EA045482B1 - NEW LXR MODULATORS WITH BICYCLIC CENTRAL FRAGMENT - Google Patents

Description

State of the art

The liver X receptors, LXRa (NR1H3) and LXRe (NR1H2), are members of the nuclear receptor superfamily of proteins. Both receptors form heterodimeric complexes with retinoid receptor X (RXRa, β or γ) and bind to LXR response elements (eg, DR4-type elements) located in the promoter regions of LXR-responsive genes. Both receptors are transcription factors that are physiologically regulated by binding ligands such as oxysterols or intermediates in cholesterol biosynthesis cascades such as desmosterol. In the absence of ligand, the LXR-RXR heterodimer presumably remains associated with the DR4-type element in complex with corepressors such as NCOR1, leading to the repression of the corresponding target genes. Upon binding of an agonist ligand, either endogenous, such as the oxysterols or intermediate steroids mentioned above, or a synthetic pharmacological ligand, a change in the conformation of the heterodimeric complex occurs, leading to the release of corepressor proteins and the recruitment of coactivator proteins, such as NCOA1 (SRC1), resulting in to transcriptional stimulation of the corresponding target genes. While LXRe is expressed in most tissues, LXRa is expressed more selectively in cells of the liver, intestine, adipose tissue and macrophages. The relative expression of LXRa and LXRe at the mRNA or protein level may vary between tissues within a species or among different species within a given tissue. LXRs regulate reverse cholesterol transport, i.e. mobilization of tissue-bound peripheral cholesterol into HDL, and from there into bile and feces, through transcriptional control of target genes such as ABCA1 and ABCG1 in macrophages and ABCG5 and ABCG8 in the liver and intestine. This explains the antiatherogenic activity of LXR agonists in dietary LDLR-KO mouse models. However, LXRs also regulate the transcription of genes involved in lipogenesis (eg, Srebp1c, Scd1, Fasn), which are the main cause of hepatic steatosis observed after long-term treatment with LXR agonists.

The tendency to cause hepatic steatosis is a major obstacle to the development of non-selective LXR agonists for the treatment of atherosclerosis.

Non-alcoholic fatty liver disease (NAFLD) is considered a manifestation of metabolic syndrome in the liver, and the incidence of NAFLD is spreading worldwide at epidemic rates (Estes et al., Hepatology 2018;67:123; Estes et al., J. Hepatol. 2018;69: 896). NAFLD pathologies range from benign and reversible steatosis to steatohepatitis (non-alcoholic steatohepatitis, NASH), which can progress to fibrosis, cirrhosis, and potentially further further to hepatocellular carcinogenesis. Classically, a two-stage model is used to describe the progression of NAFLD to NASH, in which hepatic steatosis is considered as the initial, first stage of sensitization to secondary signals (exogenous or endogenous), which leads to inflammation and liver damage (Day et al., Gastroenterology 1998; 114:842 ). The transition from benign NAFLD to the more aggressive state of NASH is now considered to be multifactorial, with genetic, environmental, lifestyle, and nutritional factors playing different roles in different individual circumstances. Regardless of disease etiology, there is a significant unmet medical need to halt the progression of NAFLD, which is driven by detrimental sequelae such as liver cirrhosis, hepatocellular carcinoma, or other forms of liver injury.

LXR expression levels are closely associated with NAFLD status. In particular, LXR expression has been shown to correlate with the degree of fat deposition as well as liver inflammation and fibrosis in patients with NAFLD (Ahn et al., Dig. Dis. Sci. 2014;59:2975). In addition, serum and liver desmosterol levels are increased in patients with NASH, but not in people with simple hepatic steatosis. Desmosterol has been described as an effective endogenous LXR agonist (Yang et al., J. Biol. Chem. 2006;281:27816). Given the known involvement of LXRs as master regulators of hepatic lipidogenesis and fat metabolism in general, and the aforementioned association of LXR expression levels with the stage of fatty liver disease, patients with NAFLD/NASH should benefit from blocking increased LXR activity in the liver using small molecule antagonists or inverse agonists that block LXR activity. When doing this, care must be taken to ensure that such LXR antagonists or inverse agonists do not interact with LXR in peripheral tissues or macrophages to avoid interfering with the anti-atherosclerotic reverse cholesterol transport driven by LXR in these tissues or cells.

Some publications (eg, Peet et al., Cell 1998;93:693 and Schultz et al., Genes Dev. 2000;14:2831) highlight the role of LXRa, in particular in relation to the stimulation of lipidogenesis and, consequently, the formation of NAFLD in liver. They indicate that LXRa is primarily responsible for hepatic steatosis, therefore, an LXRa-specific antagonist or inverse agonist may be useful or necessary for the individual treatment of hepatic steatosis. However, these data were obtained only when LXRa, LXRe, or double knockout mice were compared in wild-type mice regarding their susceptibility to developing steatosis on a high-fat diet. They do not take into account the significant difference in the relative expression levels of LXRa and LXRe in human liver as opposed to mouse liver

- 1 045482 liver. While LXRa is the predominant LXR subtype in rodent liver, in human liver LXRe is expressed to approximately the same, if not greater extent, than LXRa (data from Unigene or other expression databases). This was demonstrated by testing a selective LXRe agonist in a phase I human clinical trial (Kirchgessner et al., Cell Metab. 2016;24:223), which resulted in the onset of severe hepatic steatosis, although it was shown not to activate human LXRa.

Thus, it can be assumed that a significant preference for a specific LXR subtype should be excluded for an LXR modulator intended to treat NAFLD or NASH. A certain degree of selectivity for any LXR subtype may be acceptable if the pharmacokinetic profile of such compound clearly provides sufficient hepatic exposure and residence time to cover both LXRs in clinical use.

Thus, for the treatment of diseases such as NAFLD or NASH, LXR modulators that block LXR in a hepatoselective manner are needed, and this can be achieved through the hepatotropic pharmacokinetics and tissue distribution properties that such LXR modulators should have.

In all major cell types studied to date, LXRs are the major regulator of lipidogenesis. Cancer cells also rely heavily on de novo lipidogenesis, and therefore Flaveny et al. tested the inverse agonist, pharmacologically active compound SR9243 in cancer cells and animal models of cancer (Cancer Cell 2015;28:42). Trials have shown that SR9243 inhibits lipogenesis together with the Warburg effect of glycolysis in general, and that this molecular effect leads to apoptosis and reduced tumor growth in vivo.

State of the art

The publication by Zuercher et al. the structurally unrelated tertiary sulfonamide GSK2033 was first described as an effective cell-active LXR antagonist (J. Med. Chem. 2010;53:3412). The compound was later described to exhibit a significant degree of promiscuity, affecting a number of other nuclear receptors (Griffett & Burns, Biochem. Biophys. Res. Commun. 2016; 479:424). GSK2033 is reported to have rapid clearance (Cl _int >1.0 mL/min/mg protein) in rat and human liver microsomal assays, and that this rapid hepatic metabolism of GSK2033 precludes its use in vivo. Therefore, GSK2033 is a valuable chemical probe only for cell-based LXR studies.

GSK2033

WO 2014/085453 describes the preparation of structurally unrelated small molecule LXR inverse agonists of formula (A), in addition to the structure of GSK2033 presented above:

SRS238

Example 9

SR10388

SR9243

Several publications, mainly from the same group of researchers/inventors, further describe, in particular, the following compounds from this application: SR9238 is described as a liver-selective LXR inverse agonist that suppresses hepatic steatosis when administered parenterally (Griffett et al., ACS Chem Biol 2013;8:559). Saponification of the SR9238 ester produces the LXR inactive acid derivative SR10389. Said compound then exerts a systemic effect. In addition, SR9238 has been described to suppress fibrosis in the NASH model, also after parenteral administration (Griffett et al., Mol. Metab. 2015; 4:35). The related SR9243 has been shown to affect aerobic glycolysis (Warburg effect) and lipogenesis (Flaveny et al., Cancer Cell 2015;28:42), and NASH suppression data for SR9238 have been confirmed by Huang et al. (BioMed Res. Int. 2018; 8071093) using SR9243.

WO 2003/082802 describes structurally unrelated LXR agonists of general formula (B)

- 2 045482

In all examples, the acid-containing (hetero)aryl moiety is linked to the rest of the molecule via an oxygen atom. The most interesting examples are GW3965 (Collins et al. J. Med.

Chem. 2002;45:1963) and clinical candidate RGX-104 from Rgenix.

The publication by Yu et al. (J. Org. Chem. 2018;83:323) describes the synthesis of 2,3-disubstituted indoles according to

at the 3-position of indole in the following reaction scheme. The only example with an ortho-substituted aryl is structure C1.

WO 2016/207217 describes bicyclic derivatives of formula (D), which are not included in the scope of the present invention, since it is not possible to have an -SO ₂ -linked moiety for A, which may be a bicyclic structure including indole. However, intermediate D1 is described (Example 69, Step E), which is the only example with an ortho-substituted aryl at the indole 3-position.

where R represents an optionally substituted heterocyclic or heterobicyclic group, R ⁸ is selected from a wide range of substituents, including -SO2R ⁹ . The R ⁹ moiety may be selected from a wide range of substituents, including C ₃ -C ₈ -cycloalkyl and heterocycloalkyl. The only examples in which both the 2- and 3-positions of the azaindole are replaced by a cyclic moiety are structures E1 and E2.

WO 2013/111150 describes adamantane derivatives of formula (F) as 17βhydroxysteroid dehydrogenase type 1 inhibitors

where Ar represents an optionally substituted C ₁ -C ₁₈ -heteroaryl group, A may represent -SO2- and B may be absent. Examples not included within the scope of the present invention are not given.

WO 2013/028999 describes structures of formula (G) as potential therapeutic agents for the treatment of neuropsychiatric disorders

- 3 045482 where Z may be absent and A is a ring structure, for example a 3-substituted indole of formula (G1). Here, R ¹⁵ and R ¹⁷ may be selected from optionally substituted aryl and heteroaryl moieties. However, no examples are provided for this case.

WO 2013/012649 describes azaindoles of formula (H) for the treatment of HIV

1 ^r5 t( ⁿ )

L.- _r 7 wherein the linker element L may be -SO ₂ -, R ⁵ and R ⁶ may be independently selected from a wide range of substituents including optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In most cases, R ² is a carboxylic acid or a bioisostere thereof. Examples not included within the scope of the present invention are not given.

WO 2010/124793 and WO 2008/132434 describe azaindoles of formula (J) as fungicides

where R ⁴ can be selected from a wide range of substituents, including optionally substituted cyclyl, heterocyclyl, aryl and heteroaryl. R ³ may be selected from a wide range of substituents, including -SO2R ¹² , wherein R ¹² may also be selected from a wide range of substituents, including optionally substituted cyclyl, heterocyclyl, aryl and heteroaryl. The only example in which both the 2- and 3-positions of azaindole are replaced by a cyclic moiety is structure J1.

WO 2010/010186 describes JAK kinase inhibitors of formula (K)

R ^3b (CR ^4b _R 4C) _n

O"^(k> where the Cy ring is selected from aryl and heteroaryl. If L ¹ is SO ₂ , n is 0, R ^3a is, for example, unsubstituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and R ^3b is selected from optionally substituted cycloalkyl , heterocycloalkyl, aryl or heteroaryl, derivatives may be constructed within the scope of the present invention, but examples are not provided.

WO 2009/032116 describes indoles of formula (L) for the treatment of viral infections

where R ¹ can be selected from a wide range of substituents, including -SO2-. For R ² cyclic fragments (L1-L3) are possible, and for R ³ cyclic fragments (L4-L5) are possible. In related applications WO 2009/032125 and WO 2009/064848, additional cyclic fragments for R ³ are possible. R ¹⁰ can be selected from optionally substituted cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. In WO 2009/064852 a cyclic fragment of the L6 structure for R ³ is possible. All applications lack examples that fall within the scope of the present invention.

WO 2008/116833 describes azetidine compounds of formula (M) for the treatment of disorders that are susceptible to modulation of the serotonin 5-hydroxytryptamine-6 (5-HT6) receptor

where X ¹ and X ² independently represent N or CR ^x . The R ^x moiety may be selected from a wide range of substituents, including optionally substituted phenyl or C ₃ - ₆ -cycloalkyl. The residue A may be selected from optionally substituted C ₃ - ₆ -cycloalkyl, aryl or heteroaryl. No examples are described in which both the 2- and 3-positions of the indole are directly replaced by a cyclic moiety.

WO 2008/003736 describes azaindoles of formula (N)

- 4 045482 where R ² and R ³ may independently contain a saturated nitrogen-containing heterocyclic moiety (for example, piperidine), and m may be equal to 0. In accordance with claim 8

Q may represent a protecting group -SO ₂ -Ph. There are no examples described in which both positions,

The 2- and 3-positions of the indole are directly replaced by a cyclic moiety.

WO 2007/075555 describes CB1 antagonists of formula (P)

where R ¹ can be selected from a wide range of substituents, including substituted indole, and X can represent a bond. The only example in which the cyclic moiety is linked to the 3-position of the indole is structure P1. More specifically, indole derivatives of formula (P) are described in WO 2004/000831 as histamine H3 antagonists, and the structure of P1 is also an example.

WO 2007/134169 and WO 2006/050236 describe indole derivatives of formula (Q) as inhibitors of TNF-α production

where X may be SO ₂ , Y may be selected from a wide range of substituents including cycloalkyl, heterocycloalkyl, aryl and heterocycle, and Z may be selected from -B(OR) ₂ , -CONROR and -N(OR)COR (where R = H or alkyl). R ³ and R ⁸ can be independently selected from a wide range of substituents, including cycloalkyl and a 5- or 6-membered organic ring. No examples are described in which both the 2- and 3-positions of the indole are replaced by a cyclic moiety.

WO 2005/034941 describes bicyclic structures of formula (R) as inhibitors of hepatitis C virus polymerase

where Ar ¹ and Ar are 5-10 membered aromatic rings, A ¹ may be cycloalkyl (optionally substituted with an alkoxy group) and n may be 0. Closest examples to the present invention are the structures R1 and R2.

WO 2005/14000 describes indoles of formula (S) for the treatment of diseases associated with the 5-HT6 receptor, such as obesity and central nervous system disorders

where R ¹ is a nitrogen-attached saturated or unsaturated heterocyclic ring system, R ² can be selected from a wide range of substituents including saturated or unsaturated cycloalkyl, n is selected from 0 to 4, and residues A and B form a saturated or unsaturated cycloalkyl ring . No examples are described in which both the 2- and 3-positions of the indole are directly substituted (ie n=0) by a cyclic moiety.

WO 2002/51837 and WO 2002/36562 describe bicyclic structures of formulas (T) and (T1), respectively, for the treatment of diseases associated with the 5-HT6 receptor

- 5 045482 where X and Y may independently represent a carbon atom that is optionally substituted with an aryl or heteroaryl moiety, R ⁸ may also be an optionally substituted aryl or heteroaryl moiety. The cyclic moiety on the left side of formula (T1) is typically piperazine. No examples are described in which both the 2- and 3-positions of the (aza)indole are replaced by a cyclic moiety (eg, aryl or heteroaryl).

The closest example is the T1 structure.

WO 2002/32863 describes indoles of formula (U) for the treatment of diseases associated with the 5-HT6 receptor

where Ar can be selected from optionally substituted phenyl, naphthyl or 5-10 membered mono or bicyclic heterocyclic moieties, R ² can be unsubstituted phenyl, and R ³ is selected from hydrogen or 3-(1-azabicyclo[2.2.2]oct- 2-en)ila. However, there are no examples with suitable substitution at the 2- and 3-position of indole; the closest examples are the structures U1 and U2.

WO 9921851 describes structures of formula (V) for agricultural or horticultural fungicides

where A can be selected from a very wide range of cyclic systems, including optionally substituted indole. However, there are no examples with suitable substitution at the 2- and 3-position of indole; the closest example is the V1 structure.

WO 9857931 and WO 9822452 describe bicyclic structures of formulas (W) and (W1), respectively, as antimicrobial agents

where R ² can be selected from a very wide range of residues, including aryl and heteroaryl; and Y may be NR, where R is selected from a very wide range of residues, including an arylsulfonyl moiety. There are no examples with substitution at the 2- and 3-position of indole; the closest example is the W1 structure.

WO 9822457 describes bicyclic structures of formula (X) as anti-inflammatory agents,

where R ¹⁰ can be selected from a very wide range of substituents, including SO2R ³⁰ ; and wherein R ¹¹ , R ¹² , R ³⁰ may be selected from optionally substituted aryl and heteroaryl. However, examples where R ¹⁰ actually contains an SO ₂ -linked moiety are not shown.

- 6 045482

In WO 2001/30343, WO 2000/46199, WO 2000/46197, WO 2000/46195, JP 06145150, EP 0535926, EP

0535925 describes indole derivatives in which a 1H- or 2H-tetrazol-5-yl moiety can be attached at the 2-position of the indole moiety as the only possible cyclic moiety that acts as a carboxylic acid bioisostere. The only example with such a directly linked tetrazole moiety is described in JP 06145150 (structure Y1).

WO 2008/119657 describes imidazolidinone derivatives of formula (Z) binding to LXR, structure (Z1) being given as an illustrative example

The following four structures have been found to bind weakly to another nuclear receptor target and are therefore listed as initial hits in a confidential collaboration with another pharmaceutical company:

The essence of the invention

The present invention relates to compounds of formula (I)

to their glycine conjugates, tauroconjugates, enantiomers, diastereomers, tautomers, Noxides, solvates, prodrugs and pharmaceutically acceptable salts, where the rings A, B, C, D and the residues L and R ¹ have the meaning defined in claim 1.

The compounds of the present invention have the same or greater LXR inverse agonist activity as known LXR inverse agonists. In addition, the compounds of the present invention exhibit a preferential liver/blood ratio after oral administration, so that the impairment of anti-atherosclerotic reverse cholesterol transport controlled by LXR in peripheral macrophages can be excluded. The introduction of an acidic moiety (or its bioisostere) can improve additional parameters such as microsomal stability, solubility and lipophilicity.

Thus, the present invention further relates to a pharmaceutical composition containing compounds of formula (I) and at least one pharmaceutically acceptable carrier or excipient.

The present invention further relates to compounds of formula (I) for use in the prevention and/or treatment of diseases mediated by LXR.

Accordingly, the present invention relates to the prevention and/or treatment of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hypercholesterolemia in nephrotic syndrome, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis and hepatitis C virus infection.

Detailed Description of the Invention

The desired LXR modulator properties combined with hepatoselectivity can be achieved

- 7 045482 using compounds that have the structural structure represented by formula (I)

their glycine conjugates, tauroconjugates, enantiomers, diastereomers, tautomers, Noxides, solvates, prodrugs and pharmaceutically acceptable salts, is an annulated 5-6-membered ring forming a 6-membered aryl or 5-6-membered heteroaryl containing from 1 to 3 heteroatoms, independently selected from N, O and S, wherein said ring is unsubstituted or substituted with 1-4 substituents independently selected from the group consisting of halogen, CN, SF ₅ , NO 2 , C ₁ . ₆ alkyl, oxo, Co. ₆ alkylene-OR ¹¹ , C ₀ - ₆ alkylene-(3-6-membered cycloalkyl), C ₀ - ₆ alkylene-(3-6-membered heterocycloalkyl), C ₀ . ₆ αalkylene-S(O) _n R ¹¹ ,

From ₀ . ₆ alkylene-NR ¹¹ S(O)2R ¹¹ , C0. ₆ alkylene-S(O) ₂ NR ¹¹ R ¹² , C0.6alkylene-NR ¹¹ S(O)2NR ¹¹ R ¹² , C0.6alkylene-Co2R ¹¹ , O-C1. ₆ alkylene-CO ₂ R ¹¹ , C0.6 alkylene-O-COR ¹¹ , C0. ₆ alkylene-CONR ¹¹ R ¹² , C ₀ . ₆ alkylene-NR ¹¹ -COR ¹¹ ,

From ₀ . ₆ alkylene-NR ^Π -CONR ^Π R ¹² , C0.6 alkylene-O-CONR ¹¹ R ¹² , C0. ₆ alkylene-NR ¹¹ -CO2R ¹¹ and C0. ₆ alkylene-NR ¹¹ R ¹² where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ -C1. ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C ₁ . ₄ alkyl, halogen-C1_ ₄ alkyl, OC ₁ . ₄ alkyl and O-halogen-C1_ ₄ alkyl;

and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein the newly formed ring is unsubstituted or substituted 1 -3 substituents independently selected from halogen, CN, C ₁ . ₄ alkyl, halogen-C1_ ₄ alkyl, 3-6-membered cycloalkyl, halogen-(3-6-membered cycloalkyl), 3-6-membered heterocycloalkyl, halogen-(3-6-membered heterocycloalkyl), OH, oxo, CO2H , CO ₂ -C1. ₄ alkyl, CONHCH ₂ Co ₂ H, CONH(CH2)2SO ₃ H, OC ₁ . ₄ αlkyl and O-haloC1_ ₄ alkyl;

® is selected from the group consisting of 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from N, O and S, 6-14 membered aryl and 5-14 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, SF ₅ , NO2, oxo, C ₁ . ₄ αlkyl, C ₀ . ₆ alkylene-OR ²¹ , C0_6alkylene-(3-6-membered cycloalkyl), C0_6alkylene-(3-6-membered heterocycloalkyl), C0.6alkylene-S(O)nR ²¹ , C0. ₆ alkylene-NR ²¹ S(O)2R ²¹ , C0. ₆ alkylene-S(O) ₂ NR ²¹ R ²² , C0-6alkyleneNR ²¹ S(O)2NR ²¹ R ²² , C0.6αalkylene-CO2R ²¹ , O-C1. ₆ alkylene-Co ₂ R ²¹ , C0.6αalkylene-O-COR ²¹ , C0- ₆ alkyleneCONR ²¹ R ²² , Co.6alkylene-NR ²¹ -COR ²¹ , Co.6alkylene-NR ²¹ -CONR ²¹ R ²² , Co.6αalkylene -O-CONR ²¹ R ²² , Smalkilen-NR ²¹ -CO2R ²¹ and C0. ₆ alkylene-NR ²¹ R ²² where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ -C1_ ₄ alkyl, CONHCH2CO2H, CONH(CH2 )2SO ₃ H, C ₁ . ₄ alkyl, halogen-C1_ ₄ alkyl, OC ₁ . ₄ alkyl and O-halo-C1_ ₄ alkyl;

and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C1. ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C ₁ . ₄ αlkyl, halogen-C1_ ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C1_ ₄ alkyl;

and wherein optionally two adjacent substituents on the cycloalkyl or heterocycloalkyl moiety form a 5-6 membered unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, wherein said additional ring is unsubstituted or substituted 1-4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C1. ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C ₁ . ₄ αlkyl, halogen-C1_ ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C1_ ₄ alkyl;

® is selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl containing from 1 to 3 heteroatoms independently selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted 1-4 substituents independently selected from the group consisting of halogen, CN, SF ₅ , NO 2 , oxo, C ₁ . ₄ αlkyl, C ₀ . ₆ alkylene-OR ³¹ , C ₀ - ₆ alkylene-(3-6-membered cycloalkyl), C ₀ - ₆ alkylene-(3-6-membered heterocycloalkyl), C ₀ _ ₆ alkylene-(6-membered aryl), C ₀ _ ₆ alkylene-(5-6-membered heteroaryl), C ₀ _ ₆ alkylene-8 045482

S(O)nR ³¹ , Co-6alkylene-NR ³¹ S(O)2R ³¹ , Co-6alkylene-S(O)2NR ³¹ R ³² , Co-6alkylene-NR ³¹ S(O)2NR ³¹ R ³² , C0- 6alkylene-CO2R ³¹ , O-C1-balkylene-CO ₂ R ³¹ , C0-balkylene-O-CoR ³¹ , C0-balkylene-CONR ³¹ R ³² , C0.6alkylene-NR ³¹ COR ³¹ , C0-balkylene-NR ³¹ - CONR ³¹ R ³² , C0-balkylene-O-CONR ³¹ R ³² , C0-balkylene-NR ³¹ -CO2R ³¹ and _C0-6 alkyleneNR ³¹ R ³² , where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ C _1-4 alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C _1-4 alkyl, halogen-C _1-4 alkyl, OC _1-4 alkyl and Ohalo-C _1-4 alkyl;

and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C ₁ - ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C ₁ . ₄ αlkyl, halogen-C ₁ - ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C ₁ - ₄ alkyl;

® is selected from the group consisting of 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from N, O and S, 6-14 membered aryl and 5-14 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, SF ₅ , NO2, oxo, C ₁ . ₄ αlkyl, C ₀ . ₆ alkylene-OR ²¹ , C0-6alkylene-(3-6-membered cycloalkyl), C0-6alkylene-(3-6-membered heterocycloalkyl), C0.6alkylene-S(O)nR ²¹ , C0. ₆ alkylene-NR ²¹ S(O)2R ²¹ , C0. ₆ alkylene-S(O) ₂ NR ²¹ R ²² , C0-6alkyleneNR ²¹ S(O)2NR ²¹ R ²² , C0.6αalkylene-CR ⁴¹ (=N-OR ⁴¹ ), C0. ₆ alkylene-CO ₂ R ²¹ , O-C1.6alkylene-CO2R ²¹ , C0- ₆ alkyleneO-COR ²¹ , Co-6alkylene-CONR ²¹ R ²² , Co_6alkylene-NR ²¹ -COR ²¹ , Co_6alkylene-NR ²¹ -CONR ²¹ R ²² , C0-6alkylene-ОCONR ²¹ R ²² , Co_6alkylene-NR ²¹ -CO2R ²¹ and Co_6αalkylene-NR ²¹ R ²² , where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ -C ₁ - ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, CO-OC ₁ - ₄ alkyl, C ₁ . ₄ alkyl, halogen-C ₁ - ₄ alkyl, OC ₁ . ₄ alkyl and Ohalogen-C ₁ - ₄ alkyl;

and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C ₁ - ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C ₁ . ₄ αlkyl, halogen-C ₁ - ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C ₁ - ₄ alkyl;

and wherein optionally two adjacent substituents on the cycloalkyl or heterocycloalkyl moiety form a 5-6 membered unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, wherein said additional ring is unsubstituted or substituted 1-4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C ₁ - ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C ₁ _ ₄ αlkyl, halogen-C ₁ - ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C ₁ - ₄ alkyl;

™ ® 1 p wherein o has a substituent from the above in the 1,2-orientation relative to the bond with ν or has an annulated additional ring in the 1,2-orientation;

L is selected from the group consisting of the bond, C ₁ . ₆ αalkylene, C ₂ - ₆ alkenylene, C ₂ - ₆ alkynylene, 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene containing from 1 to 4 heteroatoms independently selected from N, O and S, 6- or 10-membered arylene and a 5-10 membered heteroarylene containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene are unsubstituted or substituted with 1-6 substituents independently selected from group consisting of halogen, CN, SF ₅ , NO2, oxo, C ₁ . ₄ αlkyl, C ₀ . ₆ αlkylene-OR ⁴¹ , C0-6alkylene-(3-6-membered cycloalkyl), C0-6alkylene-(3-6-membered heterocycloalkyl), C0.6alkylene-S(O)nR ⁴¹ , _C0-6 alkyleneNR ⁴¹ S( O)2R ⁴¹ , Co_6alkylene-S(O)2NR ⁴¹ R ⁴² , Co_6alkylene-NR ⁴¹ S(O)2NR ⁴¹ R ⁴² , Co_6alkylene-CO2R ⁴¹ , OC^kylene-cO2R ⁴¹ , CO_ ₆ alkylene-O-COR ⁴¹ , С0_6alkylene _- CONR ⁴¹ R ⁴² , С0_ ₆ alkylene-NR ⁴¹ -COR ⁴¹ , С _{0_6} alkylene-NR ⁴¹ CONR ⁴¹ R ⁴² , Co_6alkylene-O-CONR ⁴¹ R ⁴² , Co_6alkylene-NR ⁴¹ -CO2R ⁴¹ and Сo_6αalkylene-NR ⁴¹ R ⁴² where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO ₂ H, CO ₂ -C ₁ - ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, C ₁ . ₄ alkyl, halogen-C ₁ - ₄ alkyl, OC ₁ . ₄ alkyl and O-halogen-C ₁ - ₄ alkyl;

and wherein optionally two adjacent substituents on the arylene and heteroarylene moieties form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO ₂ H, CO ₂ -C ₁ - ₄ alkyl, C ₁ . ₄ alkyl, halogen- 9 045482

_C1-4 alkyl, OC _{1_4} alkyl and O-halo- _C1-4 alkyl _;

