pancreatic cancer or pancreatic cancer; bladder cancer or bladder carcinoma and other urothelial cancers; lung cancer (bronchial carcinoma) such as small cell bronchial carcinomas (oat cell carcinomas) and non-small cell bronchial carcinomas (NSCLC) such as plaque epithelial carcinomas, adenocarcinomas and large cell bronchial carcinomas ; breast cancer such as breast carcinoma, for example, infiltrating ductal carcinoma, colloid carcinoma, invasive lobular carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma, hormone receptor positive breast cancer (breast cancer positive for receptor estrogen, progesterone receptor positive breast cancer), Her2 positive breast cancer, triple negative breast cancer; non-Hodgkin's lymphomas (NHL) such as Burkitt's lymphoma, non-Hodgkin's lymphomas of low malignancy (NHL) and mycosis fungoides; uterine cancer or endometrial carcinoma or carcinoma of the body; CUP syndrome (Unknown Primary Cancer); ovarian cancer or ovarian carcinoma such as, for example, mucinous, endometrial or serous cancer; gallbladder cancer; bile duct cancer, such as Klatskin's tumor; testicular cancer, such as seminomas and non-seminomas; lymphoma (lymphosarcoma) such as malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas

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407/422 (NHL) such as, for example, chronic lymphatic leukemia, leukemic reticuloendotheliosis, immunocytoma, plasmacytoma, multiple myeloma (MM), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungo, large-cell anaplastic lymphoblastoma; laryngeal cancer, such as vocal cord tumors, supraglottic, glottic and subglottic laryngeal tumors; bone cancer such as osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumor, chondrosarcoma, osteosarcoma, Ewing sarcoma, reticulo-sarcoma, soft tissue sarcoma, liposarcoma, liposarcoma , fibrous dysplasia, juvenile bone cysts and aneurysmatic bone cysts; tumors of the head and neck, such as tumors of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer, such as liver cell carcinoma or hepatocellular carcinoma (HCC); leukemias such as, for example, acute leukemias, for example, acute lymph / lymphoblastic leukemia (ALL), acute myeloid leukemia (AML); chronic leukemias, for example, chronic lymphatic leukemia (CLL), chronic myeloid leukemia (CML); myelodysplastic syndromes (MDS); stomach cancer or gastric carcinoma such as papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small cell carcinoma and undifferentiated carcinoma; melanomas, such as superficial, nodular, lentigo-malignant and acral-lentiginous spread melanoma;

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408/422 kidney cancer such as, for example, renal cell carcinoma or hypernefroma or Grawitz tumor; esophageal cancer or carcinoma of the esophagus; cancer of the penis; prostate cancer (for example, castration-resistant prostate cancer); cancer of the throat or carcinomas of the pharynx such as, for example, carcinomas of the nasopharynx, carcinomas of the carcinomas of the oropharynx and hypopharynx; retinoblastoma, vaginal cancer or vaginal carcinoma, mesothelioma; epithelial plaque carcinomas, adenocarcinomas, carcinomas in situ, melanomas and malignant sarcomas; thyroid carcinomas such as papillary, follicular and medullary thyroid carcinoma, as well as anaplastic carcinomas; spinalioma, squamous cell carcinoma and squamous cell carcinoma of the skin; thymomas, cancer of the urethra, cervical cancer, adenoid cystic carcinoma (AdCC), adrenocortical carcinoma and cancer of the vulva.

[430] Preferably, the proliferative diseases / cancers to be treated have functional p53 and / or wild type p53. Functional p53 means that p53 is able to bind to DNA and activate the transcription of target genes.

[431] The new compounds can be used for the prevention, short-term or long-term treatment of the diseases mentioned above, optionally also in combination with radiotherapy or other advanced compounds, such as cytostatic or cytotoxic substances, inhibitors of cell proliferation , antiangiogenic substances, steroids or antibodies.

[432] The compounds of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) can be used by themselves or

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409/422 in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.

[433] Therapeutic agents (= cytostatic and / or cytotoxic active substances) that can be administered in combination with the compounds according to the invention, include, but are not limited to, hormones, hormone analogs and anti-hormonal agents (eg example, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutetimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoximesterone, anthroxyprogesterone, ocroxyproge, sterone letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (eg goserelin acetate, luprolide), growth factor inhibitors (growth factors such as “platelet-derived growth factor (PDGF ), “Fibroblast growth factor (FGF),“ vascular endothelial growth factor (VEGF), “epidermal growth factor (EGF),“ growth factors insulin-like (IGF), “human epidermal growth factor (HER, for example, HER2, HER3, HER4) and“ hepatocyte growth factor (HGF)), inhibitors are, for example, antibodies to “growth factor , antibodies to “growth factor receptor and tyrosine kinase inhibitors such as cetuximab, gefitinib, imatinib, lapatinib, bosutinib and trastuzumab); antimetabolites (eg antifolates such as methotrexate, raltitrexed, pyrimidine analogs