R ¹ is selected from the group consisting of H, halogen, CN, SF5, NO2, oxo, C1-4alkyl, C0-6alkylene-OR ⁴¹ , Y-C0_ ₆ alkylene-(3-6-membered cycloalkyl), Y-C ₀ _ ₆ alkylene-(3-6-membered heterocycloalkyl), Y-C0 ₆ alkylene-(6-membered aryl), Y-C ₀ _ ₆ alkylene-(5-6-membered heteroaryl), C ₀ _ ₆ alkylene-S (=O)(-R ⁴¹ )=NR ⁷⁵ , X-C1_6alkylene-S (=O)(-R ⁴¹ )=NR ⁷⁵ , С0-6alkylene-S(O) _n R ⁴¹ , X-C1-6alkylene-S (O)nR ⁴¹ , C0-6alkylene-S(=NR ⁷¹ )R ⁴¹ , X-C1_6alkylene-S(=NR ⁷¹ )R ⁴¹ , C0-6alkylene-S(O)(=NR ⁷¹ )R ⁴¹ , X- C1-6alkylene-S(O)(=NR ⁷¹ )R ⁴¹ , _C0-6 alkyleneS(=NR ⁷¹ )2R ⁴¹ , X-C1_ ₆ alkylene-S(=NR ⁷¹ )2R ⁴¹ , C0-6alkylene-NR ⁴¹ S (O)2R ⁴¹ , X-C1-6alkylene-NR ⁴¹ S(O)2R ⁴¹ , С0-6alkylene-S(O) ₂ NR ⁴¹ R ⁴² , X-C1-6alkylene-S(O)2NR ⁴¹ R ⁴² , С0-6alkylene-NR ⁴¹ S(O)2NR ⁴¹ R ⁴² , X-C1_ ₆ alkyleneNR ⁴¹ S(O)2NR ⁴¹ R ⁴² , С0-6alkylene-SO ₃ R ⁴¹ , X-C1-6alkylene-SO3R ⁴¹ , С0- 6alkylene-CO ₂ R ⁴¹ , X-C1-6alkylene-CO2R ⁴¹ , C0-6alkylene-O-COR ⁴¹ , X-C1-6alkylene-O-COR ⁴¹ , C0-6alkylene-CONR ⁴¹ R ⁴² , X-C1-6alkylene -CONR ⁴¹ R ⁴² , C0-6alkylene-CONR ⁴¹ OR ⁴¹ , X-C1-6alkylene-CONR ⁴¹ OR ⁴¹ , C0-6alkylene-CONR ⁴¹ SO2R ⁴¹ , X-C1_ ₆ alkyleneCONR ⁴¹ SO2R ⁴¹ , C0_ ₆ alkylene-NR ⁴¹ -COR ⁴¹ , X-C1-6С0-6alkylene-NR ⁴¹ -COR ⁴¹ , С0-6alkylene-NR ⁴¹ -CONR ⁴¹ R ⁴² , XC1_6alkylene-NR ^{41 -CONR} 41 R ⁴² , С0-6alkylene-O-CONR ⁴¹ R ⁴² , X-C1-6alkylene-O-CONR ⁴¹ R ⁴² , С0_ ₆ alkylene-NR ⁴¹ CO2R ⁴¹ , X-C1-6alkylene-NR ⁴¹ -CO2R ⁴¹ , С0-6alkylene-NR ⁴¹ R ⁴² , X-C1-6alkylene- NR ⁴¹ R ⁴² where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ C _1-4 alkyl, CONHCH2CO2H, CONH ( _CH2 )2SO ₃ H, C _{1_4} alkyl, halogen-C _1-4 alkyl, OC _{1_4} alkyl and _Ohalogen -C _1-4 alkyl;

and wherein optionally two adjacent substituents on the aryl and heteroaryl moieties form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C1- ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C ₁ _ ₄ alkyl, halogen-C1- ₄ alkyl, OC ₁ _ ₄ alkyl and O-halogen-C1- ₄ alkyl;

R ¹¹ , R ¹² , R ²¹ , R ²² , R ³¹ , R ³² , R ⁴¹ , R ⁴² , R ⁵¹ are independently selected from H and C ₁ _ ₄ alkyl, wherein the alkyl is unsubstituted or substituted with 1-3 substituents, regardless selected from halogen, CN, C ₁ - ₄ alkyl, halo-C1- ₄ alkyl, 3-6 membered cycloalkyl, halo-(3-6 membered cycloalkyl), 3-6 membered heterocycloalkyl, halo-(3-6 -membered heterocycloalkyl), OH, oxo, CO ₂ H, CO ₂ -C1_ ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, SO3H, OC ₁ - ₄ alkyl and O-halogen-C1- ₄ alkyl;

or R ¹¹ and R ¹² , R ²¹ and R ²² , R ³¹ and R ³² , R ⁴¹ and R ⁴² , respectively, together with the nitrogen atom to which they are attached, complete a 3-6 membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms independently selected from O, S or N; and wherein the newly formed ring is unsubstituted or substituted with 1-3 substituents independently selected from halogen, CN, C ₁ - ₄ alkyl, halogen-C1- ₄ alkyl, 3-6 membered cycloalkyl, halogen-(3-6 membered cycloalkyl), 3-6-membered heterocycloalkyl, halogen-(3-6-membered heterocycloalkyl), OH, oxo, CO ₂ H, CO ₂ -C1- ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, SO3H , OC ₁ _ ₄ alkyl and Ohalo-C1- ₄ alkyl;

R ⁷¹ is independently selected from H, CN; NO2, C ₁ _ ₄ alkyl and C(O)-OC1- ₄ alkyl, wherein the alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halogen, CN, C ₁ _ ₄ alkyl, halogen-C1- ₄ alkyl, 3-6-membered cycloalkyl, halogen-(3-6-membered cycloalkyl), 3-6-membered heterocycloalkyl, halogen-(3-6-membered heterocycloalkyl), OH, oxo, CO ₂ H, CO ₂ -C1- ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, SO3H, OC ₁ _ ₄ alkyl and O-halo-C1- ₄ alkyl;

R ⁷⁵ is independently selected from C _{1_4} alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6- _membered aryl and 5-6 membered heteroaryl.

wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-3 substituents independently selected from halogen, CN, Me, Et, CHF2, CF ₃ , OH, oxo, CO2H, CONHCH2CO2H, CONH(CH2)2SO3H, SO3H , OMe, OEt, OCHF2 and OCF3;

X is independently selected from O, NR ⁵¹ , S(O)n S(=NR ⁷¹ ), S(O)(=NR ⁷¹ ) and S(=NR ⁷¹ )2;

Y is independently selected from the bond, O, NR ⁵¹ , S(O)n, S(=NR ⁷¹ ), S(O)(=NR ⁷¹ ) and S(=NR ⁷¹ )2;

n independently selected from 0 to 2;

and provided that the following structures are excluded:

In a preferred embodiment, in combination with any of the above or below embodiments, Q is an annulated 5-6 membered ring forming a 6-membered aryl or 5-6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, and the specified ring is unsubstituted or substituted with 1-4 substituents, not

- 10 045482 dependently selected from the group consisting of halogen, CN, SF ₅ , NO2, C1-6alkyl, oxo, _C0-6alkylene - ^OR11 , C0-6alkylene-(3-6-membered cycloalkyl), C0-6alkylene -(3-6-membered heterocycloalkyl), Co-6alkyleneS(O)nR11, Co-6alkylene-NR ¹¹ S(O)2R ¹¹ , Co-6alkylene-S(O)2NR ¹¹ R ¹² , Co-6alkylene-NR ¹¹ S(O)2NR ¹¹ R ¹² , С06alkylene-CO ₂ R ¹¹ , O-C1-6alkylene-CO2R ¹¹ , С0-6alkylene-O-COR ¹¹ , С0-6alkylene-CONR ¹¹ R ¹² , С0-6alkylene-NR ¹¹ COR ¹¹ , C0-6alkylene-NR ¹¹ -CONR ¹¹ R ¹² , C0-6alkylene-O-CONR ¹¹ R ¹² , C0-6alkylene-NR ¹¹ -CO2R ¹¹ and _C0-6 alkyleneNR ¹¹ R ¹² , where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ -C _1-4 alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C _1-4 alkyl, halogen -C _1-4 alkyl, O-C _1-4 alkyl and O-halogen-C _1-4 alkyl; and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein the newly formed ring is unsubstituted or substituted 1 -3 substituents independently selected from halogen, CN, C _1-4 alkyl, halogen-C _1-4 alkyl, 3-6 membered cycloalkyl, halo-(3-6 membered cycloalkyl), 3-6 membered heterocycloalkyl, halogen-(3-6-membered heterocycloalkyl), OH, oxo, CO2H, CO ₂ -C _1-4 alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, O-C _1-4 alkyl and O-haloC _1-4 alkyl

In a more preferred embodiment, in combination with any of the above or below embodiments, ® is an anlated phenyl, thiophenyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein said ring is unsubstituted or substituted with 1-4 substituents independently selected from group consisting of halogen, CN, SF5, NO2, C _1-6 alkyl, oxo, C _0-6 alkylene-OR ¹¹ , C0-6alkylene-(3-6-membered cycloalkyl), C0-6alkylene-(3-6-membered heterocycloalkyl), C0-6alkylene-S(O)nR ¹¹ , C0-6alkylene-NR ¹¹ S(O)2R ¹¹ , C0-6alkylene-S(O) ₂ NR ¹¹ R ¹² , C0-6alkylene-NR ¹¹ S(O )2NR ¹¹ R ¹² , C _0-6 alkylene-CO ₂ R ¹¹ , O-C1-6 alkylene-CO2R ¹¹ , C0-6 alkylene-O-COR ¹¹ , C0-6 alkylene-CONR ¹¹ R ¹² , C0-6 alkylene-NR ¹¹ -COR ¹¹ , C _0-6 alkylene-NR ¹¹ -CONR ^11R12 , C _0-6 alkylene-O-CONR ¹¹ R ¹² , C0-6 alkylene-NR ¹¹ -CO2R ¹¹ and C _0-6 alkylene-NR ¹¹ R ¹² , where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ -C _1-4 alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C _1-4 alkyl, halo-C _1-4 alkyl, O-C _1-4 alkyl and O-halo-C _1-4 alkyl.

In an even more preferred embodiment, in combination with any of the above or below embodiments

selected from

I 17 _ where is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, oxo, C _1-4 alkyl, halogen-C _1-4 alkyl, O-C _{1 -4} alkyl, O-halo-C _1-4 alkyl, NH2, NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , SO ₂ -C _1-4 alkyl and SO ₂ -halo-C _1-4 alkyl

In the most preferred embodiment, in combination with any of the above or below embodiments,

represents where ® is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of F, Cl, Br, CN, Me, Et, CF ₃ , CHF2, OH, OMe, OCF ₃ and OCHF3.

In a preferred embodiment, in combination with any of the above or below embodiments, ® is selected from the group consisting of 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from N, O and S, 6-14 membered aryl and 5-14 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-6 substituents, independently selected from the group consisting of halogen, CN, SF ₅ , NO ₂ , oxo, C _1-4 alkyl, C _0-6 alkylene-OR ²¹ , C0-6 alkylene-(3-6 membered cycloalkyl), C0-6 alkylene- (3-6-membered heterocycloalkyl), C0-6alkylene-S(O)n ²¹ , C0-6alkylene-NR ²¹ S(O)2R ²¹ , C0-6alkylene-S(O) ₂ NR ²¹ R ²² , C0-6alkyleneNR ²¹ S(O)2NR ²¹ R ²² , С0-6alkylene-CO2R ²¹ , O-C1-6alkylene-CO ₂ R ²¹ , С0-6alkylene-O-COR ²¹ , С0-6alkyleneCONR ²¹ R ²² , С0-6alkylene-NR ²¹ -COR ²¹ , C0-6alkylene-NR ²¹ -CONR ²¹ R ²² , C0-6alkylene-O-CONR ²¹ R ²² , C0-6alkylene-NR ²¹ -CO2R ²¹ and C0-6alkylene-NR ²¹ R ²² , where alkyl, alkylene , cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ -C _1-4 alkyl,

- 11 045482

CONHCH2CO2H, CONH(CH2)2SO ₃ H, C _1-4 alkyl, halogen-C _1-4 alkyl, OC _1-4 alkyl and O-halogen-C _1-4 alkyl;

and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C _1-4 alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C _1-4 αlkyl, halogen-C _1-4 alkyl, OC _1-4 alkyl and O-halogen-C _1-4 alkyl;

and wherein optionally two adjacent substituents on the cycloalkyl or heterocycloalkyl moiety form a 5-6 membered unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, wherein said additional ring is unsubstituted or substituted 1-4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C _1-4 alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C _1-4 αlkyl, halogen-C _1-4 alkyl, OC _{1 -4} αlkyl and O-halogen-C _1-4 alkyl.

In a more preferred embodiment, in combination with any of the above or below embodiments, ® is selected from the group consisting of phenyl, pyridyl and thiophenyl, wherein the phenyl, pyridyl and thiophenyl are substituted with 1-4 substituents independently selected from the group consisting of from halogen, CN, SF ₅ , NO2, oxo, C _1-4 alkyl, C _0-6 alkylene-OR ²¹ , C0-6 alkylene-(3-6 membered cycloalkyl), C0-6 alkylene-(3-6 membered heterocycloalkyl), C0-6alkylene-S(O)nR ²¹ , C0-6αalkylene-NR ²¹ S(O)2R ²¹ , C0-6alkylene-S(O) ₂ NR ²¹ R ²² , C0-6αalkylene-NR ²¹ S(O )2NR ²¹ R ²² , C0-6alkylene-CO2R ²¹ , O-C1-6alkylene-CO ₂ R ²¹ , C0-6alkylene-O-cOR ²¹ , C0-6alkylene-CONR ²¹ R ²² , C0-6alkylene-NR ²¹ -COR ²¹ , C0-6alkylene-NR ²¹ -CONR ²¹ R ²² , Co-6alkylene-O-CONR ²¹ R ²² , Co-6alkylene-NR ²¹ -CO2R ²¹ and Co-6alkylene-NR ²¹ R ²² , where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ -C _1-4 alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C _1-4 alkyl, halogen -C _1-4 alkyl, OC _1-4 alkyl and O-halo-C _1-4 alkyl;

and wherein optionally two adjacent substituents on the phenyl and pyridyl moieties form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C _1-4 alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C _1-4 αlkyl, halogen-C _1-4 alkyl, OC _1-4 αlkyl and O-halogen-C _1-4 alkyl.

In such a more preferred embodiment, in combination with any of the above or below embodiments, ® is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidinyl, thiophenyl, thiazolyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, pentacyclo[4.2.0.0 ^2.5 .0 ^3.8 .0 ^4.7 ]octyl and piperidinyl, where the specified ring is unsubstituted or substituted with 1-3 substituents , independently selected from the group consisting of F, Cl, Br, CN, OH, oxo, C _1-4 alkyl, halo-C _1-4 alkyl, OC _1-4 alkyl, O-halo-C _1-4 alkyl, C _1-4 alkyl-OH and halogen-C _1-4 alkyl-OH; and optionally two adjacent substituents on the phenyl ring together form the group -(CH2)3-, -(CH2)4-, -OCF2O- and -OCH2O-.

In an even more preferred embodiment, in combination with any of the above or below embodiments, ® is selected from the group consisting of phenyl and pyridyl, wherein the phenyl and pyridyl are substituted with 1-2 substituents independently selected from the group consisting of F, Cl , CN, CF3, CH2F and CHF2.

In the most preferred embodiment, in combination with any of the above or below embodiments, ® is 4-difluoromethylphenyl.

In a preferred embodiment, in combination with any of the above or below embodiments, © is selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl containing from 1 to 3 heteroatoms independently selected from N , O and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents independently selected from the group consisting of halogen, CN, SF ₅ , NO2, oxo, C _1-4 αlkyl, C _0-6 αlkylene-OR ³¹ , C _0-6 alkylene-(3-6-membered cycloalkyl), C _0-6 alkylene-(3-6-membered heterocycloalkyl), C _0-6 alkylene-(6-membered aryl), C _{0 -6} alkylene-(5-6-membered heteroaryl),

C _0-b alkylene-S(O) _n R ³¹ , NR ³¹ S(O)2NR ³¹ R ³² ,

C _0-6 alkylene-NR ³ 1S(O)2R ³¹ ,

C _0-6 αlkylene-S(O) ₂ NR ³¹ R ³² ,

C _0-6 alkylene-CO ₂ R ³¹ , O-C1-6 alkylene-CO2R ³¹ , C0-6 alkylene-O-COR ³¹ ,

C _0-6 alkyleneC _0-6 alkyleneCONR ³¹ R ³² , Co-balkylene-NR ³¹ -COR ³¹ , Co-balkylene-NR ³¹ -CONR ³¹ R ³² , Co-balkylene-O-CONR ³¹ R ³² , C0-6alkylene- NR ³¹ -CO2R ³¹ and C0-balkylene-NR ³¹ R ³² , where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or

- 12 045482 substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO2C _1-4 alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, C _1-4 alkyl, halogen-C1- ₄ alkyl, OC _1-4 alkyl and Ohalogen- _{C 1_4 alkyl} ;

and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C ₁ . ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C _1-4 alkyl, halogen-C1- ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C1. ₄ alkyl.

In a more preferred embodiment, in combination with any of the above or below embodiments, © is selected from the group consisting of phenyl, pyridyl and thiophenyl, wherein the phenyl, pyridyl and thiophenyl are unsubstituted or substituted with 1-4 substituents independently selected from the group , consisting of halogen, CN, SF ₅ , NO2, oxo, C1_ ₄ alkyl, C ₀ . ₆ αlkylene-OR ³¹ , C0_6alkylene-(3-6-membered cycloalkyl), C0-6alkylene-(3-6-membered heterocycloalkyl), C0-6alkylene-(6-membered aryl), C0-6alkylene-(5-6- member heteroaryl), С0.6alkylene-S(O)nR ³¹ , С0- _6alkylene -NR ³¹ S(O)2R ³¹ , Сo.6alkylene-S(O)2NR ³¹ R ³² , Сo.6alkylene-NR ³¹ S( O)2NR ³¹ R ³² , Co.6alkylene-CO2R ³¹ , O-C16αalkylene-CO2R ³¹ , C0. ₆ alkylene-O-COR ³¹ , C0.6 alkylene-CONR ³¹ R ³² , C0. ₆ alkylene-NR ³¹ -COR ³¹ , C ₀ - ₆ alkylene ^{NR 31} -CONR ³¹ R ³² , Co.6alkylene-O-CONR ³¹ R ³² , Co.6alkylene-NR ³¹ -CO2R ³¹ and Co.6alkylene-NR ³¹ R ³² where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO ₂ H, CO ₂ C1_ ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C1_ ₄ alkyl, halogen-C1_ ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C1_ ₄ alkyl;

and the residue -LR ¹ is connected in a 1,3-orientation relative to the bond with ©O and L is not a bond.

In an even more preferred embodiment, in combination with any of the above or below embodiments, © is selected from phenyl, pyridyl and thiophenyl; wherein phenyl, pyridyl and thiophenyl are unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of F, Cl, CN, OH, oxo, C ₁ . ₄ αlkyl, halogen-C1_ ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C1_ ₄ alkyl; and the residue -LR ¹ is bonded in the 1,3 orientation relative to the bond with θ^, and L is not a bond.

In the most preferred embodiment, in combination with any of the above or below embodiments, © is phenyl, wherein the phenyl is unsubstituted or substituted with F, Cl and Me;

and wherein the -LR ¹ residue is bonded in the 1,3 orientation relative to the c bond and L is not a bond.

In a preferred embodiment, in combination with any of the above or below embodiments,

L is selected from the group consisting of the bond, C ₁ . ₆ αalkylene, C ₂ - ₆ alkenylene, C ₂ - ₆ alkynylene, 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene containing from 1 to 4 heteroatoms independently selected from N, O and S, 6- or 10-membered arylene and a 5-10 membered heteroarylene containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene are unsubstituted or substituted with 1-6 substituents independently selected from group consisting of halogen, CN, SF ₅ , NO2, oxo, C ₁ . ₄ αlkyl, C ₀ . ₆ αlkylene-OR ⁴¹ , C0_6alkylene-(3-6-membered cycloalkyl), C0_6alkylene-(3-6-membered heterocycloalkyl), C0.6alkylene-S(O)nR ⁴¹ , C0_ ₆ alkyleneNR ⁴¹ S(O)2R ⁴¹ , Co.6alkylene-S(O)2NR ⁴¹ R ⁴² , Co.6alkylene-NR ⁴¹ S(O)2NR ⁴¹ R ⁴² , Co.6alkylene-CO2R ⁴¹ , OC^kylene-cO2R ⁴¹ , C0. ₆ alkylene-O-COR ⁴¹ , C0.6 alkylene-CONR ⁴¹ R ⁴² , C0. ₆ alkylene-NR ⁴¹ -COR ⁴¹ , C0.6 alkylene-NR ⁴¹ CONR ⁴¹ R ⁴² , C0. ₆ alkylene-O-CONR ⁴¹ R ⁴² , C0.6alkylene-NR ⁴¹ -CO2R ⁴¹ and C ₀ . ₆ αlkylene-NR ⁴¹ R ⁴² where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ -C1. ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, C _1-4 alkyl, halogen-C1- ₄ alkyl, OC ₁ . ₄ alkyl and O-halogen-C1. ₄ alkyl;

and wherein optionally two adjacent substituents on the arylene and heteroarylene moieties form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C1_ ₄ alkyl, C1_ ₄ alkyl, halogenC1_ ₄ alkyl, OC ₁ . ₄ alkyl and O-halo-C1_ ₄ alkyl.

In a more preferred embodiment, in combination with any of the above or below embodiments,

- 13 045482

L is selected from the group consisting of the group consisting of 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene containing from 1 to 4 heteroatoms independently selected from N, O and S,

6-membered arylene and 5-6-membered heteroarylene containing from 1 to 2 heteroatoms independently selected from N, O and S, wherein cycloalkylene, heterocycloalkylene, arylene and heteroarylene are unsubstituted or substituted with 1-6 substituents independently selected from the group, consisting of halogen, CN, SF ₅ , NO2, oxo, C _1-4 alkyl, C _0-6 alkylene-OR ⁴¹ , C0-6alkylene-(3-6-membered cycloalkyl), C0-6alkylene-(3-6-membered heterocycloalkyl ), С0-6alkylene-S(O)nR ⁴¹ , С0-6alkylene-NR ⁴¹ S(O)2R ⁴¹ , С0-6alkylene-S(O) ₂ NR ⁴¹ R ⁴² , Сo-6alkylene-NR ⁴¹ S(O) 2NR ⁴¹ R ⁴² , Co-6alkylene-CO2R ⁴¹ , O^^kh^^R ⁴¹ , Co-6alkylene-O-COR ⁴¹ , C0-6alkylene-CONR ⁴¹ R ⁴² , C0-6alkylene-NR ⁴¹ -COR ⁴¹ , C0 -6alkylene-NR ⁴¹ -CONR ⁴¹ R ⁴² , C0-6alkylene-O-CONR ⁴¹ R ⁴² , C0-6alkylene-NR ⁴¹ -CO2R ⁴¹ and C0-6alkylene-NR ⁴¹ R ⁴² , where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ -C _1-4 alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, C _1-4 alkyl, halogen C _1-4 alkyl, OC _1-4 alkyl and O-halo-C _1-4 alkyl;

and wherein optionally two adjacent substituents on the arylene and heteroarylene moieties form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C _1-4 alkyl, C _1-4 alkyl, halogen-C _{1-4 alkyl, OC 1-4 alkyl} and O-halo-C _{1 -4} alkyl.

In an even more preferred embodiment, in combination with any of the above or below embodiments, -LR ¹ is selected from

wherein said ring is unsubstituted or substituted with 1-4 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, oxo, C _1-4 alkyl, halo-C _1-4 alkyl, OC _1-4 alkyl , O-halo-C _1-4 alkyl, C _1-4 alkyl-OH, halogen-C _1-4 alkyl-OH, SO ₂ -C _1-4 alkyl and SO ₂ -halo-C _1-4 alkyl; and optionally two adjacent substituents on the phenyl ring together form the group -( _CH2 )3-, -(CH2)4-, -OCF2O- and -OCH2O-.

In the most preferred embodiment, in combination with any of the above or below embodiments, -LR ¹ is selected from

wherein the phenyl is unsubstituted or substituted with 1-4 substituents independently selected from the group consisting of F, Cl, CN, OH, Me and OMe.

In a preferred embodiment, in combination with any of the above or below embodiments

R ¹ is selected from the group consisting of H, halogen, CN, SF5, NO2, oxo, C1-4alkyl, C0-6alkylene- ^OR41 , Y-C0-6alkylene-(3-6-membered cycloalkyl), Y- _{C0 -6} alkylene-(3-6-membered heterocycloalkyl), YC ₀₆ alkylene-(6-membered aryl), YC _0-6 alkylene-(5-6-membered heteroaryl), C _0-6 alkylene-S(=O) (-R ⁴¹ )=NR ⁷⁵ , X-C1-6alkylene-S(=O)(-R ⁴¹ )=NR ⁷⁵ , Co-6alkylene-S(O)nR ⁴¹ , X-C1-6alkylene-S(O) nR ⁴¹ , Co-6alkylene-S(=NR ⁷¹ )R ⁴¹ , X-C1-6alkylene-S(=NR ⁷¹ )R ⁴¹ , Co-6alkylene-S(O)(=NR ⁷¹ )R ⁴¹ , X-C1 -6alkylene-S(O)(=NR ⁷¹ )R ⁴¹ , C0-6alkyleneS(=NR ⁷¹ )2R ⁴¹ , X-C1-6alkylene-S(=NR ⁷¹ )2R ⁴¹ , Co-6alkylene-NR ⁴¹ S(O )2R ⁴¹ , X-C1-6alkylene-NR ⁴¹ S(O)2R ⁴¹ , С06alkylene-S(O)2NR ⁴¹ R ⁴² , X-C1-6alkylene-S(O)2NR ⁴¹ R ⁴² , Co-6alkylene-NR ⁴¹ S(O)2NR ⁴¹ R ⁴² , X^^alkyleneNR ⁴¹ S(O)2NR ⁴¹ R ⁴² , Co-6alkylene-SO3R ⁴¹ , X-C1-6alkylene-SO3R ⁴¹ , Co-6alkylene-CO2R ⁴¹ , X-C1 -6alkylene-CO2R ⁴¹ , C0-6alkylene-O-COR ⁴¹ , X-C1-6alkylene-O-COR ⁴¹ , C0-6alkylene-CONR ⁴¹ R ⁴² , X-C1-6alkylene-CONR ⁴¹ R ⁴² , C06alkylene-CONR ⁴¹ OR ⁴¹ , X-C1-6alkylene-CONR ⁴¹ OR ⁴¹ , C0-6alkylene-CONR ⁴¹ SO2R ⁴¹ , X-C1-6alkyleneCONR ⁴¹ SO2R ⁴¹ , C0-6alkylene-NR ⁴¹ -COR ⁴¹ , X-C1-6C _0-6 alkylene-NR ⁴¹ -COR ⁴¹ , C0-6alkylene-NR ⁴¹ -CONR ⁴¹ R ⁴² , XC1-6alkylene-NR ⁴¹ -CONR ⁴¹ R ⁴² , C0-6alkylene-O-CONR ⁴¹ R ⁴² , X-C1-6alkylene-O -CONR ⁴¹ R ⁴² , C _0-6 alkylene-NR ⁴¹ CO2R ⁴¹ , X- _C1-6 alkylene-NR ⁴¹ -CO2R ⁴¹ , C 0-6 alkylene-NR ⁴¹ R ⁴² , XC _1-6 alkylene-NR ⁴¹ R ⁴² where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO ₂ H, CO ₂ C _1-4 alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, C _1-4 alkyl, halogen-C _1-4 alkyl, OC _1-4 alkyl and O-halogen-C _1-4 alkyl;

- 14 045482 and optionally two adjacent substituents on the aryl and heteroaryl fragment form a 5-8-membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted with 1-4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C ₁ . ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C ₁ . ₄ alkyl, halogen- _C1 . ₄ alkyl, OC ₁ . ₄ alkyl and O-halo-C ₁ _ ₄ alkyl.

In a more preferred embodiment, in combination with any of the above or below embodiments

R ¹ is selected from CO2H, tetrazole, CH2CO2H, OCH2CO2H, SO2CH2CO2H, CHMeCO ₂ H, CMe ₂ CO ₂ H, C(OH)MeCO ₂ H, CONHSO2Me and CONH(OH); and optionally glycine and tauroconjugates thereof.

In the most preferred embodiment, in combination with any of the above or below embodiments

R ¹ is selected from CO2H and C(OH)MeCO2H; and optionally glycine and tauroconjugates thereof.

In a preferred embodiment, in combination with any of the above or below embodiments, -LR ¹ is selected from

and optionally glycine and tauroconjugates thereof.

In a more preferred embodiment, in combination with any of the above or below embodiments, -LR ¹ is selected from

and optionally glycine and tauroconjugates thereof.

In the most preferred embodiment, in combination with any of the above or below embodiments, -LR ¹ is selected from

- 15 045482 and optionally their glycine and tauroconjugates.

In a preferred embodiment, in combination with any of the above or below embodiments, © is selected from the group consisting of 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S, 6-14 membered aryl and 5-14 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of halogen, CN, SF ₅ , NO2, oxo, C ₁ _ ₄ alkyl, C ₀ _ ₆ alkylene-OR ²¹ , C0-6alkylene-(3-6-membered cycloalkyl), C0-6alkylene-(3 -6-membered heterocycloalkyl), С0_6alkylene-S(O)nR ²¹ , С0_ ₆ alkylene-NR ²¹ S(O)2R ²¹ , С0_ ₆ alkylene-S(O) ₂ NR ²¹ R ²² , С0-6alkyleneNR ²¹ S(O )2NR ²¹ R ²² , С0_6alkylene-CR ⁴¹ (=N-OR ⁴¹ ), С0_ ₆ alkylene-CO ₂ R ²¹ , О-С1_6alkylene-CO2R ²¹ , _С0-6 alkyleneO-COR ²¹ , С0_6alkylene-CONR ²¹ R ²² , С0_ ₆ alkylene-NR ²¹ -COR ²¹ , C0_6alkylene-NR ²¹ -CONR ²¹ R ²² , _C0-6 alkylene-OCONR ²¹ R ²² , C0_6alkylene-NR ²¹ -CO2R ²¹ and _{C0_6} alkylene- ^{NR 21} _R ²² , where alkyl , alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO ₂ -C1- ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, CO- _OC1-4 alkyl, _{C1_4} alkyl, halo- _C1-4 alkyl, _{OC1_4} alkyl and _Ohalogen - _C1-4 alkyl _;

and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C1- ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C ₁ _ ₄ alkyl, halogen-C1- ₄ alkyl, OC ₁ _ ₄ alkyl and O-halogen-C1- ₄ alkyl;

and wherein optionally two adjacent substituents on the cycloalkyl or heterocycloalkyl moiety form a 5-6 membered unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, wherein said additional ring is unsubstituted or substituted 1-4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C1- ₄ alkyl, CONHCH2CO2H, CONH(CH2)2SO ₃ H, C ₁ _ ₄ alkyl, halogen-C1- ₄ alkyl, OC ₁ _ ₄ alkyl and O-halo- _C1-4 alkyl;

wherein © has a substituent of the above in the 1,2-orientation relative to the bond with or has an annulated additional ring in the 1,2-orientation.

In a more preferred embodiment, in combination with any of the above or below embodiments, © is selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N , O and S, wherein aryl and heteroaryl are unsubstituted or substituted with 1-6 substituents independently selected from the group consisting of halogen, CN, SF ₅ , NO2, oxo, C ₁ _ ₄ alkyl, C ₀ _ ₆ alkylene-OR ²¹ , C0-6alkylene-(3-6-membered cycloalkyl), C06alkylene-(3-6-membered heterocycloalkyl), C0_6alkylene-S(O)nR ²¹ , C0_ ₆ alkylene-NR ²¹ S(O)2R ²¹ , C0 ₆ alkylene -S(O) ₂ NR ²¹ R ²² , С0_6alkylene-NR ²¹ S(O)2NR ²¹ R ²² , С0_6alkylene-CR ⁴¹ (=N-OR ⁴¹ ), С0_ ₆ alkylene-CO ₂ R ²¹ , O-C1_6alkylene-CO2R ²¹ , C0_ ₆ alkylene-O-COR ²¹ , C0_6alkylene-CONR ²¹ R ²² , C0_ ₆ alkylene-NR ²¹ -COR ²¹ , C0-6alkylene-NR ²¹ -CONR ²¹ R ²² , C0_ ₆ alkylene-O-CONR ²¹ R ²² , С0_6alkylene-NR ²¹ -CO2R ²¹ and _{С0_6} alkylene-NR ²¹ R ²² , where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or _substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO ₂ H, CO ₂ -C1- ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, CO-OC1- ₄ alkyl, C ₁ _ ₄ alkyl, halogen-C1- ₄ alkyl, OC ₁ _ ₄ alkyl and Ohalo- _C1-4 alkyl;

and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO ₂ H, CO ₂ -C1- ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, C ₁ _ ₄ alkyl, halogen-C1- ₄ alkyl, OC ₁ _ ₄ alkyl and O-halo-C1- ₄ alkyl;

„ „ (?) _ „„ _ „ „ „ _1П __„ „ ~___ ΘΟ where o has a substituent from the above in the 1,2-orientation relative to the bond with or has an annulated additional ring in the 1,2-orientation.

In an even more preferred embodiment, in combination with any of the above or below embodiments

CO ) /-___________________________χ selected from the group consisting of

- 16 045482 where

R ² is selected from Me, F, Cl, CN, Me, CHO, CHF ₂ , CF3, SO ₂ Me, while ® is not additionally substituted or is additionally substituted with 1-2 substituents selected from the group consisting of F, Cl , CN, Me, OMe, CHO, CHF ₂ and CF3.

In the most preferred embodiment, in combination with any of the presented

above or below embodiments, ® is selected from the group consisting of

In a preferred embodiment, in combination with any of the above or below embodiments, formula (I) contains a substituent selected from the group consisting of CO ₂ H, tetrazole, CONHSO ₂ Me and CONH(OH); and optionally glycine and tauroconjugates thereof.

In a more preferred embodiment, in combination with any of the above or below embodiments, formula (I) contains a carboxylic acid moiety and optionally a glycine or tauroconjugate thereof.

In the most preferred embodiment, the proposed connection is selected from

- 17 045482

or glycine conjugates or tauroconjugates thereof; and their enantiomers, diastereomers, tautomers, N-oxides, solvates, prodrugs and pharmaceutically acceptable salts.

In the most preferred embodiment, the present compound is 2chloro-3'-(3-(2-cyanothiophen-3-yl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2 -yl)-[1,1'-biphenyl]-4-carboxylic acid or a glycine conjugate or tauroconjugate thereof, and optionally a pharmaceutically acceptable salt thereof. Even more preferred is 2-chloro-3'-(3-(2-cyanothiophen3-yl)-1 -((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1 H-indol-2-yl)- [1,1'-biphenyl]-4-carboxylic acid and optionally a pharmaceutically acceptable salt thereof.

In such a most preferred embodiment, the present compound is 2-chloro-3'-(3-(3-cyanonirazin-2-yl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H- indol2-yl)-[1,1'-biphenyl]-4-carboxylic acid or a glycine conjugate or tauroconjugate thereof, and optionally a pharmaceutically acceptable salt thereof. Even more preferred is 2-chloro-3'-(3-(3cyanopyrazin-2-yl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[ 1,1'-biphenyl]-4-carboxylic acid and optionally a pharmaceutically acceptable salt thereof.

In such a most preferred embodiment, the present compound is 2-chloro-3'-(3-(2-cyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indole-2- yl)[1,1'-biphenyl]-4-carboxylic acid or a glycine conjugate or tauroconjugate thereof, and optionally a pharmaceutically acceptable salt thereof. Even more preferred is 2-chloro-3'-(3-(2cyanophenyl)-1 -((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-[1,1 '-biphenyl]-4-carboxylic acid and optionally a pharmaceutically acceptable salt thereof.

In such a most preferred embodiment, the present compound is 2-chloro-3'-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol- 2yl)-[1,1'-biphenyl]-4-carboxylic acid or a glycine conjugate or tauroconjugate thereof, and optionally a pharmaceutically acceptable salt thereof. Even more preferred is 2-chloro-3'-(3-(2,6dicyanophenyl)-1 -((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1 H-indol-2-yl)-[ 1 ,1'-biphenyl]-4-carboxylic acid and optionally a pharmaceutically acceptable salt thereof.

In such a most preferred embodiment, the present compound is 3'-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl) -2,6difluoro-[1,1'-biphenyl]-4-carboxylic acid or a glycine conjugate or tauroconjugate thereof, and optionally a pharmaceutically acceptable salt thereof. Even more preferred is 3'-(3-(2,6-18 045482 dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-III-indol-2-yl)-2,6 -difluoro-[1,1'-biphenyl]-4-carboxylic acid and optionally a pharmaceutically acceptable salt thereof.

In such a most preferred embodiment, the present compound is 2-chloro-3'-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol- 2yl)-5-fluoro-[1,1'-biphenyl]-4-carboxylic acid or a glycine conjugate or tauroconjugate thereof, and optionally a pharmaceutically acceptable salt thereof. Even more preferred is 2-chloro-3'(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-5- fluoro-[1,1'-biphenyl]-4-carboxylic acid and optionally a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the present invention for use as a medicine.

Also provided is a compound of the present invention for use in the prevention and/or treatment of diseases that can be treated with LXR modulators.

Also provided is a compound of the present invention for use in the treatment of an LXR-mediated disease selected from non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hypercholesterolemia in nephrotic syndrome, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis, hepatitis C virus infection or its complications and unwanted side effects of long-term glucocorticoid treatment for diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma.

In a preferred embodiment, the disease is selected from non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hypercholesterolemia in nephrotic syndrome, metabolic syndrome or cardiac steatosis.

In such a preferred embodiment, the disease is cancer.

In such a preferred embodiment, the disease is selected from viral myocarditis, hepatitis C virus infection, or complications thereof.

The present invention further provides a method of preventing and/or treating diseases mediated by LXR, comprising administering to a subject in need thereof a compound of the present invention in an effective amount.

More specifically, the present invention relates to a method for the prevention and treatment of diseases selected from non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hypercholesterolemia in nephrotic syndrome, metabolic syndrome, cardiac steatosis , cancer, viral myocarditis, hepatitis C virus infection or its complications and unwanted side effects of long-term glucocorticoid treatment for diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma.

In addition, the present invention also relates to the use of a compound of the present invention for the preparation of a medicament for the prevention and/or treatment of an LXR-mediated disease.

More particularly, the present invention relates to the use of a compound of the present invention for the preparation of a medicament for the prevention and/or treatment of an LXR-mediated disease, said disease being selected from non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, diabetes II type, familial hypercholesterolemia, hypercholesterolemia in nephrotic syndrome, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis, hepatitis C virus infection or its complications and unwanted side effects of long-term glucocorticoid treatment for diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma.

Also provided is a pharmaceutical composition containing a compound according to the present invention and a pharmaceutically acceptable carrier or excipient.

In the context of the present invention, C ₁ . ₆ αlkyl means a saturated alkyl chain containing from 1 to 6 carbon atoms, which may be straight or branched. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Likewise, C ₁ . ₄ alkyl means a saturated alkyl chain containing from 1 to 4 carbon atoms, which may be straight or branched. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

The term halogen-C1_ ₄ alkyl means that one or more hydrogen atoms in the alkyl chain are replaced by halogen. Preferred examples are CH ₂ F, CHF2 and CF3.

From ₀ - ₆ alkylene means that the corresponding group is divalent and connects the attached residue to the rest of the molecule. Moreover, in the context of the present invention, C ₀ alkylene represents a bond, and C ₁ -alkylene means a methylene linker, C ₂ -alkylene means an ethylene linker or a methyl-substituted methylene linker, etc. In the context of the present invention, C ₀ _ ₆ alkylene is preferably a bond, a methylene, ethylene or propylene group.

Likewise, C _2-6 alkenylene and C _2-6 alkynylene mean a divalent alkenyl or alkynyl group connecting the two parts of the molecule.

A 3- to 10-membered cycloalkyl group means a saturated or partially unsaturated mono-, bi-, spiro- or polycyclic ring system containing from 3 to 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octanyl, spiro[3.3]heptyl, bicyclo[2.2.1]heptyl, adamantyl and pentacyclo[ ^{4.2.0.02 .5} .0 ^3.8 .0 ^4.7 ]octyl. Therefore, a 3-6 membered cycloalkyl group means a saturated or partially unsaturated mono-, bi- or spirocyclic ring system containing from 3 to 6 carbon atoms, and a 5-8 membered cycloalkyl group means a saturated or partially unsaturated mono-, bi- or a spirocyclic ring system containing from 5 to 8 carbon atoms.

3-10 membered heterocycloalkyl group means a saturated or partially unsaturated 310-membered carbon mono-, bi-, spiro- or polycyclic ring in which 1, 2, 3 or 4 carbon atoms are replaced by 1, 2, 3 or 4 heteroatoms, respectively, the heteroatoms being independently selected from N, O, S, SO and SO2. Examples include epoxydyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1,4dihydropyridinyl and 6-azabicyclo[3.2.1]octanyl. The heterocycloalkyl group can be linked to the rest of the molecule through a carbon, nitrogen (for example, in formolin or piperidine) or sulfur atom. An example of an S-linked heterocycloalkyl is a cyclic sulfonimidamide

A 5-14 membered mono-, bi- or tricyclic heteroaromatic ring system (also referred to herein as heteroaryl) means an aromatic ring system containing up to 6 heteroatoms independently selected from N, O, S, SO and SO2. Examples of monocyclic heteroaromatic rings include pyrrolyl, imidazolyl, furanyl, thiophenyl (thienyl), pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl. The term further means a bicyclic ring system in which the heteroatom(s) may be present in one or both rings, including the atoms at the head of the bridge. Examples include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl, 1,5-naphthyridinyl, 1,7-naphthyridinyl, and pyrazolo[1,5-a]pyrimidinyl. Examples of tricyclic heteroaromatic rings include acridinyl, benzo[b][1,5]naphthyridinyl and pyrido[3,2-b][1,5]naphthyridinyl.

The nitrogen or sulfur atom in the heteroaryl system may also optionally be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.

Unless otherwise specified, the heteroaryl system may be linked via a carbon or nitrogen atom. Examples of N-linked heterocycles are

A 6-14 membered mono-, bi- or tricyclic aromatic ring system (also referred to herein as aryl) means an aromatic carbon ring such as phenyl, naphthyl, anthracenyl or phenanthrenyl.

The term N-oxide refers to compounds in which the nitrogen atom in the heteroaromatic system (preferably pyridinyl) is oxidized. Such compounds can be prepared in a known manner by reacting a compound of the present invention (eg in a pyridinyl group) with H2O2 or a peracid in an inert solvent.

The halogen is selected from fluorine, chlorine, bromine and iodine, more preferably fluorine or chlorine and most preferably fluorine.

Any formula or structure presented herein is also intended to denote the unlabeled and isotope-labeled forms of the indicated compounds. Isotopically tagged compounds have structures depicted by the formulas presented herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ^2H (deuterium, D), ^3H (tritium) , ^PS , ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. Various compounds of the present invention are provided with an isotopic label, for example, compounds into which radioactive isotopes are incorporated , such as ³ H, ¹³ C and ¹⁴ C. Such isotopically tagged compounds may be useful for metabolic studies, reaction kinetics studies, detection or imaging technologies such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) , including tests of the distribution of a drug compound or substrate in tissues, or for radioactive treatment of patients - 20 045482. The isotopically tagged compounds of the present invention and their prodrugs can generally be prepared by the methods described in the Schemes or in the Examples and Preparation Methods below by replacing the untagged reagent with an available isotopically tagged reagent.

The present invention also includes deuterated analogues of the compounds of formula (I) in which 1 to n hydrogen atoms attached to the carbon atom are replaced by deuterium, n being the number of hydrogen atoms in the molecule. Such compounds may exhibit increased resistance to metabolism and therefore be useful for increasing the half-life of any compound of formula (I) when administered to a mammal, such as a human. See, for example, Foster's publication in Trends Pharmacol. Sci. 1984:5; 524. Such compounds are synthesized by methods known in the art, for example, using starting materials in which one or more hydrogen atoms are replaced by deuterium.

The deuterium-labeled or deuterium-substituted therapeutic compounds of the present invention may have improved DMPK (drug metabolism and pharmacokinetics) distribution, metabolism, and excretion (ADME) properties. Substitution with heavier isotopes such as deuterium may provide some therapeutic benefit due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and/or improved therapeutic index. The ¹⁸ F labeled compound may be suitable for PET or SPECT studies.

The concentration of such a heavier isotope, in particular deuterium, can be determined by the isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope is any stable isotope of that atom. Unless otherwise indicated, if a position is specifically designated as H or hydrogen, that position should be understood to contain the hydrogen atom and its naturally occurring isotopic composition. Accordingly, in the compounds of the present invention, any atom specifically designated deuterium (D) is deuterium.

In addition, the compounds of the present invention are partially subject to tautomerism. For example, if a heteroaromatic group containing a nitrogen atom on the ring is replaced by a hydroxy group on a carbon atom adjacent to said nitrogen atom, the following tautomerism may occur:

o OH ό - O.

The cycloalkyl or heterocycloalkyl group can be linked through a direct bond or in a spirocyclic manner, for example, if the cyclohexane is substituted with an oxetane heterocycloalkyl group, the following structures are possible:

AND .

The term 1,3-orientation means that the substituents on the ring have at least one possibility where 3 atoms are between two substituents attached to the ring system, e.g.

The term 1,2-orientation (ortho) means that the substituents on the ring have one possibility where 2 atoms are between two substituents attached to the ring system, e.g.

alternatively, the R residue may be embedded in an annulated additional cycle, e.g.

Those skilled in the art will appreciate that if a list of alternative substituents includes members that, due to valence requirements or other reasons, cannot be used to replace a particular group, the list should be understood to the best of one's knowledge to include only those list members that suitable for replacing this particular group.

- 21 045482

The compounds of the present invention may be in the form of a prodrug compound. A prodrug compound means a derivative that is converted to the compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, such as by oxidation, reduction, hydrolysis or the like, each of which occurs enzymatically. Examples of prodrugs are compounds in which the amino group in the compound of the present invention is acylated, alkylated or phosphorylated, for example to eicosanoylamino, alanylamino, pivaloyloxymethylamino, or in which the hydroxyl group is acylated, alkylated, phosphorylated or converted to a borate, for example acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or in which the carboxyl group is esterified or amidated. Such compounds can be prepared from the compounds of the present invention by generally known methods. Other examples of prodrugs are compounds (referred to herein as ester prodrugs) in which the carboxylate in the compound of the present invention, for example, is converted to an alkyl, aryl, arylalkylene, amino, choline, acyloxyalkyl, 1-((alkoxycarbonyl)oxy )-2-alkyl or linolenoyl ether. Exemplary carboxylic acid prodrug structures are:

prodrugs. ,

An ester prodrug can also be made if a carboxylic acid forms a lactone with the hydroxy group of the molecule. An illustrative example is

BUT.

i| j p prodrug: fj j

The term -CO ₂ H or its ester means that the carboxylic acid and its alkyl esters are provided, for example,

The term glycine conjugate or tauroconjugate means that a carboxylic acid moiety in the molecule is coupled to glycine or taurine, respectively, to form a conjugate (and potentially a prodrug, solvate, or pharmaceutically acceptable salt thereof).

Metabolites of the compounds of the present invention are also included within the scope of the present invention.

If tautomerism can occur, such as, for example, keto-enol tautomerism of the compounds of the present invention or their prodrugs, then the present invention includes individual forms, such as, for example, the keto and enol form, as well as mixtures thereof in any ratio. The same applies to stereoisomers, such as, for example, enantiomers, cis/trans isomers, atropisomers, conformers, etc.

If necessary, the isomers can be separated by methods known in the art, for example, liquid chromatography. The same applies to enantiomers, using, for example, chiral stationary phases. In addition, enantiomers can be isolated by converting them into diastereomers, i.e. binding to an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomers and elimination of the auxiliary residue. Alternatively, any enantiomer of a compound of the present invention can be prepared by stereoselective synthesis using optically pure starting materials. Another method for obtaining pure enantiomers from racemic mixtures uses enantioselective crystallization with chiral counterions.

The compounds of the present invention may be in the form of a pharmaceutically acceptable salt or solvate. The term pharmaceutically acceptable salts refers to salts derived from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. If the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically acceptable salts. Thus, the compounds of the present invention which contain acidic groups may be present in said groups and can be used according to the present invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. The compounds according to the present invention are

- 22 045482 which contain one or more main groups, i.e. groups that can be protonated may be present and used according to the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acids, succinic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids , known to those skilled in the art. If the compounds of the present invention simultaneously contain acidic and basic groups in the molecule, the present invention also includes, in addition to the salt forms mentioned, internal salts or betaines (zwitterions). The corresponding salts can be prepared by conventional methods known to those skilled in the art, for example by contacting them with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention which, due to their low physiological compatibility, are not directly suitable for use in pharmaceutical preparations, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

In addition, the compounds of the present invention may be presented in the form of solvates, for example containing water as a solvate, or pharmaceutically acceptable solvates, for example, with alcohols, in particular ethanol.

The present invention further provides pharmaceutical compositions containing at least one compound of the present invention or a prodrug compound thereof, or pharmaceutically acceptable salts or solvates thereof, as an active ingredient together with a pharmaceutically acceptable carrier.

Pharmaceutical composition means one or more active ingredients and one or more inert ingredients that form the carrier, as well as any product that is formed directly or indirectly as a result of the combination, complexation or aggregation of any two or more of these ingredients, or as a result of the dissociation of one or more more of the specified ingredients, or as a result of other types of reactions or interactions of one or more of the specified ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by mixing at least one compound of the present invention and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention may further contain one or more other compounds as active ingredients, such as a prodrug compound or other nuclear receptor modulators.

The present compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most preferred route in any particular case depends on the nature and the severity of the pathological condition being treated and the nature of the active ingredient. They may be conveniently presented in unit dosage forms and may be prepared by methods known in the art of pharmacy.

The compounds of the present invention act as LXR modulators.

Nuclear receptor ligands, including LXR ligands, can act as agonists, antagonists, or inverse agonists. An agonist in this context means a small molecule ligand that binds to a receptor and stimulates its transcriptional activity, as determined, for example, by an increase in the mRNA or proteins transcribed under the control of the LXR response element. Transcriptional activity can also be determined in biochemical or cellular in vitro assays that use only the ligand binding domain of LXRa or LXRe, but use interaction with a cofactor (i.e., corepressor or coactivator), potentially in combination with a common DNA binding element , such as the Gal4 domain, to monitor agonist, antagonist or inverse agonist activity.

If an agonist by this definition simulates LXR- or LXR-Cal4-driven transcriptional activity, then the antagonist is defined as a small molecule compound that binds to LXR and thereby inhibits transcriptional activity that would otherwise occur due to the endogenous LXR ligand.

An inverse agonist differs from an antagonist in that it not only binds to LXR and inhibits transcriptional activity, but also actively stops LXR-driven transcription, even in the absence of an endogenous agonist. Although it is difficult to distinguish in vivo between antagonistic and reverse

- 23 045482 LXR agonist activity, given that a certain amount of endogenous LXR agonist is always present, biochemical or cellular reporter assays provide the ability to more clearly separate the two activities. At the molecular level, the inverse agonist does not allow the recruitment of the coactivator protein or its active particles, while it must ensure the active recruitment of the corepressor proteins and its active particles. An LXR antagonist in this context should be defined as an LXR ligand that results in neither coactivator nor corepressor recruitment, but acts only by displacing LXR agonists. Thus, the use of assays such as the mammalian Gal4 two-hybrid assay is mandatory to separate compounds that recruit LXR coactivators or corepressors (Kremoser et al., Drug Discov. Today 2007; 12:860; Gronemeyer et al., Nat. Rev. Drug Discov. 2004;3:950).

Since the boundaries between LXR agonists, LXR antagonists and LXR inverse agonists are blurred rather than sharp, the term LXR modulator covers all compounds that are not pure LXR agonists but exhibit some degree of corepressor recruitment in combination with reduced LXR transcriptional activity. Thus, LXR modulators include LXR antagonists and LXR inverse agonists, and it should be noted that even a weak LXR agonist can act as an LXR antagonist if it interferes with full transcriptional activation of the full agonist.

The drawing illustrates the distinction between LXR agonists, antagonists and inverse agonists by their different abilities to recruit coactivators or corepressors.

The proposed compounds are suitable for the prevention and/or treatment of diseases mediated by LXR. The preferred diseases are all disorders associated with steatosis, i.e. accumulation of fat in tissue. Such diseases include the full spectrum of non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis, liver inflammation and liver fibrosis, in addition to insulin resistance, metabolic syndrome and cardiac steatosis. LXR modulator-based treatments should also be suitable for treating hepatitis C virus infection or its complications, as well as preventing unwanted side effects of long-term glucocorticoid treatment for diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma.

Cancer treatment may have a different set of applications for LXR modulators. LXR antagonists or inverse agonists may be suitable to counteract the so-called Warburg effect, which is associated with the transition from normal differentiated cells to cancer cells (see Liberti et al., Trends Biochem. Sci. 2016;41:211; Ward & Thompson, Cancer Cell 2012;21:297-308). In addition, LXR is known to modulate various components of the innate and adaptive immune system. Oxysterols, which are known as endogenous LXR agonists, have been identified as mediators of LXR-dependent immunosuppressive effects occurring in the tumor microenvironment (Traversari et al., Eur. J. Immunol. 2014;44:1896). Thus, it is reasonable to speculate that LXR antagonists or inverse agonists may be capable of stimulating the immune system and antigen-presenting cells, in particular to induce an antitumor immune response. The latter effect of LXR antagonists or inverse agonists can be used to treat advanced cancers in general, and those types of solid tumor cancers that exhibit a weak immune response and significantly increased signs of Warburg metabolism in particular.

More specifically, the anticancer activity of the LXR inverse agonist SR9243 has been shown to be mediated by interference with the Warburg effect and lipogenesis in various tumor cells in vitro and in SW620 colon tumor cells from nude mice in vivo (see Flaveny et al. Cancer Cell. 2015;28 :42; Steffensen, Cancer Cell 2015;28:3).

Thus, LXR modulators (preferably LXR inverse agonists) may be useful for the treatment of Warburg-dependent cancers.

LXR modulators (preferably LXR inverse agonists) can antagonize the diabetogenic effect of glucocorticoids without attenuating the anti-inflammatory effects of glucocorticoids, and therefore can be used to prevent the unwanted side effects of long-term glucocorticoid treatment in diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma (Patel et al. al Endocrinology 2017:158:1034).

LXR modulators (preferably LXR inverse agonists) may be suitable for the treatment of hepatitis C virus-mediated hepatic steatosis (see Garcia-Mediavilla et al. Lab. Invest. 2012;92:1191).

LXR modulators (preferably LXR inverse agonists) may be suitable for the treatment of viral myocarditis (see Papageorgiou et al. Cardiovasc. Res. 2015;107:78).

LXR modulators (preferably LXR inverse agonists) may be suitable for the treatment of insulin resistance (see Zheng et al. PLoS One 2014;9:e101269).

LXR modulators (preferably LXR inverse agonists) may be suitable for the treatment of familial hypercholesterolemia (see et al. J. Biol. Chem. 2008; 283:2129).

LXR modulators (preferably LXR inverse agonists) may be suitable for the treatment of hypercholesterolemia in nephrotic syndrome (see Liu & Vazizi in Nephrol. Dial. Transplant.

- 24 045482

2014; 29:538).

Experimental section

The compounds of the present invention can be prepared by a combination of methods known in the art, including the methods described below in Schemes I-V.

The synthetic route shown in Scheme I begins with the preparation of alkynes Ic via the Sonogashira coupling reaction. The free amino group Ic is then reacted with sulfonyl chlorides Id in the presence of an appropriate base and an appropriate solvent to produce alkyne sulfonamides Ie. Compound Ic is subjected to cyclization and simultaneous reaction with aromatic halides If in the presence of an appropriate catalyst (eg Pd catalyst), an appropriate solvent and at a suitable temperature to obtain the compounds of the present invention (I). Further manipulation of the functional groups present on R ¹ using standard methods known to those skilled in the art (eg, ester hydrolysis, amide bond formation) can result in additional compounds of the present invention. Alternatively, the alkynamine Ic can be converted to the alkene trifluoroacetamide Ig, which can also be subjected to the above cyclization and simultaneous reaction with aromatic halides If to give intermediates Ih with unsubstituted NH. Reaction with sulfonyl chlorides Id in the presence of an appropriate base and an appropriate solvent also leads to the formation of compounds of formula (I).

Scheme I: Synthesis of compounds according to the present invention

An alternative to the methods presented in Scheme I is shown in Scheme II. Alkyne sulfonamide I-c is reacted in the presence of NIS to produce iodinated intermediates II-b, which can be Suzuki coupling reagents to form compounds (I). Alternatively, cyclization of alkynesulfonamide I-c in the presence of an appropriate catalyst (eg Pd catalysts), an appropriate solvent and at a suitable temperature, but without halides I-f, leads to the formation of 3-unsubstituted intermediates II-d. Reactions with NBS produce brominated intermediates II-e, which are also reagents for Suzuki coupling reactions to form compounds of formula (I).

Scheme II: Method for the synthesis of compounds according to the present invention, introducing fragment D by Suzuki coupling reaction

An additional alternative to the synthetic route depicted in Schemes I and II is presented in Scheme III. In the presence of B ₂ Pin ₂ , an appropriate catalyst (eg Pd catalysts), an appropriate solvent, additives and at a suitable temperature, intermediates Ic can undergo cyclization and concomitant formation of 3-pinacolylboronic esters III-b. They can be reagents for Suzuki coupling reactions to form compounds of the present invention of formula (I).

Scheme III: Alternative method for the synthesis of compounds according to the present invention, introducing fragment D by Suzuki coupling reaction

Scheme IV shows a synthesis method involving the introduction of -LR ¹ fragments shown on the right side into the compounds of the present invention at a late stage. Sonogashira binding of compound Ia to bromo-iodo-aromatic compounds IV-a results in the formation of bromoalkynamines IV-b, which can be converted to sulfonamides IV-c. They can be cyclized and simultaneously reacted with aromatic bromides IV-d in the presence of appropriate catalysts (e.g. Pd catalysts), an appropriate solvent and at a suitable temperature to form more complex intermediates IV-e with a bromine substituent on the C ring. Finally, the intermediates compounds IV-e can be used as Suzuki coupling reagents to produce compounds of formula (I).

Scheme IV: Method for the synthesis of compounds according to the present invention, introducing the fragment -LR ¹ by the Suzuki coupling reaction in the last step

Scheme V summarizes the synthetic methods for preparing the compounds of the present invention, starting with a preformed bicyclic aromatic compound with an annulated pyrrole at the center. N-Protected 2-pinacolylboronic esters V-a can be subjected to Suzuki coupling with halides V-b to produce intermediates V-c. Bromination with NBS produces 3-bromo intermediates V-d, which are converted to the more complex N-protected intermediates V-e after a second Suzuki coupling. Starting with N-protected 3-pinacolylboronic esters V-a, the first Suzuki coupling and subsequent bromination of the 2-position with a further second Suzuki coupling also produces intermediates V-e. After deprotection and reaction of free NH with sulfonyl chlorides I-d in the presence of an appropriate base and solvent, compounds (I) are obtained.

hal = Cl, Br or IR. hal- ¹ _v , _b

Bq ’ V-a Suzcki coding

PG - protecting group e.g. Boc group

PG

- L ^P NBS with 1

V-c

V-d PG

NBA g'

Suzuki combination

,. _t ^Combination C _; zci

PG = protective group e.g. Vas-group

PG

PG

V-h

R*

Z-yL (noun-tss; V4

--------------- _w

Combination Suzuki i'G ^ve

D) ,

GA

X' l-d base

G _

I ή [| — - T n Vi

Scheme V: Synthesis of compounds according to the present invention, starting from a pre-prepared compound with an aromatic ring.