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410/422 melphalan alkylating agents, such as 5-fluorouracil (5-FU), capecitabine and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine) ; antitumor antibiotics (eg, anthracyclines, eg, doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin, and idarrubicin, mitomycin-C, bleomycin, plastinicine, plastinicine, plastinicine, plastinicine, stromacin, dycinicin, plastinicine; platinum (for example, cisplatin, oxaliplatin, carboplatin); agents (for example, estramustine, meclorethamine, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as, for example, carmustine and lomustine, antimytopa); for example, Vinca alkaloids such as vinblastine, vindesine, vinorrelbine and vincristine; and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (eg tasquinimod), tubulin inhibitors; inhibitors of DNA synthesis; (eg sapacitabine), PARP inhibitors, topoisomerase inhibitors (eg epipodophyllotoxins such as etop osida and etoprofos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (eg PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C- inhibitors Raf, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Ka inhibitors, dual mTOR / PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK inhibitors

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411/422

1, CDK inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (eg PTK2 / FAK inhibitors), inhibitors of protein-protein interaction (eg IAP activator, Mcl-1, MDM2 / MDMX), MEK inhibitors (eg, pimasertib), ERK inhibitors, FLT3 inhibitors (eg, quizartinib), BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors ( eg venetoclax), Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (eg everolimus, temsirolimus, ridaforolimus, ridaforolimus, sirolimus ), erogen synthesis inhibitors (eg, abiraterone, TAK-700), erogen receptor inhibitors (eg, enzalutamide, RNA-509), immunotherapy (eg, sipuleucel-T), DNMT inhibitors (eg , SGI 110, temozolomide, vosaroxin), HDAC inhibitors (for

example, vorinostat, entinostat, pracinostat, panobinostat) inhibitors in ANG1 / 2 (per example, trebananib), inhibitors in CYP17 (per example, galeterone), radiopharmaceuticals (for example, radio-223,

alfaradine), immunotherapeutic agents (for example, poxvirus-based vaccine, ipilimumab, immune checkpoint inhibitors) and various chemotherapeutic agents such as amifostine, anagrelide, clodronat, filgrastine, interferon, interferon alfa, leucovorin, rituximab, procarbazine , levamisole, mesna, mitotane, pamidronate and porfin.

[434] Other possible combination partners are 2chlorodeoxyadenosine, 2-fluordesoxycytidine, 2420/452

412/422 methoxyestradiol, 2C4, 3-alethine, 131-I-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, ABT-199, ABT-263 / navitoclax, ABT-737, A 105972, A 204197, aldesleukin, alisertib / MLN8237, alitretinoin, alovectin7, altretamine, alvocidib, amonafide, anthrapirazole, AG2037, AP-5280, apaziquone, apomina, aranosis, arglabine, arzoxifen, arzoxifene, araminoxanthin, arzoxifene, araminoxanthenate , ABX-EGF, AMG-479 (ganitumab), AMG-232, AMG-511,

AMG 2520765, AMG 2112819, ARRY 162, ARRY 438162, ARRY-300, ARRY-142886 / AZD-6244 (selumetinib), ARRY-704 / AZD-8330,

ATSP-7041, AR-12, AR-42, AS-703988, AXL-1717, AZD-1480,

AZD-4547, AZD-8055, AZD-5363, AZD-6244, AZD-7762, ARQ-736,

ARQ 680, AS-703026 (primatsertib), avastin, AZD-2014, azacytidine (5-aza), azaepothilone B, azonafide, barasertib / AZD1152, BAY-43-9006, BAY 80-6946, BBR-3464,

BBR-3576, bevacizumab, BEZ-235 / dactolisib, biricodar dicitrate, birinapant, BCX-1777, BKM-120 / buparlisib, bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS275291, BMS-75791 663513, BMS-754807, BNP-1350, BNP-7787, BIBW

2992 / afatinib, BIBF 1120 / nintedanib, BI 836845, BI 2536, BI 6727 / volasertib, BI 836845, BI 847325, BI 853520, BIIB-022, bleomycinic acid, bleomycin A, bleomycin B, brivanib, briostatin-1, bortezomib, brostalicin, busulfan, BYL719 / alpelisib, CA-4, CA-4 prodrug, cabazitaxel, cabozantinib, CapCell, calcitriol, canertinib, camphosfamide, capecitabine, carboxiftalatoplatin, CCI-779,