- 26 045482

Abbreviations

Ace acetyl ACN acetonitrile AIBN azobiisobutyronitrile aq. water BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) B ₂ Pin ₂ 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane Vos tert-butyloxycarbonyl VRO dibenzoyl peroxide t-SRVA meta-chloroperbenzoic acid Su cyclohexyl DAST diethylaminosulfur trifluoride dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DXM dichloromethane DEA diethanolamine DEAD diethyl azodicarboxylate DIEA or DIPEA diisopropylethylamine DMAP 4-A/,/\/-dimethylaminopyridine DMF L/,L/-dimethylformamide dppf 1,1-bis(diphenylphosphino)ferrocene EA ethyl acetate EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide FCC flash column chromatography on silica gel h watch) HATU O-(7-azabenzotriazol-1 -yl)-L/, Ν, Ν’, Ν -tetramethyluronium hexafluorophosphate HOBt hydroxybenzotriazole IBX 2-iodibenzoic acid LDA lithium diisopropylamide LiHMDS bs/s(trimethylsilyl)lithium amide N.B.S. L/-bromosuccinimide NIS L/-IODINE succinimide Pin pinacolato (OCMe ₂ CMe ₂ O) P.E. petroleum ether npen. preparative sat. saturated (watery) Sphos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl TBAF Tetra-n-butylammonium fluoride TEA triethylamine TFC trifluoroacetic acid ATFC trifluoroacetic anhydride THF tetrahydrofuran those thin layer chromatography Tr Trityl Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Preparatory example P1.

Methyl 2-(4-bromo-3-chlorophenyl)-2-(dimethylamino)acetate (P1)

To a solution of methyl 2-amino-2-(4-bromo-3-chlorophenyl)acetate (300 mg, 1.08 mmol) in MeOH (6 ml) was added CH2O (37 wt.% in H ₂ O; 0.5 ml) and HCOOH (2.0 ml). The mixture was stirred at room temperature for 30 minutes, then NaBH(OAc) ₃ (572 mg, 2.7 mmol) was added. The mixture was stirred at room temperature for 2 hours, diluted with EA (150 ml) and washed with water (15 ml), saturated NaHCO ₃ solution (15 ml) and brine (10 ml). The organic layer was dried over

- 27 045482

Na ₂ SO ₄ was filtered, concentrated and purified by preparative TLC (EA:PE=1:4) to obtain compound P1 as a colorless oily substance.

Preparatory example P2.

Step 1: 2-((trimethylsilyl)ethynyl)pyridin-3-amine (P2a)

Pd(PPh ₃ ) ₄ (993 mg, 0.86 mmol), CuI (164 mg, 0.86 mmol) and PPh ₃ (225 mg, 0.86 mmol) were combined in a round bottom flask, then degassed three times and N2 again . TEA (43 ml), 2-bromopyridin-3-amine (1.49 g, 8.59 mmol) and ethynyltrimethylsilane (2.43 ml, 18.0 mmol) were added to the resulting mixture. The mixture was stirred at 60°C for 6 hours, cooled to room temperature, filtered through celite and washed with EA (40 ml). The filtrate was concentrated to give compound P2a as a black solid, which was used in the next step without further purification.

Step 2: 2-Ethynylpyridin-3-amine (P2)

To a solution of compound P2a (2.16, g 8.59 mmol) in THF (26 ml) was added TBAF (26 ml, 1 M in THF, 26 mmol) and the mixture was stirred at room temperature for 3 hours, concentrated and purified with using FCC (EA/PE = 1:19 - 1:0) to obtain compound P2 as a white solid.

Preparatory examples P2/1-P2/9

The following preparatory examples were prepared in the same manner as described for preparatory example P2 using the appropriate building blocks.

structure

P2/1

P2/2

P2/3

P2/4 building block

F ^Br O nh ₂ fU ^N= \ ^N= \ nh ₂ N ^/ _VBr ex ex nh ₂

Ίμη ₂

SG nh ₂

SG XX nh ₂ ciР2/5 νη ₂

C.I.

N.C.

Р2/6 nh ₂

NC

Me.

P2/7 'NH ₂

P2/8

P2/9

Br nh ₂

Me

nh ₂

Preparatory example P3.

Step 1: (4-Bromo-2-mercaptophenyl)methanol (P3a)

To a solution of 4-bromo-2-mercaptobenzoic acid (1.5 g, 6.5 mmol) in THF (30 ml) was added BH ₃ (13 ml, 1M in THF). The resulting mixture was stirred overnight and quenched with water (30 ml) and diluted

- 28 045482 li EA (20 ml). The organic layer was separated and the aqueous layer was washed with EA (3x20 ml). The combined organic layer was washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The resulting yellow solid was used in the next step without purification.

Step 2: Ethyl 2-((5-bromo-2-(hydroxymethyl)phenyl)thio)acetate (P3b)

Vg

CS ₂ CO 3 (2.0 g, 6.0 mmol) was added to a mixture of compound P3a (436 mg, 2.0 mmol) and ethyl 2- _bromoacetate (306 mg, 2.0 mmol) in DMF (10 ml). . The mixture was stirred at room temperature overnight, diluted with water (100 ml) and extracted with EA (3x30 ml). The combined organic layer was washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=5:1) to give P3b as a white solid.

Step 3: ethyl 2-((5-bromo-2-(hydroxymethyl)phenyl)sulfonyl)acetate (P3)

To a stirred solution of compound P3b (290 mg, 1.0 mmol) in DCM (5 ml) at 0°C was added mCPBA (610 mg, 3.0 mmol, 85%) and the resulting mixture was stirred at room temperature for 16 hours, diluted with saturated aqueous NaHCO ₃ solution and extracted with EA (3x20 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=5:1) to give compound P3 as a white solid.

Preparatory example P3-1.

Step 1: 4-Bromo-2-((2-ethoxy-2-oxoethyl)thio)-6-fluorobenzoic acid (P3-1a)

To a mixture of 4-bromo-2,6-difluorobenzoic acid (10.0 g, 42.4 mmol) and ethyl 2-mercaptoacetate (5.10 g, 42.4 mmol) in DMF (100 ml) was added Cs ₂ CO ₃ (41.5 g, 127 mmol) and stirred the mixture at 80°C overnight, diluted with water (1 L) and adjusted to pH = 3 with 2 M HCl, and extracted with EA (3x300 ml). The combined organic layer was washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=1:1) to give P3-1a as a yellow oil.

Step 2: Ethyl 2-((5-bromo-3-fluoro-2-(hydroxymethyl)phenyl)thio)acetate (P3-1b)

To a solution of compound P3-1a (4.10 g, 12.2 mmol) in THF (40 ml) was added B ₂ H ₆ (24.4 ml, 1 M in THF). The resulting mixture was stirred at 70°C overnight, quenched with water (100 ml) and extracted with EA (4x40 ml). The combined organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=5:1) to give compound P3-1b as a white solid.

Step 3: Ethyl 2-((5-bromo-3-fluoro-2-(hydroxymethyl)phenyl)sulfonyl)acetate (P3-1)

To a stirred solution of compound P3-1b (1.00 g, 3.40 mmol) in DCM (30 ml) at 0°C, m-CPBA (1.80 g, 10.2 mmol, 85%) was added and the mixture was stirred at room temperature for 16 hours, diluted with saturated aqueous NaHCO ₃ solution and extracted with EA (3x20 ml). The combined organic layer was dried over Na ₂ SO ₄ , concentrated and purified with FCC (PE:EA=5:1) to give compound P3-1 as a white solid.

Preparatory example P4.

Methyl 2-(3-bromophenyl)-2-methylcyclopropane-1-carboxylate(P4):

To a solution of compound P16 (1.00 g, 3.92 mmol) in DMF (15 ml) was added MeI (1.11 g, 7.84 mmol) and K2CO3 (1.35 g, 9.80 mmol). The mixture was stirred for 2 hours at 50°C, cooled, diluted with EA (100 ml) and washed with water (3x20 ml) and brine (20 ml), dried over Na ₂ SO ₄ ,

- 29 045482 filtered, concentrated and purified by preparative TLC (EA:PE=1:6) to obtain compound P4 as a yellow oily substance.

Preparatory example P5.

Methyl 3'-bromo-2-chloro-[1,1'-biphenyl]-4-carboxylate (P5):

To a solution of methyl 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (47.7 g, 161 mmol) in dioxane (300 ml) 1-bromo-3-iodobenzene (50.0 g, 177 mmol), Na ₂ CO ₃ (35.7 g, 337 mmol) and Pd(PPh ₃ ) ₄ (11.7 g, 10.1 mmol) in atmosphere N ₂ . The mixture was stirred at 90°C overnight under N2, cooled, filtered, concentrated and purified with FCC (EA:PE=1:50) to give compound P5 as a white solid.

Preparatory examples P5/1-P5/3

The following preparatory examples were prepared in the same manner as described for preparatory example P5 using the appropriate building blocks.

Preparatory example P6.

4-(methyl-b3)benzenesulfonyl chloride-2,3,5,6-b4 (P6):

To a solution of toluene-b8 (1.00 g, 10.0 mmol) in DCM (10 ml) was added CISO3H (5 ml) and the mixture was stirred at room temperature for 2 hours, poured into water (100 ml) and extracted with DCM ( 100 ml). The organic layer was concentrated to give compound P6 as a white solid.

Preparatory example P7.

tert-butyl-2-(3-bromo-4-cyanophenoxy)acetate (P7)

A mixture of 2-(3-bromo-4-cyanophenoxy)acetic acid (200 mg, 0.78 mmol), Boc ₂ O (204 mg, 0.94 mmol), DMAP (10 mg, 80 μmol) and pyridine (0. 4 ml) in t-BuOH (10 ml) was stirred at room temperature overnight, concentrated and purified with FCC (PE:EA=50:1) to give compound P7 as a yellow oily substance.

Preparatory example P7/1.

The following preparatory example was prepared in the same manner as described for preparatory example P7 using the appropriate building block.

No. building block structure

Vg Vg

- 30 045482

Preparatory example P8.

Methyl 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (P8):

To a solution of methyl 4-bromo-5-chloro-2-fluorobenzoate (2.66 g, 10.0 mmol) in dioxane (30 ml) was added B ₂ Pin ₂ (2.79 g, 11.0 mmol), KOAc (2.45 g, 25.0 mmol) and Pd(dppf)Cl ₂ (260 mg) under N ₂ atmosphere. The mixture was stirred at 80°C overnight under N2, diluted with water (50 ml) and extracted with EA (3x50 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (EA:PE=1:40) to give compound P8 as a white solid.

Preparatory example P9.

Methyl 4-(3-bromophenyl)butanoate (P9):

K2CO3 (569 mg, 4.11 mmol) and CH3I (438 mg, 3.09 mmol) were added to a solution of 4-(3-bromophenyl)butanoic acid (500 mg, 2.06 mmol) in DMF (50 mL). The mixture was stirred for 2 hours at room temperature. Insoluble salts were filtered off and washed with EA. The combined organic layer was washed with water (3x50 ml), brine (2x50 ml), dried over Na ₂ SO ₄ and filtered. The solvents were removed under reduced pressure to give P9 as a yellow solid, which was used in the next step without further purification.

Preparatory example P10.

O

Вг\ JL X XX

RU

Methyl 2-(3-bromophenoxy)acetate (P10):

To a solution of 3-bromophenol (1.72 g, 10.0 mmol) and methyl bromoacetate (1.01 mL, 11.0 mmol) in ACN (60 mL) was added K2CO3 (2.07 g, 15.0 mmol) and stirred mixture at 50°C overnight. Insoluble salts were filtered off and washed with ACN, then the solvent was removed under reduced pressure and the residue was dissolved in EA and washed successively with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give compound P10 as a colorless semi-solid.

Preparatory example P10/1.

The following example was prepared in the same manner as described for Preparatory Example P10 using the appropriate building blocks.

Preparatory example P11.

ΙΒγχ. ,Ν___o. ,Ο. Ύ Υ

P11 o

Methyl 3-((6-bromopyridin-2-yl)oxy)propanoate (P11)

_DEAD (1, 20 g, 6.89 mmol) and methyl 3-hydroxypropanoate (479 mg, 4.59 mmol). The mixture was stirred at room temperature overnight, quenched with saturated NH4Cl solution (60 ml) and extracted with EA (2x30 ml). The combined organic layer was washed with brine (2x30 ml), dried over Na ₂ SO ₄ , concentrated and purified by preparative TLC (EA:PE=1:4) to give compound P11 as a white solid.

Preparatory example P12.

Methyl 1-(3-bromophenyl)azetidine-3-carboxylate (P12):

To a solution of 1-bromo-3-iodobenzene (500 mg, 1.77 mmol) in dioxane (8 ml) was added methylazetidine-3-carboxylate hydrochloride (295 mg, 1.94 mol), Pd ₂ (dba) ₃ (35 mg , 40 µmol), XPhos (17 mg, 40 µmol) and

- 31 045482

Na2CO3 (375 mg, 3.53 mmol). The mixture was stirred at 100°C overnight, cooled to room temperature, filtered, concentrated and purified by preparative TLC (PE:EA=2:1) to give compound P12 as a yellow oily substance.

Preparatory example P12/1.

The following preparatory example was prepared in the same manner as described for preparatory example P12 using the appropriate building block.

Preparatory example P13.

Methyl 1-(3-bromophenyl)-3-methylazetidine-3-carboxylate (P13):

To a solution of 1-bromo-3-iodobenzene (500 mg, 1.77 mmol) in dioxane (15 ml) was added methyl 3-methylazetidine-3-carboxylate hydrochloride (293 mg, 1.77 mmol), Pd ₂ (dba) ₃ (32 mg, 35 µmol), Xantphos (20 mg, 35 µmol) and Cs ₂ CO ₃ (1.35 g, 3.54 mmol). The mixture was stirred at 100°C overnight under N2, cooled to room temperature, diluted with water (150 ml) and extracted with EA (3x200 ml). The combined organic layer was washed with brine (2x50 mL), dried over Na ₂ SO ₄ , concentrated and purified with FCC (EA:PE=1:5) to give P13 as a yellow oil.

Preparatory examples P13/1-P13/4

The following preparatory examples were prepared in the same manner as described for preparatory example P13 using the appropriate building blocks.

building blocks

structure

Preparatory example P14.

Methyl-1-(6-bromopyridin-2-yl)azetidine-3-carboxylate (P14):

To a solution of 2,6-dibromopyridine (500 mg, 2.11 mmol) in DMF (20 ml) was added methylazetidine-3-carboxylate hydrochloride (384 mg, 2.53 mmol) and K2CO3 (729 mg, 5.28 mmol) and stirred the mixture overnight at 80°C. After cooling to room temperature, insoluble salts were filtered off and washed with EA. The combined organic solvents were washed with water (3x50 ml), brine (2x50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (PE:EA=4:1) to give compound P14 as a yellow oily substance.

- 32 045482

Preparatory example P15.

Step 1: 3-(3-bromophenyl)-3-hydroxycyclobutane-1-carboxylic acid (P15a)

To a solution of 1-bromo-3-iodobenzene (2.82 g, 10.0 mmol) and 3-oxocyclobutane-1-carboxylic acid (1.14 g, 10.0 mmol) in THF (30 ml) at -78° n-BuLi (8 ml, 20 mmol, 2.5 M in THF) was added and the mixture was stirred at -78°C for 4 hours, quenched with NH ₄ Cl (50 ml), neutralized with 1 N. aqueous HCl solution and extracted with EA (3x). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (EA:PE=1:1) to give compound P15a as a colorless oil.

Step 2: Methyl 3-(3-bromophenyl)-3-hydroxycyclobutane-1-carboxylate (P15b)

To a solution of compound P15a (1.35 g, 5.00 mmol) in DMF (20 ml) was added K ₂ CO ₃ (1.38 g, 10.0 mmol) and CH ₃ I (710 mg, 5.00 mmol) and stirred the mixture at room temperature for 2 hours. Added water (200 ml) and extracted the resulting mixture with EA. The combined EA extracts were washed with brine, dried over Na ₂ SO ₄ and filtered. The solvent was removed under reduced pressure and the residue was purified by FCC (EA:PE=1:10) to obtain compound P15b as a colorless oily substance.

Step 3: Methyl 3-(3-bromophenyl)cyclobutane-1-carboxylate (P15)

To a solution of compound P15b (1.10 g, 3.90 mmol) in TFA (20 ml) at 0°C was added triethylsilane (680 mg, 5.85 mmol) and the mixture was stirred for 2 hours. Water was added to the resulting mixture ( 200 ml) and the mixture was extracted with EA. The solvent was removed under reduced pressure and the residue was purified by FCC (EA:PE=1:10) to obtain compound P15 as a colorless oily substance.

Preparatory example P16.

Step 1: Methyl-(E)-3-(3-bromophenyl)acrylate (P16a)

(E)-3-(3-bromophenyl)acrylic acid (3.00 g, 13.2 mmol) was dissolved in DMF (50 ml), MeI (3.75 g, 26.4 mmol) and K ₂ CO ₃ were added (2.74 g, 19.8 mmol) were added and the mixture was stirred for 2 hours at room temperature. Insoluble salts were filtered off and washed with EA, then the solvent was washed with water (3 x 50 ml), brine (2 x 50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give compound P16a as a yellow solid, which was used in the next step without any cleaning.

Step 2: rac-methyl-(1R,2R)-2-(3-bromophenyl)cyclopropane-1-carboxylate (P16)

Under argon, NaH (60%, 680 mg, 17.0 mmol) was first charged into DMSO (30 mL) and trimethylsulfoxonium iodide (3.74 g, 17.0 mmol) was added in one portion at room temperature. After gas evolution ceased, compound P16a (3.15 g, 13.1 mmol) dissolved in DMSO (10 ml) was added slowly dropwise. After stirring overnight at 50°C, the resulting mixture was partitioned between EA and water. The aqueous layer was extracted with EA. The combined organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (EA:PE=1:20) to give compound P16 as a colorless oil.

Preparatory examples P16/1-P16/2

The following preparatory examples were prepared in the same manner as described for preparatory example P16 using the appropriate building blocks.

- 33 045482 chemical name rac-methyl-(1R,2R)-2-(5-bromothiophen-2yl)cyclopropane-1-carboxylate

building no. structure block

Р16/1

Preparatory example P17.

rac-methyl-(1R,2R)-2-(3-bromo-5chlorophenyl)cyclopropane-1-carboxylate

Methyl-3'-bromo-[1,1'-biphenyl]-3-carboxylate (P17):

To a solution of (3-bromophenyl)boronic acid (1.50 g, 7.47 mmol) in dioxane (30 ml) was added methyl 3-bromobenzoate (1.93 g, 8.96 mmol), Pd(PPh ₃ ) ₄ (173 mg, 0.15 mmol) and Na ₂ CO ₃ (1.58 g, 14.9 mmol). The mixture was stirred at 100°C overnight. After cooling to room temperature, the reaction mixture was filtered, concentrated and purified by FCC to give compound P17 as a yellow oily substance.

Preparatory examples P17/1-P17/4

The following examples were prepared in the same manner as described for Preparatory Example P17 using the appropriate building blocks.

Preparatory example P18.

Step 1: Methyl 3'-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-4-carboxylate (P18a)

Pd(PPh ₃ ) ₄ (1.98 g, 1.72 mmol), CuI (327 mg, 1.72 mmol) and PPh ₃ (450 mg, 1.72 mmol) were combined in a round bottom flask and degassed and filled three times flask N2. Add TEA (86 ml), methyl 3'bromo-[1,1'-biphenyl]-4-carboxylate (P5/2, 5.00 g, 17.2 mmol) and ethynyltrimethylsilane (4.86 ml, 36. 1 mmol) and stirred the mixture at 60°C for 6 hours. After filtration through kieselguhr, the filtrate was concentrated under reduced pressure to obtain compound P18a as a black solid, which was used in the next step without further purification.

Step 2: Methyl 3'-ethynyl-[1,1'-biphenyl]-4-carboxylate (P18)

To a solution of compound P18a (6.21 g, 17.2 mmol) in THF (25 ml) was added TBAF (25 ml, 1 M in THF) and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the residue was purified using FCC (EA:PE=1:20) to obtain compound P18 as a white solid.

- 34 045482

Preparatory example P19.

Step 1: 3-Bromofuran-2-carboxamide (P19a)

To a solution of 3-bromofuran-2-carboxylic acid (1.00 g, 5.24 mmol) in DMF (10 ml) was added HATU (2.98 g, 7.85 mmol) and DIPEA (1.69 g, 13. 1 mmol) and stirred the mixture at room temperature for 1 hour. NH ₄ Cl (333 mg, 6.29 mmol) was added and stirring was continued overnight. Water (30 ml) was added and the EA mixture was extracted (3x30 ml). The combined organic layer was dried over Na ₂ SO ₄ , concentrated and purified by FCC to give compound P19a as a yellow solid.

Step 2: 3-Bromofuran-2-carbonitrile (P19)

To a solution of compound 19a (906 mg, 4.77 mmol) in DCM (10 ml) at 0°C, ATPA (2.50 g, 11.9 mmol) was added and the mixture was stirred for 2 hours, diluted with water (30 ml) and extracted with DCM (3x30 ml). The combined organic layer was dried over Na ₂ SO ₄ , concentrated and purified with FCC (EA:PE=1:20) to give compound P19 as a white solid.

Preparatory example P20.

2-Bromo-4-fluoro-6-methoxyaniline (P20):

NBS (12.4 g, 69.4 mmol) was added to a solution of 4-fluoro-2-methoxyaniline (8.90 g, 63.1 mmol) in dry DCM (217 ml) at -78°C and the mixture was stirred at - 78°C for 2 hours, then allowed to warm to 0°C and stir for 2 hours. The solvent was removed in vacuo and the resulting residue was purified using FCC (EA:PE=1:10) to give compound P20 as yellow oily substance.

Preparatory example P21.

Step 1: 2-(4-Bromophenyl)-2-((trimethylsilyl)oxy)propanenitrile (P21a)

Trimethylsilyl cyanide (4.96 g, 50.0 mmol) and zinc iodide (50 mg) were added to 1-(4-bromophenyl)ethan1-one (5.00 g, 50.0 mmol) in DCM (200 ml). The resulting mixture was stirred for 5 hours at room temperature. The mixture was washed with water (2 x 20 ml) and brine (20 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to give crude compound P21a, which was used in the next step without any purification.

Step 2: 2-(4-Bromophenyl)-2-hydroxypropanoic acid (P21b)

To a solution of compound P21a (12.2 g, 40.9 mmol) in AcOH (50 ml) was added conc. HCl (50 ml). The mixture was stirred overnight at room temperature and heated at 100°C for 2 hours. The solvent was removed under reduced pressure. H2O was added and the mixture was extracted with EA (3x200 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to give crude P21b as a yellow oil, which was used in the next step without any purification.

Step 3: Methyl 2-(4-bromophenyl)-2-hydroxypropanoate (P21c)

To a solution of compound P21b (6.50 g, 26.5 mmol) in MeOH (60 ml) was added conc. H ₂ SO ₄ (3 ml). The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, dissolved in EA (300 ml) and washed with H2O (30 ml) and saturated NaHCO ₃ solution (30 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified using FCC (EA:PE=1:2) with

- 35 045482 by obtaining compound P21c in the form of a colorless oily substance.

Step 4: Methyl 2-hydroxy-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (P21)

To a solution of compound P21c (200 mg, 0.77 mmol) in dioxane (10 ml) was added B ₂ Pin ₂ (209 mg, 0.93 mmol), KOAc (151 mg, 1.54 mmol) and Pd(dppf)Cl ₂ (56 mg, 0.08 mmol). The mixture was stirred at 100°C overnight under N2 atmosphere. After cooling to room temperature, the mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (EA:PE=1:1) to give compound P21 as a white solid.

Preparatory example P21/1.

The following example was prepared in the same manner as described for Preparation Example P21 using the appropriate building block.

building no. structure block

Preparatory example P22 (mixture of 1- and 2-trityl isomers).

Step 1: 5-(4-Bromo-3-chlorophenyl)-1H-tetrazole (P22a)

To a solution of 4-bromo-3-chlorobenzonitrile (500 mg, 2.33 mmol) in DMF (10 ml) was added NaN ₃ (1.50 g, 23.3 mmol) and NH ₄ Cl (1.20 g, 23. 3 mmol). The mixture was stirred at 100°C under N2 atmosphere overnight. DCM (100 ml) was then added and the mixture was washed with brine (30 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified with FCC (EA:PE=1:3) to give compound P22a as a white solid.

Step 2: 5-(4-Bromo-3-chlorophenyl)-1-trityl-1H-tetrazole (P22), (mixture of 1- and 2-trityl isomers)

To a solution of compound P22a (350 mg, 1.36 mmol) in DCM (50 ml) was added triphenylmethyl chloride (556 mg, 2.00 mmol) and TEA (202 mg, 2.00 mmol). The mixture was stirred at room temperature for 12 hours. DCM (50 ml) was then added and the mixture was washed with brine (30 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified with FCC (EA:PE=1:7) to give compound P22 as a white solid.

Preparatory example P23 (mixture of 1- and 2-trityl isomers).

Тг _h m NN Br L , ^N ^^s=o ^{N P23}

Step 1: N-((3-bromophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)-2,2,2-trifluoroacetamide (P23a)

To a solution of 1-bromo-3-(methylsulfinyl)benzene (950 mg, 4.38 mmol) in DCM (10 ml) was added MgO (697 mg, 17.4 mmol), 2,2,2-trifluoroacetamide (742 mg, 6.57 mmol), Rh ² (OAc) ₄ (100 mg) and (diacetoxy)iodobenzene (2.82 g, 8.76 mmol). The mixture was stirred at 40°C overnight and filtered through a pad of celite. The solvent was removed under reduced pressure and the crude product was purified by FCC (PE:EA=1:2) to give compound P23a as a white solid.

Step 2: (3-Bromophenyl)(imino)(methyl)-λ ⁶ -sulfanone (P23b) θ' -ΝΗ

CP ^P23b

Br

K2CO3 was added to a stirred solution of compound P23a (680 mg, 2.07 mmol) in MeOH (5 ml).

- 36 045482 (713 mg, 5.17 mmol) and stirring was continued at room temperature for 1 hour. Water was then added and the mixture was extracted with EA (3x20 ml). The combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated to give compound

P23b as a white solid.

Step 3: N-((3-bromophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)cyanamide (P23c) CN

M Q' Br ^p 23s

To a solution of compound P23b (430 mg, 1.86 mmol) in DCM (5 ml) was added cyanogen bromide (235 mg, 2.24 mmol) and TEA (376 mg, 3.72 mmol). The mixture was stirred at room temperature for 3 hours, diluted with water and extracted with EA (3x20 ml). The combined organic layer was washed with saturated aqueous NaHCO ₃ (20 mL), dried over Na ₂ SO ₄ and concentrated to give P23c as a yellow solid.

Step 4: ((1H-tetrazol-5-yl)imino)(3-bromophenyl)(methyl)-λ ⁶ -sulfanone (P23d)

N=N

HNyN

V ex P23d

Br

NaN ₃ (1.06 g, 16.3 mmol) and NH ₄ Cl (864 mg, 16.3 mmol) were added to a stirred solution of compound P23c (420 mg, 1.63 mmol) in DMF (5 ml). The mixture was stirred and heated to 100°C overnight. After cooling to room temperature, water was added and the mixture was extracted with EA (3x20 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative TLC (PE:EA=1:1) to give P23d as a white solid.

Step 5: (3-bromophenyl)(methyl)((1-trityl-1H-tetrazol-5-yl)imino)-λ ⁶ -sulfanone (P23) (mixture of 1- and 2-trityl isomers)

To a stirred solution of P23d (350 mg, 1.16 mmol) in DCM (20 mL) was added trityl chloride (388 mg, 1.39 mmol) and TEA (0.3 mL, 2.3 mmol). Stirring was continued at room temperature overnight. Water was then added and the mixture was extracted with DCM (3x50 ml). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, concentrated and purified with FCC (EA:PE=1:3) to give P23 as a white solid.

Preparatory example P24.

rel-methyl-(1R,3r,5S)-8-azabicyclo[3.2.1]octane-3-carboxylate hydrochloride (P24) rel-(1R,3r,5S)-8-(tert-Butoxycarbonyl)-8-azabicyclo [3.2.1]octane-3-carboxylic acid (500 mg, 1.96 mmol) was dissolved in HCl in MeOH (20 ml). The solution was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure to obtain compound P24 as a white solid.

Preparatory example P25.

Step 1: (4-Bromo-2-(methylsulfonyl)phenyl)methanol (P25a)

To a solution of methyl 4-bromo-2-(methylsulfonyl)benzoate (3.00 g, 10.2 mmol) in MeOH (20 ml) was slowly added LiBH ₄ (4.00 g, 100 mmol) at 0°C. The mixture was stirred at 80°C overnight. Water (40 ml) was added slowly while cooling in an ice bath and the mixture was extracted with EA (3x30 ml). The combined organic layer was washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound P25a as a pale yellow solid, which was used directly in the next step.

Step 2: 2-(4-Bromo-2-(methylsulfonyl)phenyl)acetonitrile (P25b)

- 37 045482

To a solution of cyanogen bromide (712 mg, 6.70 mmol) and PPh ₃ (1.76 g, 6.70 mmol) in DCM (30 ml) was added a solution of compound P25a (1.50 g, 5.60 mmol) in DCM ( 50 ml). The mixture was stirred at 15°C for 1 hour, then DBU (1.10 g, 6.70 mmol) was added at 0°C. The resulting mixture was stirred at 0~15°C for another 16 hours. The solvent was concentrated in vacuo. The residue was purified by FCC (PE:EA=4:1) to give compound P25b as a yellow solid.

Step 3: 2-(4-Bromo-2-(methylsulfonyl)phenyl)-2-methylpropanenitrile (P25c)

T R25s

To a solution of compound P25b (200 mg, 1.10 mmol) in THF (20 ml) was added potassium tert-butoxide (502 mg, 4.40 mmol) and iodomethane (624 mg, 4.40 mmol) at -78°C. The mixture was heated to -20°C and stirred overnight, diluted with aqueous NH ₄ Cl (30 ml) and extracted with EA (3x30 ml). The combined organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=100:8) to give compound P25c as a yellow solid.

Step 4: 2-(4-bromo-2-(methylsulfonyl)phenyl)-2-methylpropanoic acid (P25)

To a solution of compound P25c (850 mg, 2.80 mmol) in EtOH (5 ml) and H ₂ O (5 ml) was added KOH (1.20 g, 22.4 mmol). The mixture was stirred at 80°C for 2 days. The pH was adjusted to approximately 5 by adding 1 N. aqueous HCl solution, and extracted with a mixture of DCM/MeOH (10/1, 3x40 ml). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give P25 as a yellow solid.

Preparatory example P26.

F ₃ C ^ΒΓ ~νίι ^Р26 'Тг

4-bromo-3-(trifluoromethyl)-1-trityl-1H-pyrazole (P26)

To a stirred solution of 4-bromo-5-(trifluoromethyl)-III-pyrazole (428 mg, 2.00 mmol) in DCM (10 ml) was added TEA (606 mg, 6.00 mmol) and (chloromethanetriyl)tribenzene (1, 11 g, 4.00 mmol) and continued stirring at room temperature overnight. The solvent was then removed and H2O (50 ml) was added and the mixture was extracted with EA (3x50 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA =5:1) to give compound P26 as a white solid.

Preparatory example P27.

Step 1: tert-butyl 3-(2-bromophenyl)-3-hydroxyazetidine-1-carboxylate (P27a) kA _Br P27a

To a solution of 1-bromo-2-iodobenzene (8.43 g, 30.0 mmol) in THF (50 ml) at -78°C, i-PrMgBr in THF (0.90 M, 33 ml, 30.0 mmol). After stirring for 2 hours, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (3.20 g, 19.0 mmol) in THF (20 ml) was added dropwise to the resulting mixture at -78°C. The mixture was stirred at room temperature for 3 hours, diluted with a saturated aqueous NH4Cl solution and extracted with EA. The organic layer was washed with water and brine, dried over Na2SO4, concentrated and purified with FCC (PE:DCM=2:1) to give compound P27a as a white solid.

Step 2: tert-Butyl 3-(2-bromophenyl)-3-fluoroazetidine-1-carboxylate (P27)

To a stirred solution of compound P27a (4.30 g, 13.1 mmol) in DCM (50 ml) at 0° C. DAST (4.20 g, 26.2 mmol) was slowly added. After stirring for 4 hours, the mixture was poured into water and extracted with EA. The organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated and purified with FCC (PE:DCM = 3:1) to give compound P27 as a colorless oil.

Preparatory example P28.

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Step 1: 3-(3-Bromothiophen-2-yl)oxetan-3-ol (P28a) but ₀ SP

To a suspension of 3-bromothiophene (13.0 g, 80.2 mmol) in THF (20 ml) was added LDA (48.0 ml, 2.0 M in THF, 96.0 mmol) under N ₂ at -60° WITH. The mixture was stirred at -60°C for 45 minutes. Oxetan-3-one (8.70 g, 121 mmol) was then added and stirring was continued for 30 minutes at -60°C. Water was added slowly and the EA mixture was extracted (3x). The combined organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=10:1 - 5:1) to give compound P28a as a brown oil.

Step 2: 3-(3-Bromothiophen-2-yl)oxetane (P28)

To a mixture of compound P28a (17.0 g, 72.6 mmol) in DCM (120 ml) was added BF ₃ -Et ₂ O (18.5 ml, 146 mmol) at 0° C. under N2. The mixture was stirred at 0°C for 30 minutes. Triethylsilane (35.0 mL, 220 mmol) was then added and the mixture was stirred at 0° C. for 30 minutes. Additional triethylsilane (35.0 mL, 220 mmol) was added and the mixture was stirred at 0° C. for 30 minutes. A third portion of triethylsilane (35.0 mL, 220 mmol) was added and stirring was continued at 0° C. for 30 minutes. The resulting mixture was added to aqueous NaOH (10%, 200 g) while cooling in an ice bath and extracted with EA (3x). The combined organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE/DCM=10:1-3:1) to give P28 as a yellow oil. 1H-NMR (CDCl ₃ , 400 MHz) δ: 7.23 (d, J=5.2 Hz, 1H), 6.94 (d, J=5.2 Hz, 1H), 5.08-5, 04 (m, 2H), 4.80-4.77 (m, 2H), 4.67-4.59 (m, 1H).

Preparatory example P29.

CN

GT R29

Step 1: 2-Bromocyclohex-1-ene-1-carboxamide (P29a)

O^MNg

GT R29a

To a solution of 2-bromocyclohex-1-ene-1-carboxylic acid (1.20 g, 5.88 mmol) in DCM (20 ml) was added HATU (3.35 g, 8.82 mmol), DIPEA (2.16 g, 16.7 mmol) and NH ₄ Cl (3.20 g, 58.9 mmol). The mixture was stirred at room temperature for 24 hours, filtered, concentrated and purified using FCC (PE:EA=1:1) to obtain compound P29a as a colorless oily substance.

Step 2: 2-Bromocyclohex-1-ene-1-carbonitrile (P29)

To a solution of compound P29a (510 mg, 2.51 mmol) in DCM (20 ml) was added ATPA (1.05 g, 5.02 mmol) at 0°C. The mixture was stirred at room temperature for 12 hours, poured into water (50 ml) and extracted with DCM (3x20 ml). The combined organic layer was washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=2:1) to give P29 as a white solid.

Preparatory example P30.

Step 1: Methyl 2-chloro-3'-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-4-carboxylate (P30a)

Pd(PPh ₃ ) ₄ (553 mg, 0.48 mmol), CuI (93 mg, 0.48 mmol) and PPh ₃ (126 mg, 0.48 mmol) were combined in a round bottom flask, then degassed three times and filled with N2 . TEA (45 ml), compound P5 (2.00 g, 6.10 mmol), ethynyltrimethylsilane (786 mg, 10.2 mmol) was added to the resulting mixture and then the mixture was stirred at 60°C for 6 hours, cooled, filtered through kieselguhr and washed with EA (40 ml). The filtrate was concentrated and purified by FCC (PE:EA=20:1) to give compound P30a as a yellow solid.

Step 2: Methyl 2-chloro-3'-ethynyl-[1,1'-biphenyl]-4-carboxylate (P30)

To a solution of compound P30a (2.05 g, 5.89 mmol) in MeOH (5 ml) was added K2CO3 (778 mg, 7.07 mmol) and the mixture was stirred at room temperature for 30 min, poured into ice water

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Preparatory example P31.

1-(2-Chloropyridin-3-yl)azetidin-3-ol (P31)

To a solution of 2-chloro-3-iodopyridine (1.20 g, 5.00 mmol) in toluene (20 ml) was added azetidin-3-ol hydrochloride (1.09 g, 10.0 mmol), Cs ₂ CO ₃ ( 6.52 g, 20.0 mmol), BINAP (311 mg, 0.50 mmol) and Pd ₂ (dba) ₃ (200 mg) under N2 atmosphere. The mixture was stirred at 110°C overnight under N2 atmosphere. After cooling to room temperature, the mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by FCC (EA:PE=1:3) to give compound P31 as a yellow solid.

Preparatory example P32.

Ethyl 2-(4-bromophenyl)-2-hydroxypropanoate (P32)

To a solution of ethyl 2-(4-bromophenyl)-2-oxoacetate (512 mg, 2.00 mmol) in THF (30 ml) was added MeMgBr (2 ml, 1 M in THF) at 0°C. The mixture was stirred at 0°C for 1 hour, diluted with water (50 ml) and extracted with EA (3x50 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=5:1) to give compound P32 as a white solid.

Preparatory example P32/1.

The following preparatory example was prepared in the same manner as described for preparatory example P32 using the appropriate building block.

building no. structure block about it

Preparatory example P33.

4-Bromo-3-chlorobenzenesulfonic acid (P31).

A solution of 4-bromo-3-chlorobenzenesulfonyl chloride (576 mg, 2.00 mmol) in H ₂ O (30 ml) was stirred at 100° C. for 16 hours and concentrated to give compound P33 as a white solid.

Preparatory example P34.

Step 1: N-((4-Bromo-3-chlorophenyl)sulfonyl)acetamide (P34a)

4-Bromo-3-chlorobenzenesulfonamide (1.5 g, 5.5 mmol) was dissolved in pyridine (5 ml). DMAP (22 mg, 0.18 mmol) and _Ac2O (1.1 mL, 12 mmol) were then added and the mixture was stirred for 3 hours at room temperature, diluted with EA and washed with aqueous _NH4Cl (3x) and water . The organic layer was dried over Na ₂ SO ₄ and concentrated. The resulting oily substance was triturated with PE and the precipitate was collected by filtration to obtain compound P34a as a white solid.

Step 2: N-((3-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)acetamide (P34)

To a solution of compound P34a (310 mg, 1.00 mmol) in dioxane (5 ml) was added B ₂ Pin ₂ (381 mg, 1.50

- 40 045482 mmol), KOAc (276 mg, 2.00 mmol) and Pd(dppf)Cl ₂ (120 mg). The mixture was stirred under N2 at 90°C for 8 hours, cooled, filtered, concentrated and purified with FCC (PE:EA=5:1) to give compound P34 as a yellow solid.

Preparatory example P35.

CN

LX ^rm

Step 1: 4-Bromopyridine-3,5-dicarboxylic acid (P35a) cooh ^y ^Br P35a ⁿ '^ ^x cooh

To a solution of 4-bromo-3,5-dimethylpyridine (1.24 g, 6.72 mmol) in water (15 ml) was added KMnO ₄ (1.59 g, 10.1 mmol) and the mixture was stirred at 100°C in for 1 hour. Additional KMnO ₄ (1.59 g, 10.1 mmol) in water (15 ml) was then added and stirring continued at 100°C for 2 hours. The mixture was then filtered and the solvent concentrated to a volume of approximately 5 ml , brought to pH=2 using conc. HCl and concentrated to give compound P35a as a white solid.

Step 2: 4-Chloropyridine-3,5-dicarboxamide (P35b) conh ₂

Ιι η P35b conh ₂

To a solution of compound P35a (1.30 g, 5.30 mmol) in DCM (15 ml) was added SOCl ₂ (1.5 ml) and DMF (3 drops). The mixture was stirred at 45°C for 2 hours, concentrated and redissolved in dioxane (5 ml). ΝΗ ₃ · Η ₂ Ο (20 ml) was added dropwise to the solution at 0° C. and then concentrated to give compound P35b as a yellow solid.

Step 3: 4-Chloropyridine-3,5-dicarbonitrile (P35)

To a solution of compound P35b (188 mg, 0.94 mmol) in DMF (5 ml) was added POCl ₃ (1 ml) and the mixture was stirred at room temperature overnight, diluted with water (30 ml) and extracted with EA (3x50 ml). The combined organic layer was washed with aqueous NaHCO ₃ (30 ml), concentrated and purified using FCC (PE:EA=5:1) to obtain compound P35 as a white solid.

General Notes: A C before an example number indicates that the example indicated is a comparative example, and a P before the example number indicates that the example indicated contains a protecting group. Such examples are not included in the scope of the claims.

Example 1.

Step 1: 2-((3-Bromophenyl)ethynyl)-4-fluoroaniline (1a)

To a solution of 1-bromo-3-iodobenzene (5.00 g, 17.7 mmol) in Et ₃ N (50 ml) was added Pd(PPh ₃ ) ₄ (1.22 g, 1.06 mmol), CuI (269 mg, 1.41 mmol), PPh ₃ (278 mg, 1.06 mmol) and 2-ethynyl-4-fluoroaniline (2.86 g, 21.2 mmol). The mixture was stirred at 60°C under N ₂ for 4 hours, cooled, filtered, concentrated and purified with FCC (PE:EA=8:1) to give compound 1a as a yellow solid.

Step 2: N-(2-((3-Bromophenyl)ethynyl)-4-fluorophenyl)-4-methylbenzenesulfonamide (1b)

To a solution of compound 1a (3.50 g, 12.1 mmol) in DCM (50 ml) was added pyridine (3.5 ml), 4methylbenzene-1-sulfonyl chloride (4.58 g, 24.1 mmol) and DMAP (350 mg). The mixture was stirred at room temperature overnight, diluted with CH ₂ Cl ₂ (300 ml) and washed successively with 2 N. HCl

- 41 045482 (3x0 ml) and saturated saline solution (30 ml). The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=5:1) to give compound 1b as a white solid.

Step 3: 3-(2-(3-Bromophenyl)-5-fluoro-1-tosyl-1H-indol-3-yl)thiophene-2-carbonitrile (1)

To a solution of compound 1b (4.20 g, 9.48 mmol) in CH3CN (60 ml) was added 3-bromothiophene-2carbonitrile (3.67 g, 14.2 mmol), K ₂ CO ₃ (2.62 g, 10 .0 mmol) and Pd(PPh ₃ ) ₄ (1.09 g, 0.95 mmol) in an N2 atmosphere. The mixture was stirred at 100°C for 2 hours, cooled, poured into EA (400 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified using FCC (EA:PE=1:3) to obtain compound 1 as a white solid.

Examples 1/1-1/149.

The following examples were prepared in the same manner as described for Example 1, using the appropriate

warping building blocks. No. building block(s) °\ / V ⁰ 1/1 ^b 4j o , 1/2 0 ^F ' ^В| —0/ P5/2 - y ' ^Br ~W o , ^1/4 0 ^F ' Bg - ζ D Ί 1/5 o /=(/ ^{0 Br} -Ch. / P4 1/6 ' οψ W _р 1/7 [J ^F ' _Br /К ^{P12 Br} vy structure analytical data about , ,s> 0° NC -ά J GP οίο s?° 0'° 0 / /~° ^nc A3 \ / y $ _w 4° A? 0 / Ko zZ nc—Cj \ / Оа-<у p _о Isolation of both isomers ^with yJ under the following conditions: instrument: SFC-80 (Thar, Waters) .-/A Column: OJ 20x250 mm, 10 ), ne _F E »fi :-ΓΚ! rsvznny MKM (DaiCel) CALT- - Column temperature: 35 °C Mobile phase: CO2/MeOH (0.2% NhVOMe-) = 70/30 _g g 'Flow rate: 80 g/min. A A D Back pressure: 100 bar T| 1';, Detection wavelength: 'D/' 214 nm Y Y Cycle time: 2 min. V ' χχχ* Sample solution: 180 mg, «·>. dissolved in 30 ml MeOH Sample injection volume: 1 ml А А wA у/

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1/76 Μ Bgh^. Ύ J 1/77 I / ^Ν >< βίνχτ J C1/78 ^NC ^it 1/79 Μ F ₃ C ^X Br^. Ύ J 1/80 ί4 1/81 a,.,., Μ Br^^^ 1/82 ХД Г Вгх^^. 1/83 ХД χ F ₃ C^ ^Br WV 1/84 XJT X FjHC'^ Br^^-. 1/85 (0 ϊ_ K ,L° _H0 $ PI 2 F\^vJ /=( wX O w^ ^s ° Br Ϊ - Οί rLU Lr P ^Γ χΧχ I <l / \ '° E ^Br XX and ^N % Vo r/V L Η ⁴ | Ρ12 with Γ W\ / ^s ?° 0° Br <3 A JH ,ГГ° ^F ' ^c 0 Ρ Γ ^Ρ12 /=< WVX0 О Br UV ⁰ ^vXV Г\ ⁴ nJ 00)^ ⁷ N ^J I Р12 /=< q IV' ^Br χχ 8η Ji o ^NC 0 p •N^ ⁰ PI 2 W ⁰ /X l. -Φ V P12 ^F WwX U. / A # ^c x Y% /Y ^<o o o ^/ \ *5% ^P12 WW\ ci„ IA./U V° J w ^<0 χχ FgC ⁷ ° / ^s -i '- У -JA ^P12 YMuX a IXHJ Ύ w*° wf ₂ hc^ V? χΧχΙ ^{0 r} 12 tNA/\ a LX/vX l° v° J 0

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Example 2.

/

-Ν

Step 1: 3 -(5-Fluoro-2-(3 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-tosyl-1 H-indol- 3 yl)thiophene-2-carbonitrile (2a)

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To a solution of compound 1 (2.61 g, 4.73 mmol) in dioxane (40 ml) was added B ₂ Pin (1.44 g, 5.68 mmol), KOAc (928 mg, 9.46 mmol) and Pd( dppf)Cl ₂ (344 mg, 0.47 mmol). The mixture was stirred at 80°C overnight under N ₂ atmosphere, cooled, filtered, concentrated and purified with FCC (EA:PE=1:3) to give compound 2a as a white solid.

Step 2: 3 -(2-(2'-Chloro-4'-((dimethylamino)methyl)-[1,1'-biphenyl]-3 -yl)-5-fluoro-1-tosyl-1 H-indole -3 yl)thiophene-2-carbonitrile (2)

To a solution of compound 2a (150 mg, 0.25 mmol) in dioxane (8 ml) was added 1-(4-bromo-3chlorophenyl)-N,N-dimethylmethanamine (65 mg, 0.26 mmol), Cs ₂ CO ₃ ( 163 mg, 0.50 mmol) and Pd(PPh ₃ ) ₄ (30 mg, 25 μmol). The mixture was stirred at 100°C overnight under N2, cooled, filtered, concentrated and purified by preparative HPLC to give compound 2 as a white solid. 1H-NMR (500 MHz, DMSO^) δ: 8.29 (dd, J=9.5, 4.5 Hz, 1H), 8.02 (d, J=5.0 Hz, 1H), 7, 51-7.32 (m, 8H), 7.26-7.17 (m, 4H), 7.02-6.99 (m, 2H), 3.42 (s, 2H), 2.21 ( s, 3H), 2.18 (s, 6H); MS: 639.9 (M+1)+.

Examples 2/1-2/34.

The following examples were prepared in the same manner as described for Example 2 (and optionally for Example 1) using the appropriate building blocks.

_building no. block(s) structure analytical data

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Example 3.

2-(2-Chloro-3'-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)-[1,1'-biphenyl]-4 -yl)-2(dimethylamino)acetic acid (3)

To a solution of compound 2/3 (80 mg, 0.11 mmol) in THF (8 ml), MeOH (3 ml) and H ₂ O (3 ml) was added

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LiOH-H ₂ O (24 mg, 0.57 mmol). The mixture was stirred at room temperature for 30 min, concentrated, diluted with H2O (6 ml), adjusted to pH = 3 with 2 N. HCl and extracted with EA (2x50 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 3 as a white solid.

1H-NMR (500 MHz, DMSO) δ: 8.41 (dd, J=9.3, 4.3 Hz, 1H), 7.82 (d, J=5.0 Hz, 1H), 7.74 (d, J=2.0 Hz,

1H), 7.57 (dd, J=7.8, 1.7 Hz, 1H), 7.50-7.41 (m, 4H), 7.30-7.25 (m, 3H), 7 ,18-7.15 (m, 2H), 7.07-7.05 (m, 2H), 6.95 (d, J=5.0 Hz, 1H), 4.53 (s, 1H), 2.84 (s, 6H), 2.27 (s, 3H); MS: 683.8 (M+1) ⁺ .

Examples 3/1-3/73.

The following examples were saponified in the same manner as described for example 3, using the appropriate starting material (ester).

No. starting material structure

analytical data ¹ H-NMR (500 MHz, CD ₃ OD) b: 8.42 (dd, J = 4.5, 9.0 Hz, 1H), 7.80 (d, J = 5.0 Hz, 1H ), 7.40 (d, J = 8.0 Hz, 1H), 7.32-7.17 (m, 7H), 7.04 (dd, J = 2.8, 8.8 Hz, 1H) , 6.99 (s, 1H), 6.88 (d, J = 5.5 Hz, 1H), 2.36 (s, ZN), 1.83-1.80 (m, 1H), 1, 43 (s, ZN), 1.31-1.29 (m, 1H), 1.22-1.19 (m, 1H); MS: 568.8 (M-1)-.

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.43 (dd, J = 4.3, 8.8 Hz, 1H), 7.74 (d, J = 5.0 Hz, 1H), 7.36-7.21 (m, 8H), 7.137.04 (m, 2H), 6.75 (d, J = 5.0 Hz, 1H), 2.35 (s, ZN), 1.94 -1.92 (m, 1H), 1.631.62 (m, 1H), 1.38 (s, ZN), 1.20-1.17 (m, 1H); MS: 568.8 (M-1)-.

¹ H-NMR (500 MHz, DMSO-de) b: 8.21 (dd, J = 4.5, 9.0 Hz, 1H), 6.68 (d, J = 9.0 Hz, 2H), 7.31-7.26 (m, ZN), 7.17 (t, J = 8.0 Hz, 1H), 6.97 (dd, J = 2.5, 9.0 Hz, 1H), 6 .75 (d, J = 6.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.48 (dd, J = 2.0, 8.0 Hz, 1H) , 6.39 (d, J = 6.0 Hz, 1H), 6.26 (s, 1H), 3.93 (t, J = 8.0 Hz, 2H), 3.79 (t, J = 6.5 Hz, 2H), 3.60 (s, ZN), 3.54-3.47 (m, 1H), 2.32 (s, ZN); MS: 577.1 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.36 (dd, J = 4.3, 8.8 Hz, 1H), 7.60 (d, J = 5.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.25-7.17 (m, 4H), 6.84 (dd, J = 2.5, 8.5 Hz, 1H), 6 .75-6.70 (m, 2H), 6.55 (dd, J = 1.8, 8.3 Hz, 1H), 6.19 (t, J = 55.0 Hz, 1H), 6, 16 (s, 1H), 3.99-3.82 (m, 4H), 3.58-3.52 (m, 1H), 2.38 (s, ZH); MS: 597.1 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 12.64 (brs, 1H), 9.31 (d, J = 1.0 Hz, 1H), 8.26 (dd, J = 4.0 , 9.0 Hz, 1H), 8.10 (dd, J = 1.3, 4.8 Hz, 1H), 7.407.32 (m, 5H), 7.14-7.06 (m, ZN) , 6.60 (shs, 1H), 6.46 (dd, J = 1.8, 8.3 Hz, 1H), 6.20 (shs, 1H), 3.87 (t, J = 8.0 Hz, 2H), 3.74 (t, J = 6.5 Hz, 2H), 3.54-3.48 (m, 1H), 2.33 (s, ZH); MS:

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¹ H-NMR (500 MHz, DMSO-de) b: 8.23 (dd, J = 4.5, 9.0 Hz, 1H), 7.46 (d, J = 5.0 Hz, 1H), 7.33-7.27 (m, 5H), 7.14 (t, 0 = 7.8Hz, 1H), 6.87 (dd, J=2.5, 8.5 Hz, 1H), 6, 63-6.60 (m, 2H), 6.45 (dd, J = 2.0, 8.0 Hz, 1H), 6.18 (s, 1H), 4.14-4.09 (m, 1H), 3.89-3.73 (m, 5H), 3.54-3.48 (m, 1H), 2.99 (s, ZN), 2.31 (s, ZN); MS: 591.1 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 12.69 (bs, 1H), 11.24 (s, 1H), 8.25 (dd, J = 4.3, 9.3 Hz, 1H ), 7.49 (d, J = 5.0 Hz, 1H), 7.38-7.29 (m, 6H), 7.13 (d, J = 7.8 Hz, 1H), 6.83 (dd, J = 2.5, 8.5 Hz, 1H), 6.72 (d, J = 5.5 Hz, 1H), 6.60-6.57 (m, 1H), 6.45 ( dd, J =2.0, 8.0 Hz, 1H), 6.19 (s, 1H), 3.91-3.87 (m, 2H), 3.79-3.75 (m, 2H) , 3.54-3.50 (m, 1H), 2.32 (m, ZN); MS: 590.0 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 8.28 (dd, J = 4.8, 9.3 Hz, 1H), 8.24 (d, J = 5.0 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.42-7.33 (m, ZN), 7.23 (s, 1H), 7.157.11 (m, 2H), 6.94 (d, J = 5.0 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H), 6.47 (dd, J = 1.3, 8.3 Hz, 1H), 6 .17 (s, 1H), 3.86 (t, J = 8.0 Hz, 2H), 3.75 (t, J = 6.5 Hz, 2H), 3.45-3.40 (m, 1H), 2.28 (s, ZN); MS: 569.8 (M-1)-.

¹ H-NMR (500 MHz, DMSO-de) b: 8.28 (dd, J = 4.5, 9.5 Hz, 1H), 7.98 (d, J = 4.5 Hz, 1H), 7.71-7.67 (m, 1H), 7.547.50 (m, 4H), 7.37-7.33 (m, 1H), 7.147.11 (m, 2H), 6.93 (d, J = 5.0 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.45 (dd, J = 1.8, 8.3 Hz, 1H), 6.18 ( s, 1H), 3.83 (t, J = 7.8 Hz, 2H), 3.74 (t, J = 6.3 Hz, 2H), 3.34-3.30 (m, 1H); MS: 557.9 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 8.28 (dd, J = 4.0, 9.0 Hz, 1H), 7.98 (d, J = 5.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.37-7.33 (m, ZN), 7.16-7.11 (m, 2H), 6.94 (d, J = 5.0 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 6.48 (dd, J = 1.5, 8.0 Hz, 1H), 6.21 (s, 1H), 3.89 (t, J = 7.5 Hz, 2H), 3.77 (t, J = 6.3 Hz, 2H), 3.493.44 (m, 1H), 2.63 (k, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5 Hz, ZN); MS: 586.8 (M+1) ⁺ .

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¹ H-NMR (500 MHz, DMSO-de) b: 8.28 (dd, J = 4.3, 9.3 Hz, 1H), 7.99 (d, J = 5.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 2H), 7.52-7.23 (m, 4H), 7.15-7.12 (m, 2H), 6.95 (d, J = 5.0 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.49-6.48 (m, 1H), 6.27 (s, 1H), 3.90 ( t, J = 8.0 Hz, 2H), 3.79 (t, J = 6.5 Hz, 2H), 3.46-3.41 (m, 1H); MS: 623.7 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 8.28 (dd, J = 4.5, 9.0 Hz, 1H), 7.97 (d, J = 5.0 Hz, 1H), 7.37-7.30 (m, ZN), 7.27 (s, 1H), 7.15-7.10 (m, 2H), 6.94 (d, J = 5.5 Hz, 1H) , 6.54 (d, J = 7.5 Hz, 1H), 6.46 (dd, J = 1.8, 8.3 Hz, 1H), 6.14 (s, 1H), 3.84 ( t, J = 8.0 Hz, 2H), 3.74 (t, J = 6.5 Hz, 2H), 3.41-3.35 (m, 1H), 2.88-2.80 (m , 4H), 2.02-1.97 (m, 2H); MS: 598.2 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 8.38 (dd, J = 4.0, 9.5 Hz, 1H), 8.18 (s, 1H), 8.06-7.96 (m, 4H), 7.76-7.68 (m, 2H), 7.46 (d, J = 9.0 Hz, 1H), 7.39-7.36 (m, 1H), 7. 15-7.12 (m, 2H), 6.95 (d, J = 5.0 Hz, 1H), 6.59 (d, J = 7.0 Hz, 1H), 6.45 (d, J = 7.5 Hz, 1H), 6.08 (s, 1H), 3.69-3.59 (m, 4H), 3.42-3.32 (m, 1H); MS: 608.2 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 8.16 (dd, J = 4.5, 9.0 Hz, 1H), 7.98 (d, J = 5.5 Hz, 1H), 7.36-7.17 (m, 4H), 7.05 (t, J = 7.5 Hz, 2H), 6.99 (d, J = 5.0 Hz, 1H), 6.45-6 .40 (m, 2H), 5.97 (s, 1H), 3.79 (t, J = 8.0 Hz, 2H), 3.68 (t, J = 6.3 Hz, 2H), 3 .45-3.40 (m, 1H), 2.36 (s, ZN); MS: 589.9 (M+1) ⁺ .

^1H -NMR (500 MHz, DMSO-de) b: 8.42 (d, J = 8.5 Hz, 1H), 8.03-8.01 (m, 1H), 7.83 (d, J = 5.0 Hz, 1H), 7.79 (s, 1H), 7.67-7.62 (m, 2H), 7.56-7.53 (m, 1H), 7.42-7, 39 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 5.0 Hz, 1H), 4.26 (s, 2H), 2.35 (s, ZN); MS: 576.7 (M+1) ⁺ , ¹ H-NMR (500 MHz, DMSO-de) b: 12.07 (brs, 1H), 8.28 (d, J = 8.0 Hz, 1H) , 8.02 (d, J = 5.0 Hz, 1H), 7.537.50 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 4.0 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 3.5 Hz, 1H), 6.99 (d, J = 5, 5 Hz, 1H), 6.83 (d, J = 4.0 Hz, 1H), 2.97 (s, 2H), 2.31 (s, ZH), 1.09 (s, 6H); MS: 559.0 (M-1)-.

- 71 045482

¹ H-NMR (500 MHz, DMSO-de) b: 8.26 (d, J = 11.0 Hz, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.54- 7.32 (m, 8H), 7.04 (d, J = 6.0 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 2.39-2.34 (m , 1H), 2.32 (s, ZN), 1.75-1.70 (m, 1H), 1.39-1.35 (m, 1H), 1.20-1.15 (m, 1H ); MS: 562.1 (M+18) ⁺ .

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.41 (d, J = 10.0 Hz, 1H), 7.80 (d, D = 6.5 Hz, 1H), 7.65- 7.49 (m, ZN), 7.43-7.21 (m, 9H), 6.96 (d, J = 6.5 Hz, 1H), 6.35 (d, J = 20.0 Hz , 1Н),2.36 (s, ЗН); MS: 524.6 (M+1) ⁺ .