CC-115, CC-223, CEP-701, CEP-751, CBT-1 cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleucine, cemadotine, CGM-097, CH4987655 / RO-4987655, chlorotrianisene, cilengitide, cyclosporine, CD20

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413/422 antibodies, CDA-II, CDC-394, CKD-602, CKI-27, clofarabine, cholcicin, combretastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptoficina 52, CPI-613, CTPCTLA-4 (for crizotinib, cytarabine, D example,

CV-247,

24851,

37, monoclonal antibodies ipilimumab), CP-461, cyanomorpholinodoxorubicin, dasatinib, decitabine, deoxorubicin, deoxyrubicin, deoxychoformicin, depsipeptide, deoxiepotilone B, dexamethasone, dexrazoxane t, diethylstilbestrol, ddxastatin, di, dxxazamine, ddxastanazole, ddxxazan, dx, dxxazan, dx 3032, E7010, E-6201, edatrexat, edotreotide, efaproxiral, eflornithine, EGFR inhibitors, EKB-569, EKB509, enzastaurine, elesclomol, elsamitrucine, epothilone B, epratuzumab, EPZ-004777, ER-86526, ER-865 -OCH ₃ , ethinylcytidine, ethinylestradiol, exactecan, exactecan mesylate, exemestana, exisulind, fenretinide, figitumumab, floxuridine, folic acid, FOLFOX, FOLFOX4, FOLFIRI, formestane, fostamatinib, gumltin, gumltin, gumltin, gumltin, gumltin, gumltin, gumltin, gumltin, gumltin, gumltin, gumltin, gumltin, gumltol, , gemtuzumab ozogamycin, gimatecan, glufosfamide, GCS-IOO, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC0068, GDC-0349, GDC-0879, immunogen G17DT, GMK, GMX-1778,

GPX-100, gp100-peptide vaccines, GSK-5126766, GSK690693, GSK-1120212 (trametinib), GSK-1995010, GSK-2118436 (dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2334470, GSK2110183 2141795, GSK-2636771, GSK-525762A / I-BET-762,

GW2016, granisetron, herceptin, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, HDM-201, ibandronate, ibritumomab, ibrutinib / PCI-32765,

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414/422 idasanutline, idatrexate, idelalisib / CAL-101, idenestrol, from IGF-1R, IMC-1C11, IMC-A12 indulge, pegylated interferon alfa-2a, alpha-2b,

IDN-5109, inhibitors (c ixutumumab), immunol, interferon alfa-2b, leflunomide, leuporelin, lobaplatin, leuprolide, interferon interleukin-2, INK-1117, INK-128, INSM-18, ionafarnib, iproplatin, irofulven, isohomolic B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, JQ-1, J-107088, conjugated estrogens, kahalid F, ketoconazole, KW-2170, KW2450, KU-55933, LCL-161, lenalidomide, lenograstim, lexidronam, LGD-1550, linezolid, lovastatin, lutetium texafirine, lometrexol, lonidamine, losoxantrone, LU 223651, lurbinectedina, lurtotecan, LY-S6AKT1, LY-2780301, LY2109761 / galunisertib, maprosamide, mafosamide, , MEK-162, methyltestosteron, methylprednisolone, MEDI-573, MEN-10755,

MDX-H210, MDX-447, MDX-1379, MGV, midostaurine, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, MLN-0128, MLN-2480, motexafin gadolinium, MS-209 , MS-275, MX6, nerhydronate, neratinib, Nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, NU-7441 06benzylguanine, oblimersen, omeprazole, olaparib, onx, onco antibodies OX44, OSI-027, OSI-906 (linsitinib), antibodies 4-1BB, oxantrazole, estrogen, onapristone, palbocyclib / PD0332991, panitumumab, panobinostat, patupilone, pazopanib, pegfilgrastim, PCK-3145, pegfilgrastim, PBI 140 , PD0325901, PD-1 and PD-L1 antibodies (for example, pembrolizumab, nivolumab, pidilizumab, MEDI423 / 452