Ή-NMR (500 MHz, DMSO-de) b: 12.47 (brs, 1H), 8.25 (d, J = 10.5 Hz, 1H), 8.07 (d, J = 6.5 Hz , 1H), 7.70 (d, J = 20.0 Hz, 1H), 7.56-7.51 (m, 4H), 7.42-7.32 (m, 4H), 7.23 ( d, J = 4.5 Hz, 1H), 7.09 (d, J = 6.5 Hz, 1H), 6.18 (d, J = 20.0 Hz, 1H), 2.31 (s, ZN); MS: 530.7 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 12.39 (brs, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 5.0 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.40-7.28 (m, 9H), 7.06 (s, 1H), 6.92 (d, J = 4.0 Hz, 1H), 2.30 (s, ZN), 1.36 (s, 6H); MS: 563.1 (M+Na) ⁺ .

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.26 (dd, J = 4.5, 9.0 Hz, 1H), 8.10 (d, J = 1.0 Hz, 1H), 7.99 (dd, J = 1.8, 7.8 Hz, 1H), 7.86 (d, J = 5.5 Hz, 1H), 7.567.51 (m, ZN), 7.44 (s , 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.25-7.21 (m, 1H), 7.15 (dd, J = 2.8, 8.8 Hz, 1H), 6.98 (d, J = 4.5 Hz, 1H), 3.48 (d, J = 12.5 Hz, 2H), 2.53-2.48 (m, 2H), 1, 47 (d, J = 12.5 Hz, 2H), 1.33-1.28 (m, 1H), 0.86-0.77 (m, 5H); MS: 633.9 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.44 (dd, J = 4.5, 9.0 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 8.00 (dd, J = 1.5, 7.5 Hz, 1H), 7.82 (d, J = 5.0 Hz, 1H), 7.527.44 (m, ZN), 7.39 (d , J = 8.0 Hz, 1H), 7.29-6.95 (m, 4H); MS: 632.0 (M-1)-.

- 72 045482

- 73 045482

- 74 045482

F ₃ C

He

^1H -NMR (500 MHz, DMSO-de) b: 8.31-8.28 (m, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.39 (td, J = 9.1, 2.5 Hz, 1H), 7.15-7 .11 (m, 2H), 6.94 (d, J = 5.1 Hz, 1H), 6.54-6.47 (m, 2H), 6.24 (s, 1H), 3.89 ( t, J = 7.9 Hz, 2H), 3.78 (t, J = 6.4 Hz, 2H), 3.44-3.47 (m, 1H); MS: 625.8 (M+1) ⁺ .

^1H -NMR (500 MHz, DMSO-de) b: 8.30-8.27 (m, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.40-7.35 (m, 1H), 7.15-7.12 (m, 2H) , 7.09 (t, J = 55.5 Hz, 1H), 6.96 (d, J = 5.1 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 6 .48 (d, J = 8.0 Hz, 1H), 6.24 (s, 1H), 3.88 (t, J = 7.9 Hz, 2H), 3.77 (t, J = 6, 5 Hz, 2H), 3.42-3.48 (m, 1H); MS: 607.8 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.248.21 (m, 1H), 7.79 (d, J = 5.1 Hz, 1H), 7.23-7.15 (m, 2H ), 7.11 (dd, J = 8.7, 2.5 Hz, 1H), 6.86 (d, J = 5.1 Hz, 1H), 6.77 (d, J = 7.6 Hz , 1H), 6.56-6.53 (m, 2H), 4.05-4.01 (m, 2H), 3.94-3.90 (m, 2H), 3.50-3.56 (m, 1H), 3.47 (d, J = 12.9 Hz, 2H), 2.48 (t, J = 11.7 Hz, 2H), 1.49 (dd, J = 13.0, 2.1 Hz, 2H), 1.39-1.26 (m, 1H), 0.90-0.76 (m, 5H); MS: 579.0 (M+1) ⁺ .

^1H -NMR (500 MHz, DMSO-de) b: 12.77 (s, 1H), 8.27 (dd, J = 9.2, 4.4 Hz, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.45-7.28 (m, 5H), 7.19-7.08 (m, 2H), 6.95 (d, J = 5.1 Hz, 1H) , 6.59-6.57 (m, 1H), 6.51-6.47 (m, 1H), 6.21 (s, 1H), 3.92 (d, J = 7.2 Hz, 2H ), 3.54 (d, J = 7.2 Hz, 2H), 2.33 (s, ZN), 1.52 (s, ZN); MS: 586.2 (M+1) ⁺ .

¹ H-NMR (400 MHz, CD ₃ OD) b: 8.40 (dd, J = 9.2, 4.4 Hz, 1H), 7.88 (d, J = 5.1 Hz, 1H), 7.41-7.57 (m, ZN), 7.357.20 (m, 5N), 7.10-6.98 (m, ZN), 3.733.69 (m, 2N), 3.47-3, 41 (m, 2H), 2.802.67 (m, 1H), 2.36 (s, ZN), 2.26 (d, J = 14.1 Hz, 2H), 2.13-1.98 (m , 2H); MS: 600.2 (M+1) ⁺ .

- 75 045482

¹ H-NMR (500 MHz, DMSO-de) b: 12.14 (s, 1H), 8.30 (dd, J = 9.2, 4.4 Hz, 1H), 8.00-7.97 (m, 1H), 7.43-7.20 (m, 7H), 7.17-7.08 (m, 2H), 7.06-6.91 (m, 2H), 3.62-3 .29 (m, 1H), 3.10-2.92 (m, 1H), 2.50-2.39 (m, 2H), 2.32 (s, ZN), 2.24-2.02 (m, 2H); MS: 568.7 (M-1)-.

Voh ¹ H-NMR (500 MHz, DMSO-de) b: <4 12.68 ( ^{s 1 n} )' ⁸ ' ²⁸ (DD ^{J = 9} ' ² ' ^{4 4 NC} UL O Hz, 1H), 7.98(d, J = 5.1 Hz, 1H), 7.59 /=< (d, J = ⁸ ' ^{4 G} D' ^2H )' 7.44-7.32 (m, ZN),

T TuCH } 7.28-7.17 (m, 2H), 6.94 (d, J = 5.1 Hz, o / 1H), 6.54 (dd, J = 8.7, 2.8 Hz, 1Н), ~Х _П ^С| 6.40 (d, J = 2.3 Hz, 1H), 4.02-3.93 (m, fl 2H), 3.90-3.77 (m, 2H), 3.59-3.48 (m,

U=/ 1H), 2.36 (s, ZN); MS: 606.1 (M+1) ⁺ .

Voh ¹ H-NMR (500 MHz, CDCI ₃ ) b: 8.30 mgTT No. (DD' ^{J = 9} ' ² ' ⁴ ' ^{4 G} D' ^{1 n} )' ⁷ ' ⁴⁹ (D' ^J = ^NC uL R ⁵ ' ¹ Hz- ¹ I)' ⁷ ' ⁴² (D' ^J = ⁸ ' ³ Hz- ^2H )'/=< 7.20-7.12 (m, ZN), 7.05 (dd, J = 8, 4,

T TuCH } 2.4 Hz, 1H), 6.90 (t, J = 8.9 Hz, 1H), o/ 6.83 (d, J = 5.1 Hz, 1H), 6.56-6 .49 (m, ^F 1H), 6.39-6.35 (m, 1H), 4.12-3.98 (m,

LC ° 4H), 3.63-3.55 (m, 1H), 2.35 (s, ZN);

U=/MS: 590.1 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.348.29 (m, 1H), 7.78 (d, J = 5.0 Hz, 1H), 7.34-7.15 (m, 6H ), 6.87 (d, J = 5.0 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H), 6.57 (dd, J = 1.5 Hz, 1.0 Hz, 1H), 6.18 (s, 1H), 4.00 (t, J = 8.0 Hz, 2H), 3.89 (t, J = 7.5 Hz, 2H), 3.58- 3.54 (m, 1H), 2.38 (s, ZN); MS: 589.7 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 12.69 (brs, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 6.5 Hz, 1H), 7.457.32 (m, 5H), 7.14 (t, J = 9.5 Hz, 1H), 6.95 (d, J = 6.0 Hz, 1H), 6.55- 6.48 (m, 2H), 6.15 (s, 1H), 3.89 (t, J = 9.5 Hz, 2H), 3.74 (t, J = 8.5 Hz, 2H), 3.543.49 (m, 1H), 2.34 (s, ZN); MS: 606.1 (M+1) ⁺ .

- 76 045482

- 77 045482

- 78 045482

- 79 045482

- 80 045482

- 81 045482

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.38 (dd, J = 9.3, 4.3 Hz, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.97 (dd, J = 8.0, 1.5 Hz, 1H), 7.55-7.47 (m, 8H), 7.39 (t, J = 8.0 Hz, 1H), 7 .33 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 2.5, 9.2 Hz, 1H), 7.26 (shs, 1H), 7.10-6, 59 (m, 4H); MS: 670.9 (M-1)-.

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.57 (s, 1H), 8.09-8.07 (m, ZN), 8.00 (dd, J = 8.3, 1, 8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.61-7.43 (m, 7H), 7.36 (d, J = 8.0 Hz, 1H) , 7.02 (s, 1H), 6.70 (t, J = 55.5 Hz, 1H), 6.14 (d, J = 1.0 Hz, 1H); MS: 681.1 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.44 (dd, J = 4.3, 9.3 Hz, 1H), 8.07-7.97 (m, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.53-7.44 (m, 7H), 7.34 (dt, J = 2.5, 9.0 Hz, 1H), 6.94- 6.91 (m, 2H), 6.706.65 (m, 2H), 6.68 (t, J = 55.5 Hz, 1H), 4.71 (s, 2H); MS: 712.0 (M-N)-.

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.45 (dd, J = 9.0, 4.5 Hz, 1H), 8.17-7.92 (m, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.57-7.48 (m, 7H), 7.36-7.29 (m, ZN), 6.95-6.92 (m, 2H ), 6.65 (t, J = 55.8 Hz, 1H), 1.75 (s, ZN); MS: 726.0 (MΉ-NMR (500 MHz, CD ₃ OD) b: 8.45 (dd, J = 4.3, 9.3 Hz, 1H), 8.07-8.02 (m, 2H ), 7.71 (t, J = 8.0 Hz, 1H), 7.56-7.48 (m, 7H), 7.34 (dt, J = 2.5, 9.5 Hz, 1H) , 7.02 (d, J = 8.5 Hz, 2H), 7.01-6.93 (m, 2H), 6.66 (t, J = 55.5 Hz, 1H), 3.68 ( s, 2H); MS: 652.0 (MSOgH)-.

Example 4.

trans-2-(3-(3-(2-cyanothiophen-3-yl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-2-yl)phenyl)cyclopropane1-carboxylic acid (4)

A mixture of compound 2/4 (178 mg, 0.32 mmol) and LiOH H ₂ O (67 mg, 1.62 mmol) in THF (4.1 ml), MeOH (4.1 ml) and water (0. 81 ml) was stirred at room temperature for 3 hours, adjusted to pH=3 with 1 N. HCl, concentrated, diluted with EA (50 ml) and washed with water (3x5 ml) and brine (5 ml). The organic layer was concentrated under reduced pressure, the residue was dissolved in DMF (2.5 ml), filtered and the filtrate was purified by preparative HPLC to give compound 4 as a white solid. 1H-NMR (500 MHz, CD3OD) δ: 8.90 (dd, J=8.5, 1.5 Hz, 1H), 8.60 (dd, J=4.8, 0.8 Hz, 1H) , 7.79 (d, J=5.0 Hz, 1H), 7.62 (dd, J=8.5, 4.5 Hz, 1H), 7.32-7.25 (m, 6H), 7.15-7.13 (m, 1H), 6.95 (d, J=5.0 Hz, 1H), 6.76 (s, 1H), 2.39-2.38 (m, 4H) , 1.77-1.73 (m, 1H), 1.55-1.51 (m, 1H), 1.25 (shs, 1H); MS: 540.1 (M+1) ⁺ .

Examples 4/1-4/3.

The following examples were prepared in the same manner as described for Example 4 using the appropriate starting material.

- 82 045482 No. starting material

structure

analytical data

Ή-NMR (500 MHz, CD3OD) b: 9.84 (s, 1H), 8.65 (d, J = 6.0 Hz, 1H), 8.03 (d, J = 6.0 Hz, 1H ), 7.87 (d, J = 5.0 Hz, 1H), 7.34-7.28 (m, 6H), 7.12 (d, J = 6.0 Hz, 1H), 6.99 (d, J = 5.0 Hz, 1H), 6.71 (s, 1H), 2.42-2.36 (m, 4H), 1.761.73 (m, 1H), 1.54-1, 51 (m, 1H), 1.23 (shs, 1H); MS: 540.1 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD3OD) b: 8.51 (dd, J = 1.5, 5.0 Hz, 1H), 7.87 (dd, J = 1.5, 8.0 Hz, 1H ), 7.79 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.41 (dd, J = 5.3, 7.7 Hz , 1H), 7.347.26 (m, 4H), 7.21 (dd, J = 7.5, 1.5 Hz 1H), 7.00 (s, 1H), 6.89 (d, J = 5 .0 Hz, 1H), 2.472.44 (m, 1H), 2.40 (s, ZN), 1.80-1.78 (m, 1H), 1.56-1.52 (m, 1H) , 1.30-1.29 (m, 1H); MS: 540.0 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 7.91 (d, J = 5.5 Hz, 1H), 7.68 (d, J = 5.5 Hz, 1H), 7.617.60 ( m, 1H), 7.38-7.32 (m, 4H), 7.15 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 4.5 Hz, 1H), 6.536.50 (m, 2H), 6.13 (d, J = 1.5 Hz, 1H), 3.90 (t, J = 7.8 Hz, 2H), 3.76 (t, J = 6 ,3 Hz, 2H), 3.533.49 (m, 1H), 2.35 (s, ZN); MS: 560.0 (M+1) ⁺ .

Example 5.

2-((5-(3-(3-(2-Cyanothiophen-3-yl)-1-tosyl-1H-indol-2-yl)phenyl)pyridin-3-yl)sulfonyl)acetic acid (5)

To a mixture of compound 2/8 (110 mg, 0.17 mmol) in MeOH (2 ml) and THF (1 ml) was added LiOH (2 M, 0.3 ml) and the mixture was stirred at room temperature for 1 hour. Mixture neutralized with 1 N. HCl solution and extracted with EA (3x). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 5 as a white solid. 1H-NMR (500 MHz, CD3OD) δ: 9.09 (d, J=2.0 Hz, 1H), 9.03 (d, J=2.0 Hz, 1H), 8.44-8.42 (m, 2H), 7.85-7.80 (m, 2H), 7.57-7.39 (m, 6H), 7.33 (d, J=8.0 Hz, 2H), 7, 20 (d, J=8.0 Hz, 2H), 7.06 (d, J=4.5 Hz, 1H), 4.54 (s, 2H), 2.29 (s, 3H); MS: 554.1 (M+1) ⁺ .

Examples 5/1-5/10.

The following examples were prepared in the same manner as described for Example 5 using the appropriate starting material.

No. starting material

structure

analytical data ¹ H-NMR (500 MHz, DMSO-de) b: 13.30 (shs, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.05-8.00 (m , 2H), 7.92-7.86 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.55-7.51 (m, ZN), 7.42- 7.28 (m, 7H), 7.08 (d, J = 5.5 Hz, 1H), 4.96 (s, 2H), 4.61 (s, 2H), 2.26 (s, ZN ); MS: 699.8 (M+18) ⁺ .

- 83 045482

5/2

5/3

5/4

5/5

5/6

5/7

5/

Ή-NMR (500 MHz, DMSO-de) δ: 12.43 (s, 1H), 8.27 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 5.0 Hz , 1H), 7.53-7.49 (m, 1H), 7.38-7.22 (m, 9H), 6.98-6.95 (m, 2H), 2.32 (s, ZN ), 2.14 (s, 6H); MS: 562.8 (M-1)-.

¹ H-NMR (500 MHz, DMSO-de) δ: 13.05 (s, 1H), 8.31 (dd, J = 9.2, 4.4 Hz, 1H), 8.04-8.02 (m, ZN), 7.80 (d, J = 7.7 Hz, 1H), 7.68 (d, u = 8, ZHz, 2H), 7.567.47 (m, 2H), 7.44- 7.33 (m, ZN), 7.307.26 (m, ZN), 7.19 (dd, J = 8.6, 2.5 Hz, 1H), 7.07 (d, J = 5.1 Hz , 1Н), 2.25 (s, ЗН); MS: m/z 590.6 (M-1)-.

¹ H-NMR (500 MHz, DMSO-de) δ: 12.91 (brs, 1H), 8.27 (dd, J = 9.3, 4.8 Hz, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.457.33 (m, 7H), 7.22-7.17 (m, ZN), 6.97 (d, J = 5.0 Hz, 1H), 2.33 (s, ZN), 1.48 (s, 6H); MS: 583.1 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD3OD) b: 8.41 (dd, J = 9.0, 4.5 Hz, 1H), 7.85 (d, J = 5.0 Hz, 1H), 7. 64 (d, J = 7.5 Hz, 1H), 7.57-7.50 (m, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.32-7.23 (m, 6H), 7.07 (dd, J = 8.5, 2.5 Hz, 1H), 7.02 (d, J = 5.0 Hz, 1H), 6.90 (dd, J = 7.3, 1.8 Hz, 1H), 2.33 (s, ZN); MS: 609.9 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 8.73 (d, J = 5.5 Hz, 1H), 8.30 (dd, J = 9.3, 4.3 Hz, 1H), 8.08-8.04 (m, 5N), 7.92 (s, 1N), 7.48-7.40 (m, ZN), 7.33-7.30 (m, ZN), 7, 23 (dd, J = 8.5, 2.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 1H), 2.29 (s, ZN); MS: 594.1 (M+1) ⁺ .

Ή-NMR (500 MHz, DMSO-de) b: 8.28 (dd, J = 9.0, 4.5 Hz, 1H), 7.99 (d, J = 4.5 Hz, 1H), 7 .61 (dd, J = 6.8,2.3 Hz, 2H), 7.50 (dd, J = 6.8, 1.8 Hz, 2H), 7.39-7.35 (m, 1H ), 7.16-7.12 (m, 2H), 6.95 (D, J = 5.0 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 6.48 (dd, J = 8.3, 1.8 Hz, 1H), 6.23 (s, 1H), 3.89 (t, J = 7.8 Hz, 2H), 3.79 (t, J = 6.3 Hz, 2H), 3.48-3.43 (m, 1H); MS: 589.6 (M-1)-.

^1H -NMR (500 MHz, DMSO-de) b: 8.328.27 (m, 2H), 7.99 (d, J = 5.0 Hz, 1H), 7.68 (dd, J = 8.8 , 2.8 Hz, 1H), 7.397.35 (m, 1H), 7.17-7.13 (m, 2H), 6.966.91 (m, 2H), 6.55 (d, J = 7, 5 Hz, 1H), 6.48 (dd, J = 8.0, 2.0 Hz, 1H), 6.23 (s, 1H), 3.90-3.87 (m, 5H), 3, 79 (t, J = 6.5 Hz, 2H), 3.46-3.43 (m, 1H); MS: 586.7 (M-1)-.

Ή-NMR (500 MHz, CD3OD) b: 8.418.38 (m, 1H), 7.80 (d, J = 5.0 Hz, 1H) 7.34-7.21 (m, 7H), 7. 09 (d, J = 7.0 Hz, 1H), 7.04-7.02 (m, 1H), 6.97 (s, 1H), 6.90 (d, J = 5.0 Hz, 1H ), 3.11-3.07 (m, 1H), 2.96-2.94 (m, 1H), 2.79-2.74 (m, 1H), 2.50-2.44 (m , 1H), 2.36 (s, ZN), 2.08-1.98 (m, 2H), 1.87-1.82 (m, 1H), 1.59-1.51 (m, 1H ), 0.86 (d, J = 6.0 Hz, ZN); MS: 614.0 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD3OD) b: 8.53 (dd, J = 9.2, 4.3 Hz, 1H), 8.12 (s, 1H), 8.06-8.04 (m , 1H), 7.99-7.97 (m, 1H), 7.70-7.14 (m, 13H), 6.77 (t, J = 55.5 Hz, 1H), 4.37- 4.27 (m, 1H), 3.78-3.36 (m, ZN), 3.24-3.20 (m, 1H); MS: 704.1 (M+1) ⁺ .

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Example 6.

3'-(3-(2-Cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)-N-hydroxy-[1,1'-biphenyl]-4-carboxamide ( 6)

To a mixture of compound 5/3 (120 mg, 0.20 mmol) in DMF (5 ml) was added hydroxylamine hydrochloride (27 mg, 0.40 mmol), HATU (114 mg, 0.30 mmol) and DIPEA (103 mg, 0.80 mmol) and stirred the mixture at room temperature overnight, diluted with EA (40 ml) and washed with H ₂ O (30 ml), 1 N. HCl (20 ml) and saturated saline (30 ml). The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 6 as a white solid. 1H-NMR (500 MHz, DMSO-d6) δ: 10.69 (brs, 1H), 9.15 (brs, 1H), 8.31 (dd, J=9.3, 4.3 Hz, 1H) , 8.02 (d, J=5.0 Hz, 1H), 7.86 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.0 Hz, 1H), 7 .62 (d, J=8.5 Hz, 2H), 7.50-7.47 (m, 2H), 7.41-7.25 (m, 6H), 7.19 (dd, J=8 ,5, 2.5 Hz, 1H), 7.07 (d, J=5.0 Hz, 1H), 2.25 (s, 3H); MS: 605.8 (M-1) ^- .

Examples 6/1-6/3.

The following examples were prepared in the same manner as described for Example 6 using the appropriate starting material.

analytical data

Example 7.

starting material structure

6/1

6/2

6/3

^1H -NMR (500 MHz, DMSO-de) δ: 8.39 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 5.5 Hz, 1H), 7.53- 7.23 (m, 9H), 7.04-7.01 (m, 2H), 6.94 (d, J = 5.0 Hz, 1H), 2.432.38 (m, 1H), 1.76 -1.72 (m, 1H), 1.541.50 (m, 1H), 1.25-1.20 (m, 1H); MS: 574.1 (M+1) ⁺ .

^1H -NMR (500 MHz, DMSO-de) δ: 8.29 (dd, J = 9.0, 4.0 Hz, 1H), 8.04-7.96 (m, 4H), 7.78 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.50-7.36 (m, 6H), 7.26 (d, J = 8.0 Hz, 2H), 7.17 (dd, J = 8.0,2.5 Hz, 1H), 7.06 (d, J = 5.0 Hz, 1H), 2.25 (s, 3 N); MS: 589.8 (M-1)-.

¹ H-NMR (400 MHz, CDsOD) b: 8.43 (dd, J = 4.4, 9.2 Hz, 1H), 8.05 (d, J = 7.6 Hz, 2H), 7. 96 (d, J = 1.2 Hz, 1H), 7.84 (dd, J = 1.8, 7.8 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.54-7.30 (m, 9H), 7.09 (s, 1H), 6.94 (dd, J = 2.4, 8.4 Hz, 1H), 6.67 (t, J = 55.4 Hz, 1H), 4.03 (s, 2H), 1.51 (s, 9H); MS: 793.1 (M-1)-.

Methyl 4-(3 -(3 -(2-cyanothiophen-3-yl)-5-fluoro-1-tosyl-1 H-indol-2-yl)phenyl)-2,2-dimethylbut-3-inoate (7 )

To a solution of compound 1 (234 mg, 0.52 mmol) in Et ₃ N (1.5 ml) was added Pd(PPh ₃ ) ₄ (47 mg), CuI (80 mg), PPh ₃ (11 mg) and methyl 2,2-dimethylbut-3-inoate (78 mg, 0.62 mmol). The mixture was stirred at 60°C under N ₂ for 4 hours, cooled, filtered, concentrated and purified with FCC (PE:EA=8:1) to give compound 7 as a yellow solid.

Example 8.

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-(5-Fluoro-2-(4'-((4-methylpiperazin-1 -yl)methyl)-[1,1'-biphenyl]-3 -yl)-1 -tosyl-1 H-indol-3 yl )thiophene-2-carbonitrile (8)

To a solution of compound 1 (250 mg, 0.45 mmol) in dioxane (20 ml) was added (3-((4-methylpiperazin1-yl)methyl)phenyl)boronic acid (116 mg, 0.50 mmol), Cs ₂ CO ₃ (293 mg, 0.90 mmol) and Pd(PPh ₃ ) ₄ (52 mg, 50 μmol). The mixture was stirred at 100°C overnight under N ₂ , cooled, filtered, concentrated and purified by preparative HPLC to give compound 8 as a white solid. 1H-NMR (500 MHz, CD3OD) δ: 8.43 (dd, J=4.5, 9.5 Hz, 1H), 7.82 (d, J=5.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.47-7.41 (m, 5H), 7.31-7.15 (m, 7H), 7.06 (dd, J=2.5 , 8.5 Hz, 1H), 6.96 (d, J=5.0 Hz, 1H), 3.61 (s, 2H), 2.61-2.48 (m, 8H), 2.31 (s, 3H), 2.27 (s, 3H); MS: 661.0 (M+1)+.

Examples 8/1-8/8.

The following examples were prepared in the same manner as described for Example 8 using the appropriate starting materials.

No. starting substance(s)

analytical data ¹ H-NMR (500 MHz, DMSOde) b: 8.31 (dd, J = 4.5, 9.0 Hz, 1H), 8.02 (d, J = 5.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.49-7.35 (m, 9H), 7.27-7.17 (m, 4H), 7.06 (d, J = 5.0 Hz, 1H), 3.43 (s, 2H), 2.25 (s, ZN), 2.17 (s, 6H); MS: 606.0 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.60 (d, J = 5.9 Hz, 1H), 8.43 (d, J = 6.0 Hz, 1H), 8.37 ( s, 1H), 8.06 (s, 1H), 7.99-7.97 (m, 1H), 7.76-7.08 (m, 13H), 6.74 (T,J = 55, 5 Hz, 1H), 4.65-4.56 (m, 1H), 4.53-4.49 (m, 1H), 4.41-4.37 (m, 1H), 4.30-4 .26 (m, 1H), 3.90-3.78 (m, 1H); MS: 671.1 (M+1) ⁺ .

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8/7

8/8

^1H -NMR (500 MHz, CD3OD) 6:8.81 (dd, J = 8.5, 1.5 Hz, 1H), 8.56 (dd, J = 4.8, 1.3 Hz, 1H ), 8.06 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.65-7.04 (m, 13H), 6.70 (t, J = 55.5 Hz, 1H); MS: 640.2 (M+1) ⁺ .

¹ H-NMR (400 MHz, CD3OD) 6: 8.42 (dd, J = 9.4, 4.2 Hz, 1H), 8.05-8.03 (m, ZH), 7.96 (dd , J = 8.2, 1.8 Hz, 1H), 7.70 (dd, J = 8.4, 7.6 Hz, 1H), 7.51-7.44 (m, 8H), 7, 32 (td, J = 9.2, 2.4 Hz, 1H), 6.97 (s, 1H), 6.94 (dd, J = 8.4,2.4 Hz, 1H), 6.62 (t, J = 55.4 Hz, 1H), 2.00 (s, ZN); MS: 757.0 (M-1)-.

Example 9.

Methyl-3 '-(3 -(2,6-bis(difluoromethyl)phenyl)-1 -((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1 H-indol2-yl)-2-chloro- [1,1'-biphenyl]-4-carboxylate (9)

To a solution of compound 1/55 (180 mg, 0.26 mmol) in DCM (10.0 ml) was added DAST (209 mg, 1.30 mmol) and the mixture was stirred at room temperature overnight, poured into EA (200 ml ) and washed with H ₂ O (2x20 ml) and brine (20 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by preparative TLC (EA:PE=1:3) to obtain compound 9 as a colorless oily substance.

Example 9/1.

The following example was prepared in the same manner as described for Example 9 using the appropriate starting material.

Example 10.

2-(2-Chloro-3 '-(3 -(2-cyanothiophen-3 -yl)-5 -fluoro-1 -tosyl-1 H-indol-2-yl)-[1,1 '-biphenyl] - 4carboxamido)ethane-1-sulfonic acid (10)

To a solution of compound 3/48 (100 mg, 0.20 mmol) in DMF (10 ml) was added EDCI (100 mg, 0.50 mmol), DMAP (60 mg, 0.50 mmol) and 2-aminoethane-1- sulfonic acid (22 mg, 0.20 mmol). The mixture was stirred at room temperature for 12 hours, diluted with water (100 ml) and extracted with EA (3x100 ml). The combined organic layer was washed with brine (50 mL), concentrated and purified with FCC (PE:EA=1:4) to give compound 10 as a white solid. 1H-NMR (500 MHz, DMSO^) δ: 8.68 (t, J=5.3 Hz, 1H), 8.29 (dd, J=4.5, 9.0 Hz, 1H), 8, 03 (d, J=5.0 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.81 (dd, J=1.8, 8.3 Hz, 1H), 7.54-7.17 (m, 10H), 7.03-7.01 (m, 2H), 3.56-3.52 (m, 2H), 2.70-2.67 (m, 2H ), 2.21 (s, 3H); MS: 731.9 (M-1) ^- .

Examples 10/1-10/4.

The following examples were prepared in the same manner as described for Example 10 using the appropriate starting material.

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analytical data ¹ H-NMR (500 MHz, CD3OD) b: 8.458.43 (m, 1H), 8.07 (brs, 2H), 7.94 (d, J = 2.0 Hz, 1H), 7, 82 (dd, J = 8.0, 1.5 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.557.43 (m, 7H), 7.36-7.28 (m, 2H), 7.04 (s, 1H), 6.95 (dd, J = 8.5, 2.5 Hz, 1H), 6.68 (t, J = 55.5 Hz, 1H) , 3.84 (t, J = 6.5 Hz, 2H), 3.13 (t, J = 6.5 Hz, 2H); MS: 786.9 (M-1)-.