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4736 / durvalumab, RG-7446 / atezolizumab), PD-616, PEGpaclitaxel, albumin-stabilized paclitaxel, PEP-005, PF05197281, PF-05212384, PF-04691502, PF-3758309, PHA-665752, PHT-4265752, PHT-42775 04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine, perilyl alcohol, pertuzumab, pevonedistat, PI3K inhibitors, PI3K / mTOR inhibitors, PG-TXL, PG2, PLX-4032 / RO-5185426 (vemurafeniben) , PLX3603 / RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol O, PKI166, plevitrexed, plicamycin, polyprenic acid, ponatinib, porfiromycin, predaconamide, predaconazole, predaconazole, predaconazone, , quinupristin, quizartinib / AC220, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119 / BAY 869766, RDEA-436, rebecamycin analogs, tyrosine kinase receptor (RTK) inhibitors, revimid, RG-7167, RG-7112 , RG-7304, RG-7421, RG-7321, RG-7356, RG 7440, RG-7775, rhizoxin, rhu-MAb, rigosfabib rinfabato, risedronate, rituximab, robatumumab, rofecoxib, romidepsin, RO-49 29097, RO-31-7453, RO-5126766, RO-5068760, RPR 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, ruxolitinib, S-9788, sabarubicin, SAHA, esapacitabine, SAR-405838, sargramostim, satra , SB-408075, SB431542, Se-015 / Ve-015, SU5416, SU6668, SDX-101, selinexor, semustine, seocalcitol, SM-11355, SN-38, SN-4071, SR-318947, SR-31747, SR -13668, SRL-172, sorafenib, spiroplatin, squalamine, STF-31, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAE-684, TAK-733, TAS-103, tacedinalina, talaporfina, tanespimicina, Tarceva, tariquitar, tasisulam, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate,

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416/422 tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, thymectacin, teralux, thiazofurin, timalfasin, tirapazamine,

TransMID-107, tremelimumab acid, tretinoin, terarrubicin, tipifarnib, tocladesin, tomudex, toremofin, tosedostat, trabectedin, transretinic, traszutumab, triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TYRT, valkyrid, tyKy 286TXD, valkyrid, tyKy 286TXD , vandetanib, vatalanib, vincristine, vinflunine, virulizine, vismodegib, vosaroxin, WX-UK1, WX-554, vectibix, XAV-939, xeloda,

XELOX, XL-147, XL-228, XL-281, XL-518 / R-7420 / GDC-0973, XL765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD- 0473,

ZD-6126, ZD-9331, ZDI839, ZSTK-474, zosuquidar.

[435] Treatment methods and medical uses that include the use of the compounds of the invention in combination with immunotherapeutic agents, for example, checkpoint inhibitors, including anti-PD-1 and anti-PD-L1 agents (such as, for example, pembrolizumab, nivolumab, pidilizumab, MEDI-4736 / durvalumab and RG-7446 / atezolizumab) and anti-LAG3 agents. Thus, an aspect of the invention consists of methods of treatment and medical uses that include the use of a compound (I) of the invention in combination with an anti-PD-1 agent or an anti-PD-L1 agent (such as, for example) , pembrolizumab, nivolumab, pidilizumab, MEDI-4736 / durvalumab and RG-7446 / atezolizumab). Another aspect of the invention are methods of treatment and medical uses that include the use of a compound (I) of the invention in combination with an anti-LAG3 agent. A further aspect of the invention consists of (I) the

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417/422 syrups, sachets, dispersible. Methods of treatment and medical uses which include the use of a compound (I) of the invention in combination with an anti-PD-1 agent and an anti-LAG3 agent.

[436] Suitable preparations include, for example, tablets, pills, capsules, suppositories, lozenges, lozenges, solutions - particularly solutions for injection (sc, iv, im) and infusion (injectables) - elixirs, emulsions, puffs for inhalation or content of the pharmaceutically active compound (or compounds) must be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the composition as a whole, that is, in quantities that are sufficient to obtain the range of dosage specified below. The specified doses can, if necessary, be given several times a day.

[437] Suitable tablets can be obtained, for example, by mixing the active substance (or active substances) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as eg corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, release delay agents, eg carboxymethylcellulose, phthalate acetate or cellulose polyvinyl acetate , carriers, adjuvants, surfactants. The tablets can also comprise several layers.

[438] Coated tablets can be prepared accordingly by coating cores produced analogously to tablets with substances normally

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418/422 used for tablet coatings, for example, collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or avoid incompatibilities, the core can also consist of several layers. Similarly, the coating of the tablet may consist of several layers to obtain delayed release, possibly using the excipients mentioned above for the tablets.

[439] Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar, and a flavor enhancer, for example, a flavoring like, for example, vanillin or orange extract. They may also contain suspension aids or thickeners such as, for example, sodium carboxymethylcellulose, wetting agents such as products of condensation of fatty alcohols with ethylene oxide, or preservatives such as, for example, p-hydroxybenzoates.

[440] Solutions for injection and infusion are prepared in the usual way, for example, with the addition of isotonic agents, preservatives such as, for example, p-hydroxybenzoates, or stabilizers such as, for example, alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and / or dispersants, while if water is used as the diluent, for example, organic solvents can optionally be used as solvating agents or dissolution aids, and transferred to injection vials or ampoules or infusion bottles.

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419/422 [441] Capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substances with inert carriers such as, for example, lactose or sorbitol, and their packaging in gelatin capsules.

[442] Suitable suppositories can be made, for example, by mixing with carriers provided for this purpose, for example, neutral fats or polyethylene glycol or derivatives thereof.

[443] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as, for example, paraffins (for example, petroleum fractions), vegetable oils (for example, peanut or sesame oil), mono alcohols - or polyfunctional (for example, ethanol or glycerol), carriers such as, for example, natural mineral powders (for example, kaolin, clays, talc, chalk), synthetic mineral powders (for example, highly dispersed silicic acid and silicates), sugars (for example, cane sugar, lactose and glucose), emulsifiers (for example, lignin, sulphite residual liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (for example, magnesium stearate, talc, stearic acid and sodium lauryl sulfate ).

[444] The preparations are administered by the usual methods, preferably orally or transdermally, more preferably orally. For oral administration, the tablets may, of course, contain, in addition to the carriers mentioned above, additives such as, for example, sodium citrate, calcium carbonate and calcium diphosphate, together with various additives such as, for example,

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420/422 starch, preferably potato starch, gelatin and the like. In addition, lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, can be used at the same time for the tablet production process. In the case of aqueous suspensions, the active substances can be combined with various flavor enhancers or colorants, in addition to the excipients mentioned above.

[445] For parenteral use, solutions of the active substances with suitable liquid carriers can be used.

[446] The dosage range for the compounds of formula (I), (Ia), (Ib), (Ic), (Ia *), (Ib *) or (Ic *) applicable per day is normally 1 mg to 2,000 mg, preferably 50 to 1,000 mg, more preferably 100 to 500 mg.

[447] The dosage for intravenous use is 1 mg to 1,000 mg per hour, preferably between 5 mg and 500 mg per hour.

[448] However, it is sometimes necessary to deviate from the specified amounts, depending on body weight, route of administration, individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered . Thus, in some cases, it may be sufficient to use less than the minimum dose shown above, while in other cases the upper limit may have to be exceeded. When large quantities are administered, it may be advisable to divide them into several smaller doses spread throughout the day.

[449] The following formulation examples illustrate the present invention, without restricting its scope (the active substance in all examples is a compound according to formula (I), (Ia), (Ib), (Ic), ( Ia *), (Ib *) or (Ic *)):

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421/422

Examples of pharmaceutical formulations A) Tablets per tablet

Active substance 100 mg Lactose 140 mg Maize starch 240 mg Polyvinylpyrrolidone 15 mg Magnesium stearate 5 mg TOTAL: 500 mg

[450] The finely divided active substance, lactose and some of the corn starch are mixed together. The mixture is sieved, and then moistened with a solution of polyvinylpyrrolidone in water, worked, wet granulated and dried. The granules, the remaining corn starch and the magnesium stearate are sieved and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

B) Tablets per tablet

Active substance 80 mg Lactose 55 mg Maize starch 190 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 15 mg Carboxymethyl sodium starch 23 mg Magnesium stearate 2 mg TOTAL: 400 mg

[451] The finely divided active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and worked with the remaining corn starch and water to form a granulate that is dried and sieved. Starch from

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422/422 sodium carboxymethyl and magnesium stearate are

added and mixed and the form pills of a size mixture is compressed appropriate. for C) Pills per pill Active substance 25 mg Lactose 50 mg Microcrystalline cellulose 24 mg Magnesium stearate 1 mg TOTAL: 10 0 mg [452] The active substance, lactose and cellulose are mixed together. The mixture it's small, and then

moistened with water, worked, wet granulated and dry or dry granulated or directly blended at the end with magnesium stearate and compressed into tablets of suitable shape and size. When wet granulated, more lactose or cellulose and magnesium stearate is added, and

the mixture is compressed to produce pills in Format and size. D) Ampoule solution Active substance 50 mg Sodium chloride 50 mg Water for injection 5 ml [453] The substance active is dissolved in water in your pH itself or optionally at pH 5.5 to 6.5 and chloride

sodium is added to make it isotonic. The solution obtained is filtered free of pyrogens and the filtrate is transferred under aseptic conditions to ampoules, which are then sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

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1/20

Claims (21)