¹ H-NMR (500 MHz, CD3OD) b: 8.44 (dd, J = 9.3, 4.3 Hz, 1H), 8.06 (brs, 2H), 7.72 (t, J = 7 .8 Hz, 1H), 7.597.47 (m, 9H), 7.35-7.32 (m, 2H), 7.026.58 (m, ZN), 3.97-3.77 (m, 2H) , 3.243.10 (m, 5H); MS: 801.0 (M-1)-.

¹ H-NMR (500 MHz, CD3OD) b: 8.42 (dd, J = 9.0, 4.5 Hz, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7. 85-7.81 (m, 2H), 7.567.49 (m, 6H), 7.44 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H ), 7.31 (td, J = 9.0, 2.5 Hz, 1H), 7.09-7.06 (m, 2H), 6.98 (d, J = 5.0 Hz, 1H) , 6.71 (t, J = 55.5 Hz, 1H), 3.84 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H); MS: 768.0 (M-1)-.

Ή-NMR (400 MHz, CD3OD) b: 8.37 (dd, J = 9.2, 4.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.40-7.35 (m, ZN), 7.26-7.14 (m, 4H), 6.95-6.64 (m, ZN ), 3.69-3.61 (m, 2H), 3.00 (t, J = 6.6 Hz, 2H), 2.33-2.28 (m, 1H), 1.64 (shs, 1H), 1.47-1.42 (m, 1H), 1.06 (shs, 1H); MS: 735.0 and 737.0 (M1)-.

Example 11.

2-Chloro-3'-(3-(2-cyanophenyl)-5-fluoro-1-tosyl-1H-indol-2-yl)-[1,1'-biphenyl]-4-carboxylic acid (11)

To a solution of compound 1/32 (165 mg, 0.26 mmol) in HCl/dioxane (4 N, 5 ml) was added H ₂ O (0.5 ml). The mixture was stirred at 90°C overnight, cooled, concentrated, diluted with water and extracted with EA (3x). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 11 as a white solid. 1H-NMR (500 MHz, DMSO-d ₆ ) δ: 13.36 (brs, 1H), 8.28 (dd, J=4.5, 9.5 Hz, 1H), 7.97-7.94 (m, 2H), 7.86 (d, J=7.5 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.55-7.31 (m, 9H) , 7.24 (d, J=8.5 Hz, 2H), 7.02-7.00 (m, 2H), 2.21 (s, 3H); MS: 619.0 (M-1) ^- .

Examples 11/1-11/69.

The following examples were prepared in the same manner as described for Example 11 using the appropriate starting material.

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11/1 starting material structure

11/2

11/3

11/4

11/5

11/6

11/7

11/8

11/9

analytical data ¹ H-NMR (500 MHz, CD3OD) b: 8.41 (dd, J = 9,3,4,3 Hz, 1H), 8.08 (d, J = 1.0 Hz, 1H), 8.02 (dd, J = 1.8, 8.3 Hz, 1H), 7.69-7.64 (m, 1H), 7.49-7.26 (m, 8H), 7.18- 1.15 (m, ZN), 7.02 (s, 1H), 6.97 (dd, J = 2.5, 8.5 Hz, 1H), 2.25 (s, ZN); MS: 637.0 (M-1)-.

¹ H-NMR (500 MHz, CD3OD) b: 8.39 (dd, J = 9,3,4,3 Hz, 1H), 8.05 (d, J = 1.5 Hz, 1H), 7, 98 (dd, J = 8.0, 1.5 Hz, 1H), 7.51-7.43 (m, 4H), 7.39 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.28-6.98 (m, 7H), 6.88 (dd, J = 8.5, 2.5 Hz, 1H), 2.51 ( s, ZN), 2.24 (s, ZN); MS: 633.0 (M-1)-.

¹ H-NMR (500 MHz, CD3OD) b: 8.38 (dd, J = 9.0, 4.5 Hz, 1H), 8.07 (d, J = 1.5 Hz, 1H), 8. 00 (dd, J = 8.0, 1.5 Hz, 1H), 7.57-7.54 (m, 1H), 7.48-7.44 (m, ZN), 7.37 (d, J = 7.5 Hz, 1H), 7.277.14 (m, 6H), 7.03 (s, 1H), 6.88 (dd, J = 8.3,2.8 Hz, 1H), 6, 83 (shs, 1N), 3.95 (s, ZN), 2.24 (s, ZN); MS: 649.0 (M-1)-.

H-NMR (500 MHz, CD3OD) b: 8.38 (dd, J = 9.3,4.3 Hz, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.99 (dd, J = 8.0, 1.5 Hz, 1H), 7.63-7.54 (m, 1H), 7.45-7.42 (m, 4H), 7.36 (d, J = 8.0 Hz, 1H), 7.307.14 (m, 6H), 7.02 (s, 1H), 6.88 (dd, J = 8.5, 2.5 Hz, 1H), 2.39 (s, ZN), 2.24 (s, ZN); MS: 633.0 (M-1)-.

¹ H-NMR (500 MHz, CD3OD) b: 8.39 (dd, J = 9.0, 4.5 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 8. 00 (dd, J = 8.0, 1.5 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.467.44 (m, ZN), 7.36 (d, J = 8.5 Hz, 1H), 7.33-7.14 (m, 7H), 7.03 (s, 1H), 6.89 (dd, J = 8.3, 2.8 Hz, 1H) ,2.35 (s, ZN), 2.24 (s, ZN); MS: 633.0 (M-1)-.

¹ H-NMR (500 MHz, CD3OD) b: 8.40 (dd, J = 9.3, 4.3 Hz, 1H), 8.08 (s, 1H), 8.00 (dd, J = 8 ,0, 1.5 Hz, 1H), 7.587.15 (m, 13H), 6.71 (dd, J = 8.0, 2.5 Hz, 1H), 2.25 (s, ZN), 1 .90 (s, ZN); MS: 633.0 (M-1)-.

¹ H-NMR (500 MHz, CD3OD) b: 8.43 (dd, J = 9.0, 4.5 Hz, 1H), 8.03 (d, J = 7.0 Hz, 1H), 7, 85 (d, J = 5.5 Hz, 1H), 7.57-7.44 (m, 5H), 7.38 (d, J = 8.5 Hz, 2H), 7.30 (dt, J = 2.7, 9.2 Hz, 1H), 7.21 (d, J = 10.5 Hz, 1H), 7.15 (s, 1H), 7.07 (dd, J = 8.5, 2.5 Hz, 1H), 6.99 (d, J = 5.5 Hz, 1H), 5.35 (d, J = 47.0 Hz, 2H); MS: 660.9 (M-1)-.

¹ H-NMR (500 MHz, CD3OD) b: 8.43 (dd, J = 9.3, 4.3 Hz, 1H), 8.03 (d, J = 6.5 Hz, 1H), 7, 86 (d, J = 5.0 Hz, 1H), 7.58-7.49 (m, 6H), 7.43 (d, J = 7.5 Hz, 1H), 7.31 (td, J = 9.0, 2.5 Hz, 1H), 7.22 (d, J = 10.5 Hz, 1H), 7.16 (s, 1H), 7.09 (dd, J = 2.5, 8.5 Hz, 1H), 7.01 (d, J = 5.0 Hz, 1H), 6.73 (t, J = 55.5 Hz, 1H); MS: 678.9 (M-1)-.

¹ H-NMR (500 MHz, CD3OD) b: 9.33 (s, 1H), 8.46 (dd, J = 9.3, 4.3 Hz, 1H), 8.04 (d, J = 6 .5 Hz, 1H), 7.61-7.50 (m, 6H), 7.41 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H ), 7.27 (d, J = 11.0 Hz, 1H), 7.21-7.18 (m, 2H), 6.73 (t, J = 55.5 Hz, 1H); MS: 679.9 (M-1)-.

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- 97 045482 ¹ H-NMR (500 MHz, DMSO-de) b: 8.36 (dd, J = 9.5, 4.0 Hz, 1H), 8.25 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 7.79 (t, J = 7.8 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H) , 7.60-7.56 (m, 4H), 7.507.40 (m, ZN), 7.26 (dd, J = 2.5, 8.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.04 (t, J = 55.3 Hz, 1H); MS: 646.0 (M—o but

11/51

eleven/

eleven/

eleven/

eleven/

¹ H-NMR (500 MHz, CD3OD) b; 8.45 (dd, J = 9.5,4.0 Hz, 1H), 8.06 (shs, 2H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H), 7 .78-7.63 (m, ZN), 7.56-7.29 (m, 9H), 6.95 (dd, J = 8.5, 2.5 Hz, 1H), 6.69 (t , J = 55.8 Hz, 1H); MS: 664.0 (M-1)-.

Ή-NMR (500 MHz, CD3OD) b: 8.45 (dd, J = 9.0.4.5 Hz, 1H), 8.07 (brs, 2H), 7.77-7.64 (m, ZN), 7.57-7.48 (m, 5H), 7.41-7.29 (m, ZN), 7.21-7.18 (m, 1H), 6.96 (dd, J = 8.5, 2.5 Hz, 1H), 6.71 (t, J = 55.8 Hz, 1H); MS: 682.0 ^1H -NMR (500 MHz, CD3OD) b: 8.44 (dd, J = 9.0.4.0 Hz, 1H), 8.07-8.03 (m, 2H), 7.72 (t, J = 8.3 Hz, 1H), 7.667.50 (m, 9H), 7.33 (td, J = 9.0, 2.5 Hz, 1H), 7.00 (s , 1H), 6.95 (dd, J = 8.0, 2.5 Hz, 1H), 6.68 (t, J = 55.5 Hz, 1H); MS: 682.0 (M-1)-.

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.44 (dd, J = 9.3,4.8 Hz, 1H), 8.12-8.02 (m, 2H), 7.77 -7.72 (m, 1H), 7.62-7.51 (m, 7H), 7.35 (td, J = 9.3, 2.8 Hz, 1H), 7.06 (s, 1H ), 6.97 (dd, J = 8.0, 2.5 Hz, 1H), 6.71 (t, J = 55.5 Hz, 1H); MS: 737.1 (M+18) ⁺ .

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eleven/

eleven/

eleven/

eleven/

eleven/

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.42 (dd, J = 9.5, 4.0 Hz, 1H), 8.09-8.04 (m, ZN), 8.00 (dd, J = 1.5, 8.0 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.497.44 (m, ZN), 7.38-7.29 ( m, 6H), 7.05 (d, J = 1.0 Hz, 1H), 6.95 (dd, J = 8.5, 2.5 Hz, 1H); MS: 663.9/666.0 (M-1)-.

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.43 (d, J = 8.5 Hz, 1H), 8.09-8.04 (m, ZH), 7.98 (dd, J = 7.5, 1.5 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.58-7.47 (m, 8H), 7.42 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.07 (s, 1H), 6 .66 (t, J = 55.5 Hz, 1H); MS: 661.9 (M-1)-.

¹ H-NMR (400 MHz, CD ₃ OD) b: 8.60 (d, J = 2.0 Hz, 1H), 8.44 (dd, J = 4.4, 9.2 Hz, 1H), 8.10 (s, 1H), 8.03-7.31 (m, 9H), 7.21 (s, 1H), 7.09 (dd, J = 2.8,8.4 Hz, 1H) , 7.00 (d, J = 4.8 Hz, 1H), 6.65 (t,J = 54.6 Hz, 1H); MS: 663.8 (M+1) ⁺ .

Ή-NMR (500 MHz, CD ₃ OD) b: 8.45 (dd, J = 9.3,4.3 Hz, 1H), 8.07-7.98 (m, 2H), 7.69 ( t, J = 8.0 Hz, 1H), 7.58 (d, 0 = 8.5 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.37-7.31 (m, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.97-6.93 (m, 2H) , 6.79 (t, J = 55.8 Hz, 1H), 1.90-1.87 (m, 6H), 1.701.67 (m, 6H); MS: 678.0 (M-1)-.

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.46 (dd, J = 9.2, 4.3 Hz, 1H), 8.05 (d, J = 7.9 Hz, 2H), 7.75-7.62 (m, 4H), 7.52 (k, J = 8.6 Hz, 4H), 7.47-7.28 (m, 5H), 7.21 (d, J = 7.8 Hz, 1H), 6.96 (dd, J = 8.3, 2.5 Hz, 1H), 6.67 (t, J = 55.6 Hz, 1H), 1.79 (s, ZN); MS: 690.0 (M-1)-.

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- 100 045482

Example 12.

Step 1: Methyl-2-chloro-3'-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)-5-methyl-[1, 1'biphenyl]-4-carboxylate (12a)

To a solution of compound 2a (200 mg, 0.33 mmol) in dioxane (2 ml) and water (0.4 ml) was added methyl 4bromo-5-chloro-2-methylbenzoate (105 mg, 0.40 mmol), Cs ₂ CO ₃ (215 mg, 0.66 mmol) and Pd(dppf)Cl ₂ (20 mg). The mixture was stirred under N ₂ at 100° C. for 8 hours, cooled to room temperature, poured into EA (40 ml) and washed with H ₂ O (40 ml) and brine (40 ml). The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (EA:PE=1:8) to give compound 12a as a white solid.

Step 2: 2-Chloro-3'-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)-5-methyl-[1,1' -biphenyl]-4-carboxylic acid (12)

To a solution of compound 12a (150 mg, 0.23 mmol) in a mixture of HCl/dioxane (4 N, 5 ml) was added H ₂ O (0.5 ml) and the mixture was stirred at 90 ° C overnight, concentrated, diluted water and extracted with EA (3x). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 12 as a white solid. 1H-NMR (500 MHz, DMSO-d ₆ ) δ: 8.29 (dd, J=9.0, 4.5 Hz, 1H), 8.03 (d, J=5.0

- 101 045482

Hz, 1H), 7.82 (s, 1H), 7.54-7.46 (m, 3H), 7.40-7.32 (m, 3H), 7.24 (d, J=8, 0 Hz, 2H), 7.18 (dd, J=8.0, 3.0 Hz, 2H),

7.04-7.00 (m, 2H), 2.53 (s, 3H), 2.21 (s, 3H); MS: 638.9 (M-1) ^- .

Examples 12/1-12/10.

The following examples were prepared in the same manner as described for Example 12 using the appropriate building block.

building block analytics data

12/1

12/2

12/3

12/4

12/5

12/6 structure but

Ή-NMR (500 MHz, DMSO-de) b: 8.29 (dd, J = 9.3, 4.3 Hz, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7 .68 (d, J = 8.0 Hz, 1H), 7.53-7.15 (m, JN), 7.03 (d, J = 5.0 Hz, 1H), 6.98 (s, 1H), 2.55 (s, ZN), 2.23 (s, ZN); MS: 639.0 (M-1)-.

Ή-NMR (500 MHz, DMSO-de) b: 8.42 (dd, J = 9.0, 4.5 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7 .84 (d, J = 5.0 Hz, 1H), 7.53-7.46 (m, ZN), 7.30-7.26 (m, ZN), 7.19-6.97 (m , 6H), 2.28 (s, ZN); MS: 643.0 (M-1)-.

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.42 (dd, J = 9.3, 4.3 Hz, 1H), 7.85-7.80 (m, 2H), 7.537.47 (m, ZN), 7.30-7.25 (m, ZN), 7.17 (d, J = 8.0 Hz, ZN), 7.07 (dd, J = 7.8, 2.8 Hz, 1H), 7.04-6.96 (m, 2H), 2.27 (s, ZN); MS: 642.9 (M-1)-.

¹ H-NMR (500 MHz, DMSO-de) b: 8.29 (dd, J = 9.3, 4.3 Hz, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.59-7.50 (m, ZN), 7.43 (d, J = 7.5 Hz, 1H), 7.40-7.34 (m, ZN), 7.24 (d, J = 8.5 Hz, 2H), 7.17 (dd, J = 8.5, 2.5 Hz, 1H), 7.10 (s, 1H), 7.06 (d, J = 5.5 Hz, 1H), 6.94 (s, 1H), 3.82 (s, ZN), 2.22 (s, ZN); MS: 655.0 (M-1)-.

Ή-NMR (500 MHz, CD ₃ OD) b: 8.42 (dd, J = 9.3, 4.3 Hz, 1H), 7.84 (d, J = 5.0 Hz, 1H), 7 .69 (d, J = 7.5 Hz, 1H), 7.51-7.45 (m, ZN), 7.29-7.24 (m, ZN), 7.16 (d, J = 8 ,0 Hz, 2H), 7.09-7.05 (m, 2H), 6.97-6.95 (m, 2H), 3.95 (s, ZN), 2.27 (s, ZN) ; MS: 655.0 (M-1)-.

Ή-NMR (500 MHz, DMSO-de) b: 8.30 (dd, J = 9.2,4.4 Hz, 1H), 7.98 (d, J = 5.1 Hz, 1H), 7 .88 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.487.33 (m, 4H), 7.29 (d, J = 8.3 Hz, 2H), 7.257 .13 (m, 2H), 6.99 (d, J = 5.0 Hz, 1H), 6.93 (shs, 1H), 2.28 (s, ZN); MS: 581.0 (M-1)-.

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12/7

12/8

12/9

12/

Example 13.

¹ H-NMR (500 MHz, DMSO-de) b: 8.30 (dd, J = 9.2,4.4 Hz, 1H), 7.98 (d, J = 5.1 Hz, 1H), 7.61 (shs, 1H), 7.52 (shs, 1H), 7.48-7.28 (m, 7H), 7.20-7.17 (m, 1H), 7.06 (d, J = 4.5 Hz, 1H), 6.64 (shs, 1H), 3.76 (shs, ZN), 2.28 (s, ZN); MS: 597.2 (M+H) ⁺ .

Ή-NMR (500 MHz, DMSO-de) b: 8.29 (dd, J = 9.2, 4.4 Hz, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7 .59-7.49 (m, 2H), 7.45-7.31 (m, 4H), 7.28 (d, J = 8.3 Hz, 2H), 7.20 (dd, J = 8 ,6, 2.6 Hz, 1H), 7.10-7.00 (m, 2H), 6.61 (s, 1H), 4.254.22 (m, 1H), 2.26 (s, ZN) , 1.30 (d, J = 6.5 Hz, 6H); MS: 623.0 (M-1)-.

¹ H-NMR (500 MHz, DMSO-de) b: 8.31 (dd, J = 9.2,4.4 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.68 (s, 1H), 7.55-7.44 (m , 2H), 7.407.36 (m, 4H), 7.28-7.24 (m, ZN), 7.19 (dd, J = 8.5, 2.5 Hz, 1H), 7.09 ( d, J = 5.1 Hz, 1H), 2.22 (s, ZN); MS: 631.0 (M-1)-.

Ή-NMR (500 MHz, CD ₃ OD) b: 8.44 (dd, J = 9.5, 4.5 Hz, 1H), 8.06 (brs, 2H), 7.89 (d, J = 1.5 Hz, 1H), 7.80 (dd, J = 1.3, 7.8 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.55-7, 48 (m, 7H), 7.36-7.31 (m, 2H), 7.02 (s, 1H), 6.95 (dd, J = 2.3, 8.3 Hz, 1H), 6 .68 (t, J = 55.8 Hz, 1H); MS: 715.9 (M-1)-.

3-(1 -((4-Chlorophenyl)sulfonyl)-5 -hydroxy-2-(thiophen-2-yl)-1 H-indol-3 -yl)thiophene-2-carbonitrile (13)

To a solution of compound 1/39 (775 mg, 1.52 mmol) in DCM (10 ml) was added BBr ₃ (2 ml, 3 N in DCM) at 0°C and the mixture was stirred for 2 hours, poured into water ( 50 ml) and extracted with EA (3x20 ml). The combined organic layer was washed with aqueous K ₂ CO ₃ (30 ml) and brine (2x30 ml), dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 13 as a yellow solid. 1H-NMR (500 MHz, DMSO-d ₆ ) δ: 9.63 (s, 1H), 8.05-8.03 (m, 2H), 7.73 (d, J=5.0 Hz, 1H ), 7.59 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.19 (d, J=3.0 Hz, 1H), 7.12-7.10 (m, 1H), 7.01-6.96 (m, 2H), 6.58 (s, 1H); MS: 496.9 (M+1)+.

Example 13/1.

The following example was prepared in the same manner as described for Example 13 using the appropriate starting material.

structure

analytical data ¹ H-NMR (500 MHz, DMSO-de) b: 9.99 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.70-7.68 (m , 2H), 7.63 (d, J = 9.0 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.16-7.15 (m, 2H), 7.097 .08 (m, 1H), 7.00 (d, J = 5.0 Hz, 1H), 6.87 (dd, J = 2.0, 8.5 Hz, 1H); MS: 496.7 (M+1) ⁺ .

Example 14.

Methyl-2-(( 1 -((4-chlorophenyl)sulfonyl)-3 -(2-cyanothiophen-3 -yl)-2-(thiophen-2-yl)-1 H-indol-5 -yl)oxy) acetate (14)

K ₂ CO ₃ (69 mg, 0.50 mmol) was added to a solution of compound 13 (120 mg, 0.25 mmol) in DMF (5 ml)

- 103 045482 and methyl 2-bromoacetate (46 mg, 0.30 mmol). The mixture was stirred at room temperature overnight, diluted with water and extracted with EA (3x20 ml). The combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified by FCC to give 14 as a brown solid.

Example 15.

2-(( 1 -((4-Chlorophenyl)sulfonyl)-3 -(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-1 H-indol-5-yl)oxy)acetic acid (15)

To a solution of compound 14 (74 mg, 0.13 mmol) in MeOH (3 ml) was added LiOH (1 ml, 2 N) and the mixture was stirred at room temperature overnight, evaporated, adjusted to pH < 2 with 2 N . HCl and extracted with EA (3x20 ml). The combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 15 as a white solid. ¹ H-NMR (500 MHz, DMSO-66) δ: 13.02 (brs, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.05 (d, J=5.0 Hz, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H), 7.21-7.11 (m, 3H), 7.03 (d, J=5.0 Hz, 1H), 6.77 (d, J=2.5 Hz, 1H), 4, 67 (s, 2H); MS: 554.6 (M+1)+.

Examples 15/1-15/6.

The following examples were prepared in the same manner as described for Example 14 (optional) and Example 15 using the appropriate building blocks.

structure analytical data 'H-NMR (500 MHz, DMSO-de) b: 8.02 (d, J =

5.0 Hz, 1H), 7.74 d, J = 2.0 Hz, 1H), 7.71 d, J = 5.5 Hz, 1H, 7.61 d, J = 8.5 Hz, 2H , 7.54 d,

J = 8.0 Hz, 2Н, 7.25 d, J = 9.0 Hz, 1Н, 7.18 d, J = 3.0 Hz, 1Н, 7.11-7.00 m, ЗН, 4, 13 t, J = 6.5 Hz, 2H), 2.38 t, J = 7.3 Hz, 2H), 2.031.97 (m, 2H); MS: 583.0 (M+1) ⁺ .

Ή-NMR 500 MHz, DMSO-de b: 13.20 s, 1H).

8.03 d, J = 5.0 Hz, 1H, 7.72 (d, J = 5.0 Hz,

2Н, 7.60 d, J = 8.5 Hz, 2Н, 7.54 d, J = 8.5

Hz, 2H, 7.26 d, J = 9.0 Hz, 1H, 7.19 d, J =

3.5 Hz, 1H), 7.12-7.10 m, 1H), 7.05 dd, J =

2.0, 9.0 Hz, 1H), 7.01 (d, J = 5.0 Hz, 1H), 4.86 s, 2H); MS: 554.6 (M+1) ⁺ .

building olok (and 'H-NMR (500 MHz, DMSO-de) b: 8.03 (d, J =

5.0 Hz, 1H), 7.74 d, J = 1.5 Hz, 1H), 7.71 d, J = 5.5 Hz, 1H), 7.61 d, J = 8.5 Hz, 2H), 7.54 d.

J = 8.5 Hz, 2H, 7.25 d, J = 9.0 Hz, 1H, 7.18 d, J = 4.0 Hz, 1H, 7.10 t, J = 4.3 Hz, 1H ,

7.05-7.03 m, 1H), 7.01 d, J = 5.0 Hz, 1H), 4.12 t, J = 6.0 Hz, 2H), 2.31 t, J = 7 ,3 Hz, 2H).

1.83-1.78 m, 2H), 1.73-1.68 m, 2H); MS: 597.0

M+1) ⁺ .

'H-NMR (500 MHz, DMSO-de) b: 12.20 (shs,

1H), 8.26 d, J = 8.5 Hz, 1H), 7.98 d, J = 5.0

Hz, 1H), 7.50-7.47 m, 1H), 7.40-7.32 m, 4H),

7.22 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.5 Hz,

2H), 6.99 d, J = 9.0 Hz, 2H), 6.93 d, J = 5.0

Hz, 1H), 3.78 s, ZN), 2.87 t, J = 7.5 Hz, 2H),

2.59 t, J = 7.5 Hz, 2H); MS: 542.9 M+1 ⁺ .

'H-NMR (500 MHz, DMSO-de) b: 12.12 (s, 1H),

8.14 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 5.0 Hz,

1H), 7.73 (d, J = 4.5 Hz, 1H), 7.59 (d, J = 9.0

Hz, 2H), 7.48 (d, J = 9.0 Hz, 2H), 7.20 (d, J =

2.5 Hz, 1H), 7.15-7.11 (m, 2H), 7.02 d, J = 5.0

Hz, 1H), 6.77 (d, J = 3.0 Hz, 1H), 3.97 (t, J =

5.5 Hz, 2H), 2.37 (t, J = 7.3 Hz, 2H), 1.93 (t, J = 6.8 Hz, 2H); MS: 582.7 (M+1G.

'H-NMR (500 MHz, DMSO-de) b: 12.03 (shs.

1H), 8.14 (d, J = 9.5 Hz, 1H), 8.04 (d, J = 5.0

Hz, 1H), 7.74 (d, J = 5.0 Hz, 1H), 7.59 (d, J =

8.0 Hz, 2H), 7.48 (d, J = 9.0 Hz, 2H), 7.21-7.20 m, 1H), 7.15-7.11 (m, 2H), 7 .02 (d, J = 4.5 Hz,

1H), 6.77 (d, J = 2.5 Hz, 1H), 3.96 (t, J = 6.0

Hz, 2H), 2.27 (t, J = 7.3 Hz, 2H), 1.75-1.62 m,

4H); MS: 596.9 (M+1) ⁺ .

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Example 16.

tert-Butyl-3-(1-((4-chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-5-hydroxy-2-(thiophen-2-yl)1 H-indol-6- yl)propanoate (16)

To a solution of compound 13 (120 mg, 0.25 mmol) in DMF (3 ml) was added K2CO3 (69 mg, 0.50 mmol) and methyl 2-bromoacetate (38 mg, 0.30 mmol). The mixture was stirred at room temperature overnight, diluted with water and extracted with EA (3x20 ml). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by FCC to give 16 as a brown solid; MS: 624.7 (M+1)+.

Example 17.

3-(1-((4-Chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-5-hydroxy-2-(thiophen-2-yl)-1H-indol-6yl)propanoic acid (17 )

To a solution of compound 16 (32 mg, 50 µmol) in MeOH (2 ml) was added NaOH (0.5 ml, 2 N) and the mixture was stirred at room temperature overnight, concentrated, adjusted to pH < 2 with 2 N . HCl and extracted with EA (3x20 ml). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by preparative HPLC to give 17 as a white solid. 1H-NMR (500 MHz, DMSO-d ₆ ) δ: 12.46 (s, 1H), 10.42 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 7. 77 (d, J=5.0 Hz, 1H), 7.70 (d, J=5.0 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.57 ( d, J=9.0 Hz, 2H), 7.18 (d, J=3.0 Hz, 1H), 7.13-7.11 (m, 1H), 7.06 (d, J=5 .0 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 4.43-4.37 (m, 2H), 2.61 (t, J=7.8 Hz, 2H ); MS: 568.7 (M+1) ⁺ .

Example 18.

Step 1: Methyl 3-amino-4-(thiophen-2-ylethynyl)benzoate (18a)

Methyl 3-amino-4-iodobenzoate (1.0 g, 3.6 mmol) was dissolved in degassed THF (10 ml) and the mixture was degassed by passing a moderate stream of N2 through the solution. After ~5 min, DIPEA (5.0 mL, 29 mmol) was added and bubbling for a few more minutes, then 2-ethynylthiophene (0.41 mL, 4.3 mmol) was added. CuI (28 mg, 0.15 mmol) was then added directly, followed by PdCl ₂ (PPh ₃ ) ₂ (49 mg, 70 µmol). The mixture was stirred at room temperature for 2.5 hours, filtered through celite and washed with THF. EA (200 ml) was added and the mixture was washed with water (50 ml) and brine (50 ml). The organic layer was dried over Na2SO4, filtered, concentrated and purified by FCC to give 18a. 1H-NMR (400 MHz, CDCl3): 3.90 (s, 3H), 4.36 (brs, 2H), 7.02-7.04 (m, 1H), 7.30-7.34 (m , 2H), 7.35-7.41 (m, 3H).

Step 2: Methyl 4-(thiophen-2-ylethynyl)-3-(2,2,2-trifluoroacetamido)benzoate (18b)

Compound 18a (450 mg, 1.68 mmol) was dissolved in dry THF (1 ml) and the mixture was cooled to 0°C. 2,2,2-trifluoroacetic anhydride (0.47 ml, 3.4 mmol) was then added dropwise and the mixture was stirred for 15 minutes, diluted with EA (100 ml) and washed with NaHCO ₃ -water (1:1, 50 ml) and saturated saline (50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by FCC to give 18b as a yellow solid. 1H-NMR (400 MHz, CDCl ₃ ): 3.95 (s, 3H), 7.08-7.10 (m, 1H), 7.37-7.38 (m, 1H), 7.43- 7.44 (m, 1H), 7.60-7.63 (m, 1H), 7.90- 105 045482

7.92 (m, 1H), 8.75 (shs, 1H), 8.97 (d, 1H).