1. A compound characterized by formula (I) in which: R ¹ is a group optionally substituted by one or more R ^bl and / or R ^cl identical or different, selected from Cl - ₆ alkyl, C2 -6 alkenyl, C2 -6 alkynyl, C ₆ haloalkyl, C3-7 cycloalkyl , C4-7 cycloalkenyl, C ₆ -io aryl, 510 membered heteroaryl and 3-10 membered heterocyclyl; each R ^bl is independently selected from -0R ^cl , NR ^cl R ^cl , halogen, -CN, -C (O) R ^cl , -C (O) OR ^cl , -C (0) NR ^cl R ^cl , S (O ) 2 R ^c1, -S (0) 2NR R ^{c1 c1,} -NHC (O) R ^c1, -N (CI - ₄ alkyl) C (0) R ^cl and the bivalent substituent = 0, just as = 0 may be a substituent on non-aromatic ring systems; each R ^cl, independently of one another represents hydrogen or optionally substituted by one or more R ^dl and / or R ^el identical or different, selected from Cl - ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, Cl - ₆ haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C ₆ -io aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each R ^dl is independently selected from -0R ^el , 432/452 2/20 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 (Cx-4 alkyl) C (O) R ^e1 and the divalent substituent = O, while = O can only be a substituent in non-aromatic ring systems; each R ^e1 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^f1 and / or R ^g1 , selected from 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, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each R ^f1 is 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 (Cx-4 alkyl) C (O) R ^g1 and the bivalent substituent = O, while = O can only be one substituent on non-aromatic ring systems; each R ^g1 is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; R and R, each independently, are selected from hydrogen, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein said C6-10 aryl, 5-10 membered heteroaryl and heterocyclyl 3-10 members are optionally substituted by one or more identical or different R ^b2 and / or R ^c2 ; each R ^b2 is 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 _X -4 alkyl) C (O) R ^c2 and the divalent substituent = O, while = O can only be a substitute in non-aromatic ring systems; 433/452 3/20 each R ^c2 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^d2 and / or R ^e2 , 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, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each R ^d2 is 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 (C1-4 alkyl) C (O) R ^e2 and the divalent substituent = O, while = O can only be one substituent on non-aromatic ring systems; each R ^e2 , independently of one another, represents hydrogen or a group selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, C6-10 aryl , 5-10 membered heteroaryl and 3-10 membered heterocyclyl; A is selected from phenyl and 5-6 membered heteroaryl if F is carbon or A is 5-6 membered heteroaryl containing nitrogen if F is nitrogen; each R ⁴ is independently selected from R ^a4 and R ^b4 ; each R ^a4 , independently of one another, is a group optionally substituted by one or more identical or different R ^b4 and / or R ^c4 , selected from C1-6 alkyl, C2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} haloalkyl, C _3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each R ^b4 is 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 (C1-4 434/452 4/20 alkyl) SO2R ^c4 , -NHC (O) R ^c4 and -N (C1-4 alkyl) C (O) R ^c4 ; R ^c4 each, independently of one another represents hydrogen or optionally substituted by one or more R ^d4 and / or R ^e4 IDENT single or different, selected from Cl - ₆ alkyl, _C2-6 alkenyl, _C2-6 alkynyl , C _1-6 haloalkyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each R ^d4 is 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 ) OR ^{e4 g4} NR, -S (O) 2 R ^e4, -S (O) 2NR R ^{e4 e4,} -NHC (O) R ^e4 and -N (C 1 -C ₄ alkyl) C (O) R ^e4; each R ^e4 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^f4 and / or R ^g4 , selected from 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, 510 membered heteroaryl and 3-10 membered heterocyclyl; each R ^f4 is 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 (Cx-4 alkyl) C (O) R ^g4 ; each R ^g4 is 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 , 5-10 membered heteroaryl and 3-10 membered heterocyclyl; r represents the number 0, 1, 2 or 3; n represents the number 1, 2 or 3; each R is independently selected from halogen, C _1-4 alkyl, -CN, C _1-4 haloalkyl, -OC _1-4 alkyl and -OC _1-4 haloalkyl; 435/452 5/20 q represents the number 0, 1, 2 or 3; W, X and Y are selected, each independently, from -N = and -CH =, provided that the hydrogen in each -CH = can be replaced by a substituent R ⁷ , if present, and that a maximum of two of W , X and Y can 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 like this. Compound according to claim 1, characterized in that it is of formula (Ia) or (Ib) or (Ic) (Ia) (Ib) (Ic) or a salt thereof. Compound according to claim 2, characterized in that it is of formula (Ia *) or (Ib *) or (Ic *) 436/452 6/20 (la *) (Ib *) (Ic *) or a salt thereof. 4. A compound, according to any of the preceding claims, characterized by the fact that: R ¹ is a group optionally substituted by one or more R ^bl and / or R ^cl identical or different, selected from Cl - ₆ alkyl, C2 -6 alkenyl, C2 -6 alkynyl, C ₆ haloalkyl, C3-7 cycloalkyl , C4-7 cycloalkenyl, C ₆ -io aryl, 510 membered heteroaryl and 3-10 membered heterocyclyl; each R ^bl is independently selected from -0R ^cl , NR ^cl R ^cl , halogen, -CN, -C (O) R ^cl , -C (O) OR ^cl , -C (0) NR ^cl R ^cl , S (O ) 2 R ^c1, -S (0) 2NR R ^{c1 c1,} -NHC (0) R ^c1 and -N (CI - ₄ alkyl) C (0) R ^c1; each R ^cl, independently of one another represents hydrogen or optionally substituted by one or more ^dL R and / or R ^el identical or different, selected from CI_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, CI_ ₆ haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C ₆ -io aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each R ^dl is independently selected from -0R ^el , NR ^el R ^el , halogen, -CN, -C (O) R ^el , -C (O) OR ^el , -C (0) NR ^el R ^el , S (O ) 2R ^el , -S (0) 2NR ^el R ^el , -NHC (0) R ^el and -N (C _1-4 alkyl) C (0) R ^el ; each R ^el , independently of each other, represents 437/452 7/20 hydrogen or a group optionally substituted by one or more identical or different R ^f1 and / or R ^g1 , selected from 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, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each R ^f1 is 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 ; each R ^g1 is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; or a salt like this. 5. Compound, according to any of the preceding claims, characterized by the fact that: R and R, each independently, are selected from hydrogen, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein said C _6-10 aryl, 5-10 membered heteroaryl and heterocyclyl 3-10 members are optionally replaced by one or more identical or different R ^b2 and / or R ^c2 ; each R ^b2 is 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, represents hydrogen or a group optionally substituted by one or more identical or different R ^d2 and / or R ^e2 , selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1- 6 haloalkyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, C6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; 438/452 8/20 each R ^d2 is 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 (Cx-4 alkyl) C (O) R ^e2 ; each R ^e2 , independently of one another, represents hydrogen or a group 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, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; or a salt this ^. 6. Compound, according the claim 5, featured fur fact that: one from R ² and R ³ is hydrogen and the other is selected in between phenyl and 5-6 heteroaryl members, on what the said and 5-6 membered heteroaryl are optionally substituted by one or more identical or different R ^b2 and / or R ^c2 ; each R ^b2 is 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 (C1-4 alkyl) C (O) R ^c2 ; each R ^c2 , independently of one another, represents hydrogen or a group selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, phenyl, heteroaryl 5-6 members and 3-7 members heterocyclyl; or a salt this ^. 7. Compound, according the claim 6, featured fur fact that: one from R ² and R ³ is hydrogen and the other is selected in between phenyl and 5-6 heteroaryl members, on what the referred to and 5-6 membered heteroaryl are optionally 439/452 9/20 substituted by one or more identical or different substituents selected from -OC _1-6 alkyl, halogen, C _1-6 alkyl and C _1-6 haloalkyl; or a salt like this. 8. Compound, according to any of the preceding claims, characterized by the fact that: R ³ is hydrogen; or a salt like this. 9. Compound, according to any of the preceding claims, characterized by the fact that: A is phenyl and F is carbon; each R ⁴ is independently selected from R ^a4 and R ^b4 ; each R ^a4 , independently of each other, is a group optionally replaced by one or more R ^b4 and / or R ^c4 identical or different, selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl and 3-10 membered heterocyclyl; each R ^b4 is 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, represents hydrogen or a group optionally substituted by one or more identical or different R ^d4 and / or R ^e4 , selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 3-10 membered cycloalkyl and heterocyclyl; each R ^d4 is independently selected from -OR ^e4 , NR ^e4 R ^e4 and -S (O) ₂ R ^e4 ; each R ^e4 , independently of one another, represents hydrogen or a group optionally substituted by one or more identical or different R ^f4 and / or R ^g4 , selected from C1-6 alkyl and 3-10 membered heterocyclyl; 440/452 10/20 each R ^f4 is -OR ^g4 ; each R ^g4 is independently selected from hydrogen and C _1-6 alkyl; r represents the number 0, 1, 2 or 3; or a salt like this. 10. Compound according to any of the preceding claims, characterized by the fact that: A is selected from phenyl and 5-6 membered heteroaryl if F is carbon or A is 5-6 membered heteroaryl containing nitrogen if F is nitrogen; each R ⁴ is independently selected from R ^a4 and R ^b4 ; each R ^a4 , independently of one another, is a group optionally substituted by one or more identical or different R ^b4 and / or R ^c4 , selected from C1-6 alkyl, C2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} haloalkyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, C _6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; each R ^b4 is 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 , -NHSO2RA -N (Cx-4 alkyl) SO2R ^c4 , -NHC (O) R ^c4 and -N (CX-4 alkyl) ) C (O) R ^c4 ; each R ^c4 , independently of each other, is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-10 aryl, heteroaryl 5-10 limbs and 3-10 limbs heterocyclyl; r represents the number 0, 1, 2 or 3; or a salt like this. 11. Compound, according to any of the 441/452 11/20 preceding claims, characterized by the fact that: A, together with the R substituents R ⁴ , is R ⁸ is selected from hydrogen, C ₆ alkyl, -0Ci- ₆ alkyl, halogen, -CN, -C (O) OH, -C (O) OCi- ₆ alkyl, -C (O) NH _2, -C (O) NHC- ₆ alkyl, -C (O) N (C- ₆ alkyl) ₂ and -S (O) ₂ C- ₆ alkyl; R ⁹ is selected from hydrogen, alkyl CI_ _6, -0Ci- ₆ alkyl, halogen, -CN, -C (O) OH, -C (O) OCi- ₆ alkyl, -C (O) NH _2, -C ( O) NHC- ₆ alkyl, -C (O) N (C- ₆ alkyl) ₂ and -S (O) ₂ C- ₆ alkyl; R ¹⁰ is selected from hydrogen, C ₆ alkyl, -0Ci- ₆ alkyl, halogen, -CN, -C (O) OH, -C (O) OCi- ₆ alkyl, -C (O) NH _2, -C (O) NHCi_ ₆ alkyl, -C (O) N (CI ₆ alkyl) ₂ and -S (O) ₂ Cl - ₆ alkyl; provided that at least one of R to R, but not all of R to R ¹⁰ , is hydrogen; or a salt like this. 12. Compound, according to any of the preceding claims, characterized by the fact that: n represents the number 1 or 2; or a salt like this. 13. Compound, according to any of the preceding claims, characterized by the fact that: each R ⁷ is independently halogen or -CN eq is 1 or 2; 442/452 12/20 or a salt of this. 14. A compound, according to any of the preceding claims, characterized by the fact that: W, X and Y are -CH =, provided that the hydrogen in each -CH = can be replaced by a substituent R ⁷ , if present; or a salt like this. 15. Compound characterized by being selected from: Ia-25 Cl N Chiral Ia-27 OH jQ> ° CI ^^ N H Chiral 443/452 13/20 Ia-28 The _f ~ ^{N OH} Cl Ti jõSX _C, AAn Chiral O ^ ^OH O Ia-29 Cl J <j vx ^N > c, AAn Chiral oA O Cl _F ^N \ Í Ia-30 Xf so xy5x ci- ^ A Chiral 444/452 14/20 Ia-32 O ^ ^OH H Chiral Ia-33 O ^ ^OH Cl jfY 1 / nA CI ^ An H Chiral Ia-34 O ^ ^OH ci f ⁿ * À H Chiral 445/452 15/20 Ia-35 O ^ ^OH ci r- ^N * I icfev CI ^^ N Chiral Ia-36 O ~ - ^OH ci f ⁿ ^ X Cl _H Ia-38 O ^ ^OH ci f ⁿ * X Cl _H Chiral 446/452 16/20 Ia-40 oA ^{H c |} _f ⁿ OT H Chiral Ia-43 oA ^H Cl JCj nA cAAn Chiral Ia-50 H o _v ^N > A '—oh ci _f ⁿ 0Í ₀ , ΛΛν H Chiral 447/452 17/20 or a salt of this. 16. Synthetic intermediate characterized by being formula B-20 of 448/452 18/20 where: R ² , R ³ , R ⁴ , R ⁷ , A, V, W, X, Y, req are defined as in any one of claims 1 to 14. 17. Use of a synthetic intermediate of formula B-20, as defined in claim 16 - or a salt thereof characterized in that it is in the synthesis of compounds (I) or (Ia), as defined in any one of claims 1 to 14. A compound according to any one of claims 1 to 15 - or a pharmaceutically acceptable salt thereof characterized by the fact that it is for use as a medicament. 19. Pharmaceutical composition characterized in that it comprises at least one compound, as defined in any one of claims 1 to 15, - or a pharmaceutically acceptable salt thereof - and a pharmaceutically acceptable carrier. 20. Pharmaceutical preparation characterized by comprising a compound, as defined in any one 449/452 19/20 of claims 1 to 15, - or a pharmaceutically acceptable salt thereof - and at least one other cytostatic and / or cytotoxic active substance. 21. Method for synthesizing the intermediate B-20 ( ^Rl ! R characterized by the fact that it comprises a reaction of a compound B-2 B-2 with a B-19 imine where: 450/452 20/20 2 3 4 7 R, R, R, R, A, V, W, X, Y, r and q are defined as in any of the preceding claims. 451/452 1/1