Step 3: Methyl 3-(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-1H-indole-6-carboxylate (18c)

Compound 18b (187 mg, 0.53 mmol), Cs ₂ CO ₃ (259 mg, 0.79 mmol), Pd(PPh ₃ ) ₄ (31 mg, 0.03 mmol) and 3 were charged into a dried microwave reactor tube. -bromothiophene-2-carbonitrile (149 mg, 0.79 mmol). Add degassed CH3CN (2.5 mL) and flush the tube with N2. The mixture was stirred at 100°C for 1 hour, cooled, diluted with EA (80 ml) and washed with NaHCO ₃ :water (1:1, 40 ml), water (20 ml) and brine (15 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give 18c as a yellow solid. ¹ NMR (400 MHz, DMSO-d ₆ ): 3.88 (s, 3H), 7.17-7.19 (m, 1H), 7.33-7.46 (m, 3H), 7.64 -7.71 (m, 2H), 8.10 (s, 1H), 8.19-8.21 (m, 1H), 12.32 (s, 1H).

Step 4: Methyl 1-((4-chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-1H-indole-6carboxylate (18)

Compound 18c (180 mg, 0.49 mmol) was dissolved in THF (15 ml) and NaH (3.9 mmol, dispersed in mineral oil) was added, followed by 4-chlorobenzenesulfonyl chloride (188 mg, 0.89 mmol). The mixture was stirred at room temperature for 1 hour, quenched by carefully adding water, diluted with EA (250 ml) and washed with water (100 ml) and brine (100 ml). The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified using FCC and then preparative

HPLC (55-60% acetonitrile in 15 mM NH4HCO3 buffer, pH 10) gave compound 18 as a white solid.

Example 19.

1-((4-Chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-1H-indole-6-carboxylic acid (19)

Compound 18 (77 mg, 0.14 mmol) was dissolved in THF (4 ml) and cooled to 0°C. In a separate 4 ml flask, LiOH (48 mg, 2.0 mmol) was dissolved in water (4 ml) and cooled to 0°C. The alkaline solution was added dropwise to the solution of compound 18 and the resulting mixture was stirred vigorously overnight (the reaction mixture was slowly brought to room temperature). The reaction mixture was again cooled to 0°C, quenched with 2 N. HCl solution (1.4 ml) and extracted with EA (3x20 ml). The combined organic layer was dried over MgSO ₄ , filtered, concentrated and purified by preparative HPLC (Xbridge, 30-60% acetonitrile in 0.1% TFA buffer) to give compound 19 as a white solid. 1H-NMR (400 MHz, DMSO- _d6 ): 7.07 (d, 1H), 7.12-7.15 (dd, 1H), 7.24-7.25 (dd, 1H), 7. 40-7.50 (m, 3H), 7.55-7.63 (m, 2H), 7.76-7.77 (dd, 1H), 7.97-8.00 (dd, 1H), 8.06 (d, 1H), 8.89 (m, 1H), 13.29 (shs, 1H); MS: 542 (M+NH ₃ +1)+.

Example 20.

Step 1: 2-(Thiophen-2-ylethynyl)aniline (20a)

To a mixture of 2-iodoaniline (40.0 g, 183 mmol), CuI (700 mg, 3.70 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (1.30 g, 1.83 mmol) and TEA (120 ml ) to ACN (1 L), 2-ethynylthiophene (24.0 g, 219 mmol) was added via syringe under N2. The mixture was stirred at 50°C overnight, cooled, filtered, concentrated and purified with FCC (PE:EA=50:1) to give compound 20a as a yellow solid.

Step 2: 4-Chloro-N-(2-(thiophen-2-ylethynyl)phenyl)benzenesulfonamide (20b)

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To a solution of compound 20a (10.0 g, 50.3 mmol), 4-chlorobenzenesulfonyl chloride (13.1 g, 62.3 mmol) and pyridine (4.17 g, 52.8 mmol) in DCM (150 ml) was added DMAP (306 mg, 2.5 mmol) at room temperature. The mixture was heated to reflux overnight, cooled, and washed with 2 N. HCl solution and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and then washed with PE to give 20b as a yellow solid.

Step 3: 1-((4-Chlorophenyl)sulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(thiophen2-yl)-1H- indole (20s)

A mixture of compound 20b (11.0 g, 29.4 mmol), Cs ₂ CO ₃ (19 g, 59 mmol), AsPh ₃ (1.36 g, 4.40 mmol), Pd ₂ (dba) ₃ (1, 34 g, 1.48 mmol) and B ₂ Pin ₂ (15 g, 59 mmol) in dioxane (175 ml) were stirred under N2 at 60°C for 2 hours, cooled, filtered, concentrated and purified using FCC ( PE:EA=20:1 - 5:1) to obtain compound 20c as a white solid.

Step 4: 1-((4-Chlorophenyl)sulfonyl)-3-(2-chlorothiophen-3-yl)-2-(thiophen-2-yl)-1H-indole (20)

A solution of compound 20c (200 mg, 0.40 mmol), 3-bromo-2-chlorothiophene (79 mg, 0.40 mmol), Pd(PPh ₃ ) ₄ (46 mg, 40 μmol) and K3PO4 (404 mg, 1 .6 mmol) in dioxane/H ₂ O (10:1, 22 ml) was stirred under N2 at 100°C overnight, cooled, filtered and washed with DCM. The filtrate was then concentrated and purified by preparative HPLC to give compound 20 as a white solid. 1H-NMR (CDCl ₃ , 300 MHz) δ: 8.35 (d, J=6.6 Hz, 1H), 7.40-7.25 (m, 8H), 7.13 (d, J=0 .6 Hz, 1H), 7.057.03 (m, 2H), 6.61 (d, J=4.2 Hz, 1H); MS: 589.0 (M+1)+.

Examples 20/1-20/25.

The following examples were prepared in the same manner as described for Example 20 using the appropriate building blocks.

- 107 045482 analytical data

¹ H-NMR (CDCb, 300 MHz) b: 1.02 (s, 9H), 6.67 (s, 1H), 6.98-7.01 (m, 1H), 7.08 (s, 1H ), 7.19 (s, 1H), 7.287.30 (m, ZN), 7.35-7.43 (m, ZN), 7.47-7.50 (m, 2H), 8.32 ( s, 1H).

¹ H-NMR (CDCb, 300 MHz) b: 7.047.01 (m, 1H), 7.42-7.19 (m, 8H), 7.48-7.57 (m, 2H), 8.41 (d, J = 8.4 Hz, 1H), 8.55 (s, 1H), 8.70 (d, J = 4.5 Hz, 1H); MS: 476.0 (M+1) ⁺ .

Ή-NMR (CDCb, 300 MHz) b: 6.29 (t, J = 54.9 Hz, 1H), 6.72-6.73 (m, 1H), 7.03 (dd, J = 3, 8, 5.0 Hz, 1H), 7.10 (d, J = 2.7 Hz, 1H), 7.25-7.46 (m, 9H), 8.37 (d, J = 8.4 Hz, 1H); MS: 505.9 (M+1) ⁺ .

Ή-NMR (CDCb, 300 MHz) b: 7.04 (dd, J = 3.8, 5.3 Hz, 1H), 7.15 (d, J = 3.3 Hz, 1H), 7.20 (dd, J = 0.9, 3.6 Hz, 1H), 7.26-7.47 (m, 8H), 7.94 (d, J = 3.3 Hz, 1H), 8.36 ( d, J = 8.4 Hz, 1H); MS: 498.0 (M+18) ⁺ .

Ή-NMR (CDCb, 300 MHz) b: 2.54 (s, ZH), 6.97 (dd, J = 3.8, 8.6 Hz, 1H), 7.02 (s, 1H), 7 .07-7.10 (m, 1H), 7.23-7.57 (m, JN), 8.14-8.17 (m, 1H), 8.32 (d, J = 8.4 Hz , 1H); MS: 545.0 (M+18) ⁺ .

Ή-NMR (CDCb, 300 MHz) b: 6.997.02 (m, 1H), 7.16-7.42 (m, 11H), 7.47 (t, J = 8.4 Hz, 1H), 8 .36 (d, J = 8.4 Hz, 1H); MS: 493.0 (M+1) ⁺ .

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Ή-NMR (CDCb, 300 MHz) b: 7.09 (dd, J = 3.9, 5.1 Hz, 1H), 7.26-7.28 (m, 2H), 7.36-7, 41 (m, 6H), 7.487.52 (m, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8, 79 (d, J = 2.4 Hz, 1H); MS: 477.0 (M+1) ⁺ .

¹ H-NMR (CDCb, 300 MHz) b: 6.80 (d, J = 5.1 Hz, 1H), 6.98-7.08 (m, ZN), 7.20-7.22 (m , 1H), 7.33-7.53 (m, 7H), 8.39 (d, J = 8.4 Hz, 1H); MS: 482.0 (M+18) ⁺ .

Ή-NMR (CDCb, 300 MHz) b: 6.746.84 (m, 2H), 6.89 (d, J = 5.1 Hz, 1H), 7.00-7.03 (m, 1H), 7 .20 (d, J = 2.7 Hz, 1H), 7.32-7.51 (m, 6H), 8.30 (d, J = 9.0 Hz, 1H); MS: 483.0 (M+1) ⁺ .

Ή-NMR (CDCb, 300 MHz) b: 6.81 (d, J = 4.8 Hz, 1H), 7.06 (dd, J = 3,2,5,0 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.29-7.49 (m, 9H), 8.38 (d, J = 8.7 Hz, 1H).

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¹ H-NMR (CDCb, 300 MHz) b: 3.79 (s, ZN), 6.77-6.79 (m, ZN), 7.05 (dd, J = 3.8, 5.0 Hz , 1H), 7.19 (dd, J = 0.9, 3.6 Hz, 1H), 7.31-7.49 (m, 7H), 8.41 (d, J = 8.4 Hz, 1H); MS: 477.0 (M+1) ⁺ .

¹ H-NMR (CDCb, 300 MHz) b: 2.552.60 (m, 2H), 2.93 (t, J = 7.5 Hz, 2H), 3.63 (s, ZH), 6.79 ( d, J = 5.1 Hz, 1H), 7.04(dd, J = 3.9, 5.1 Hz, 1H), 7.15-7.18 (m, ZN), 7.33-7 .50 (m, 7H), 8.40 (d, J = 8.4 Hz, 1H); MS: 550.0 (M+18) ⁺ .

¹ H-NMR (DMSO-cb, 400 MHz) b: 8.17 (d, J = 8.4 Hz, 1H), 7.48-7.33 (m, JH), 6.98-6.94 (m, 2H), 3.75 (s, ZN), 2.29-2.08 (m, ZN), 1.77-1.36 (m, 5H); MS: 486.2 (M+18) ⁺ .

¹ H-NMR (DMSO-cb, 400 MHz) b: 8.61 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.83-7.79 (m, 1H), 7.55 -7.48 (m, ZN), 7.37-7.29 (m, 7N), 7.057.03 (m, 2H), 3.79 (s, ZN); MS: 516.1 (M+1) ⁺ .

¹ H-NMR (DMSO-cb, 300 MHz) b: 8.31 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.61- 7.50 (m, 2H), 7.437.01 (m, 13H), 3.79 (s, ZN); MS: 538.1 (M+18) ⁺ .

¹ H-NMR (DMSO-de, 400 MHz) b: 8.23 (d, J = 8.4 Hz, 1H), 7.51-7.21 (m, 14H), 7.00 (d, J = 8.8 Hz, 2H), 3.77 (s, ZN), 2.86-2.80 (m, 1H), 2.60-2.49 (m, 2H), 2.15-2, 09 (m, 1H); MS: 534.1 (M+18) ⁺ .

¹ H-NMR (DMSO-de, 400 MHz) b: 9.07 (dd, J = 1.2, 4.0 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.29(d, J = 8.4 Hz, 1H), 8.24(d, J = 8.8 Hz, 1H), 7.79 (dd, J = 4.2, 8.6 Hz, 1H ), 7.60 (d, J = 8.8 Hz, 1H), 7.53-7.45 (m, ZN), 7.36-7.27 (m, 7H), 7.03 (d, J = 9.2 Hz, 2H), 3.79 (s, ZH); MS: 516.1 (M+1) ⁺ .

20/

20/

20/

20/

20/

^1H -NMR (DMSO-de, 400 MHz) b: 8.21 (d, J = 8.4 Hz, 1H), 7.47-7.25 (m, JN), 7.14 (d, J = 8.0 Hz, 1H), 7.01-6.97 (m, 2H), 6.65 (d, J = 4.8 Hz, 1H), 3.76 (s, ZN), 1.85 (s, ZN); MS: 460.1 (M+1) ⁺ .

¹ H-NMR (DMSO-de, 400 MHz) b: 8.20 (d, J = 8.4 Hz, 1H), 7.44-7.29 (m, JH), 7.02-6.98 (m, 2H), 6.75 (d, ΰ = 6.0Γμ, 1H), 6.41 (d, J = 5.6 Hz, 1H), 3.77 (s, ZN), 3.54 ( s, ZN); MS: 476.1 (M+1) ⁺ .

^1H -NMR (DMSO-de, 400 MHz) b: 8.26 (d, J = 8.0 Hz, 1H), 7.52-7.28 (m, JN), 7.01 (d, J = 9.2 Hz, 2H), 6.77 (s, 1H), 3.77 (s, ZN), 2.43 (s, ZN); MS: 502.1 (M+18) ⁺ .

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Example 21.

3-(1 -((4-Chlorophenyl)sulfonyl)-2-(thiophen-2-yl)-1 H-indol-3-yl)thiophene-2-carboxylic acid (21)

A solution of compound 20/1 (95 mg, 0.24 mmol) and TFA (0.5 ml) in DCM (2.5 ml) was stirred at room temperature for 4 hours, concentrated and then the residue was triturated with PE containing a small amount EA to give compound 21 as a white solid. 1H-NMR (CDCl ₃ , 400 MHz) δ: 6.79 (d, J=3.9 Hz, 1H), 7.02-7.04 (m, 1H), 7.11 (dd, J=1 ,1, 2.6 Hz, 1H), 7.21 (d, J=5.7 Hz, 1H), 7.26-7.40 (m, 6H), 7.45-7.49 (m, 1H), 7.55 (d, J=3.9 Hz, 1H), 8.35 (d, J=6.3 Hz, 1H); MS: 497.9 (M-1) ^- .

Examples 21/1-21/3.

The following examples were prepared in the same manner as described for Example 20 using the appropriate starting material.

analytical data starting material structure

21/1

21/2

21/3

¹ H-NMR (DMSO-de, 300 MHz) b: 8.21 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 4.8 Hz, 1H), 7.58- 7.48 (m, 6H), 7.377.32 (m, 1H), 7.16-7.04 (m, 4H), 6.87 (d, J = 7.8 Hz, 1H), 4.83 (s, 2H); MS: 546.9 (M-1)-.

Ή-NMR (CD ₃ OD, 400 MHz) b: 8.43 (dd, J = 9.4, 4.2 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7 .98 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.0, 2.0 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H) , 7.54-7.30 (m, 9H), 7.09 (s, 1H), 6.94 (dd, J = 8.4, 2.8 Hz, 1H), 6.67 (t, J = 55.6 Hz, 1H), 4.12 (s, 2H); MS: 737.0 (M-1)-.

¹ H-NMR (CDCh, 400 MHz) b: 8.34 (d, J = 6.3 Hz, 1H), 7.58-7.13 (m, JN), 6.97-6.87 (m , 2H), 6.66 (s, 1H), 4.49 (shs, 2H); MS: 547.0 (MExample 22.

3-(1 -((4-Chlorophenyl)sulfonyl)-2-(thiophen-2-yl)-1 H-indol-3 -yl)thiophene-2-carboxamide (22)

To a solution of compound 21 (90 mg, 0.18 mmol) and HATU (137 mg, 0.36 mmol) in DMF (5 ml) was added DIEA (116 mg, 0.90 mmol) at room temperature. The solution was stirred for 20 minutes, then NH4Cl (19 mg, 0.36 mmol) was added and the mixture was stirred at room temperature for 2 hours, cooled, diluted with water and stirred for 10 minutes. The mixture was filtered to obtain compound 22 as a yellow solid. 1H-NMR (CDCl ₃ , 300 MHz) δ: 5.16 (brs, 2H), 6.68 (d, J=5.1 Hz, 1H), 7.03 (dd, J=3.6, 5 ,1 Hz, 1H), 7.14 (dd, J=1.2, 3.6 Hz, 1H), 7.23-7.49 (m, 9H), 8.39 (d, J=8, 4 Hz, 1H); MS: 499.0 (M+1)+.

Example 23.

1-((4-Chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-1H-indole-5-carboxylic acid (23)

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A solution of compound 20/10 (49 mg, 90 µmol) and LiOH-H ₂ Q (12 mg, 0.27 mmol) in THF/H2O (3:1, 8 ml) was stirred at room temperature overnight, concentrated, adjusted to pH 5-6 with 1 N. HCl and purified by preparative HPLC to give compound 23 as a yellow solid. ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.48 (d, J=8.7 Hz, 1H), 8.22-8.18 (m, 2H), 7.53 (d, J= 5.1 Hz, 1H),

7.44-7.26 (m, 6H), 7.10-7.07 (m, 1H), 6.88 (d, J=4.8 Hz, 1H); MS: 522.8 (M-1) ^- .

Examples 23/1-23/3.

The following examples were prepared in the same manner as described for Example 23 using the appropriate starting material.

Example 24.

starting material structure

23/1

23/2

23/3

analytical data ¹ H-NMR (CDCb, 400 MHz) b: 8.37 (d, 0 = 8.7 Hz, 1H), 7.77 (d, J = 5.1, 1H), 7.52-7, 45 (m, 2H), 7.39-7.25 (m, 6H), 7.15 (d, J = 3.6 Hz, 1H), 7.07-7.04 (m, 1H), 6 .91 (d, J = 5.4 Hz, 1H), 2.922.86 (m, 2H), 2.56 (t, J = 7.4 Hz, 2H); MS: 519.0 (M+1) ⁺ , 536.1 (M+18) ⁺ .

Step 1: Methyl 3-((2-iodophenyl)amino)propanoate (24a)

A mixture of 2-iodoaniline (50 g, 288 mmol) and methyl acrylate (103 ml, 1.14 mol) in AcOH (60 ml) was stirred at 90°C in a closed tube for 48 h, cooled and filtered. The filtrate was concentrated, diluted with aqueous Na ₂ CO ₃ and extracted with EA (2x100 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to give 24a as a yellow oil.

Step 2: Methyl 3-((2-iodophenyl)(methyl)amino)propanoate (24b)

A mixture of compound 24a (17.7 g, 58.1 mmol), CH ₃ I (29 ml, 46 mmol) and K ₂ CO ₃ (16.3 g, 118 mmol) in ACN (120 ml) was stirred at 80°C in a closed tube for 48 hours, cooled and filtered. The filtrate was concentrated, diluted with H ₂ O and extracted with EA (2x100 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to give crude compound 24b as a yellow oil.

Step 3: Methyl 3-(methyl(2-(thiophen-2-ylethynyl)phenyl)amino)propanoate (24c)

A mixture of compound 24b (24.8 g, 77.7 mmol), 2-ethynylthiophene (15.6 ml, 154 mmol), CuI (296 mg, 1.56 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (546 mg , 0.778 mmol) and TEA (39.3 g, 389 mmol) in ACN (90 ml) were stirred at 80°C in a closed tube overnight, cooled and filtered. The filtrate was concentrated and purified with FCC (PE:EA=20:1) to give compound 24c as a brown oil.

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Step 4: Methyl 3-(3-(2-cyanothiophen-3-yl)-2-(thiophen-2-yl)-III-indol-1-yl)propanoate (24d)

A mixture of compound 24c (23.2 g, 77.6 mmol), 3-bromothiophene-2-carbonitrile (16.1 g, 85.6 mmol), nBu ₄ NI (2.90 g, 7.76 mmol) and PdCl ₂ (dppf) (1.70 g, 2.33 mmol) in ACN (150 ml) was stirred at 90°C under N2 overnight, cooled, quenched with H ₂ O and extracted with EA (2x150 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated and purified with FCC (PE:EA=5:1) to give 24d as a brown oil; MS: 393.0 (M+1)+.

Step 5: 3-(2-(Thiophen-2-yl)-1H-indol-3-yl)thiophene-2-carbonitrile (24e) ^NC

CYWl 24e

H

A mixture of compound 24d (12.6 g, 32.1 mmol) and DBU (10.1 ml, 64.2 mmol) in DMF (100 ml) was stirred at 120°C overnight, cooled, diluted with H ₂ O and extracted EA (2x100 ml). The combined organic layer was washed with H ₂ O (2x100 ml) and brine, dried over Na ₂ SO ₄ , concentrated and purified with FCC (PE:EA = 5:1) to give compound 24e as a yellow solid; MS: 307.0 (M+1) ⁺ .

Step 6: 3-(1-(Cyclohexylsulfonyl)-2-(thiophen-2-yl)-1H-indol-3-yl)thiophene-2-carbonitrile(24)

To a solution of compound 24e (200 mg, 0.65 mmol) in THF (20 ml) at -78°C under N2, LiHMDS (1.0 M in THF, 0.8 ml, 0.8 mmol) was added dropwise. The mixture was stirred at -78°C for 30 minutes, then cyclohexanesulfonyl chloride (144 mg, 0.80 mmol) was added. The mixture was stirred at -78°C for 2 hours, diluted with aqueous NH ₄ Cl and extracted with DCM (3x). The combined organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 24 as a yellow solid. ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.08-1.12 (m, 3H), 1.46-1.60 (m, 3H), 1.73-1.77 (m, 4H ), 3.06-3.16 (m, 1H), 6.86 (d, J=5.4 Hz, 1H), 7.05 (dd, J=3.6, 4.8 Hz, 1H) , 7.27-7.51 (m, 6H), 8.19 (d, J=8.4 Hz, 1H); MS: 467.7 (M+Na) ⁺ .

Example 25.

Step 1: tert-Butyl-2-(thiazol-5-yl)-1H-indole-1-carboxylate (25a)

Vn 25a

Vos

A mixture of tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (4.20 g, 12.2 mmol), 5-bromothiazole (2.00 g, 12.2 mmol), Pd(dppf)Cl ₂ (877 mg, 1.20 mmol) and K ₂ CO ₃ (5.10 g, 36.6 mmol) in a dioxane/ H ₂ O (50 ml/5 ml) was stirred at 100°C under N2 overnight, cooled, diluted with EA (300 ml) and washed with brine. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=5:1) to give compound 25a as a colorless oil.

Step 2: tert-Butyl-3-bromo-2-(thiazol-5-yl)-1H-indole-1-carboxylate (25b) Br

Οζ/* ^- Ό 25b

Vos

A mixture of compound 25a (2.6 g, 8.7 mmol) and NBS (1.85 g, 10.4 mmol) in DMF (50 ml) was stirred at room temperature under N ₂ overnight, diluted with water and extracted with EA (3x50 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=10:1) to give 25b as a yellow solid.

Step 3: tert-Butyl-3-(2-cyanothiophen-3-yl)-2-(thiazol-5-yl)-1H-indole-1-carboxylate (25c)

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Mixture of compound 25b (620 mg, 1.60 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2yl)thiophene-2-carbonitrile (376 mg, 1.60 mmol ), Pd(dppf)Cl ₂ (117 mg, 160 μmol) and K ₂ CO ₃ (662 mg, 4.80 mmol) in a mixture of dioxane/H ₂ O (20 ml/2 ml) were stirred at 100 ° C in the atmosphere N ₂ overnight, cooled, diluted with EA (200 ml) and washed with brine. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=5:1) to give compound 25c as a yellow oil.

Step 4: 3-(2-(Thiazol-5-yl)-1H-indol-3-yl)thiophene-2-carbonitrile (25d)

A mixture of compound 25c (320 mg, 0.79 mmol) and TFA (4 ml) in DCM (10 ml) was stirred at room temperature overnight, concentrated, neutralized with saturated aqueous NaHCO ₃ and extracted with EA (3x30 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give compound 25d, which was used in the next step without further purification.

Step 5: 3-(1-((4-Chlorophenyl)sulfonyl)-2-(thiazol-5-yl)-1H-indol-3-yl)thiophene-2-carbonitrile (25)

To a solution of compound 25d (200 mg, 0.65 mmol) in THF (10 ml) was added NaH (39 mg, 0.98 mmol) under N ₂ at 0°C. The mixture was stirred at 0°C for 30 minutes, then 4chlorobenzenesulfonyl chloride (165 mg, 0.78 mmol) was added. The mixture was stirred at 0°C for 30 min, poured into saturated aqueous NH ₄ Cl (50 ml) and extracted with EA (3x50 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC (CH3CN/H2O = 20-95%, 5 mmol NH4HCO3) to give compound 25 as a yellow solid. ^1H -NMR (DMSO- _d6 , 400 MHz) δ: 9.28 (d, J=0.8 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.08 (d, J=5.2 Hz, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.66-7.56 (m, 5H), 7.43-7.39 ( m, 2H), 7.11 (d, J=5.2 Hz, 1H); MS: 481.8 (M+1)+.

Example 26.

Step 1: tert-Butyl-3-(2-cyanothiophen-3-yl)-1H-indole-1-carboxylate (26a)

To a solution of tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-III-indole-1-carboxylate (2.0 g, 5.8 mmol) , 3-bromothiophene-2-carbonitrile (1.1 g, 5.8 mmol) and K ₂ CO ₃ (2.40 g, 17.4 mmol) in dioxane/H ₂ O (20 ml/2 ml) were added Pd(dppf)Cl ₂ (413 mg, 0.58 mmol) under N ₂ atmosphere. The mixture was stirred at 90°C for 4 hours, evaporated and purified using FCC (PE:EA=20:1-10:1) to obtain compound 26a as a yellow oily substance.

Step 2: tert-Butyl-2-bromo-3-(2-cyanothiophen-3-yl)-1H-indole-1-carboxylate (26b)

To a solution of compound 26a (1.30 g, 4.01 mmol) in CCl ₄ (20 ml) was added NBS (1.40 g, 8.02 mmol) and AIBN (65.4 mg, 401 μmol). The mixture was stirred at 100°C for 48 hours, evaporated and purified using FCC (PE:EA=10:1) to obtain compound 26b as a yellow oily substance.

Step 3: tert-Butyl 3-(2-cyanothiophen-3-yl)-2-phenyl-1H-indole-1-carboxylate (26c)

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Pd(dppf) was added to a solution of compound 26b (500 mg, 1.24 mmol), PhB(OH) ₂ (302 mg, 2.48 mmol) and K2CO3 (513 mg, 3.72 mmol) in dioxane (15 ml) Cl ₂ (88.4 mg, 124 µmol) under N2 atmosphere. The mixture was stirred at 90°C overnight, concentrated and purified with FCC (PE:EA=10:1) to give compound 26c as a yellow oily substance.

Step 4: 3-(2-Phenyl-1H-indol-3-yl)thiophene-2-carbonitrile (26d)

To a solution of compound 26c (616 mg, 1.54 mmol) in DCM (4 ml) was added TFA (2 ml). The mixture was stirred at room temperature for 2 hours, concentrated and purified to give compound 26d as a white solid.

Step 5: 3-(1-((4-chlorophenyl)sulfonyl)-2-phenyl-1H-indol-3-yl)thiophene-2-carbonitrile (26)

To a solution of compound 26d (147 mg, 488 μmol) in DMF (5 ml) was added NaH (78 mg, 2.0 mmol) under N ₂ atmosphere at 0°C. The mixture was stirred at 0°C for 30 minutes, then 4chlorobenzenesulfonyl chloride (310 mg, 1.46 mmol) was added. The mixture was stirred at 0°C for 30 min, quenched with saturated aqueous NH4C1 and extracted with DCM (3x20 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=20:1) to give compound 26 as a white solid. 1H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.25 (d, J=8.0 Hz, 1H), 7.99 (d, J=5.2 Hz, 1H), 7.59 ( dd, J=2.0, 6.8 Hz, 2H), 7.53-7.27 (m, 10H), 6.96 (d, J=4.8 Hz, 1H); MS: 491.7 (M+18)+.

Example 26/1.

The following example was prepared in the same manner as described for Example 26 using the appropriate starting material.

_Ν θ starting material structure analytical data

¹ H-NMR (DMSO-de, 400 MHz) b: 8.25 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.617.58 ( m, 2H), 7.55-7.48 (m, ZN), 7.43-7.32 (m, 4H), 7.25-7.21 (m, 2H), 7.00 (d, J = 4.8 Hz, 1H); MS: 509.6 (M+18) ⁺ .

Example 27.

2-(4-((3-(2-cyanothiophen-3-yl)-2-phenyl-1H-indol-1-yl)sulfonyl)phenoxy)acetic acid (27)

To a solution of compound 1/43 (70 mg, 130 µmol) in MeOH (5 ml) was added NaOH (2 N, 0.5 ml) and the mixture was stirred overnight. Then MeOH was removed and the solution was adjusted to pH < 2 with 2 N. HCl, extracted with EA (10 ml) and washed with brine (10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 27 as a white solid. 1H-NMR (500 MHz, DMSO-66) δ: 13.21 (brs, 1H), 8.26 (d, J=8.5 Hz, 1H), 7.99 (d, J=5.0 Hz , 1H), 7.52-7.34 (m, 8H), 7.27 (d, J=7.0 Hz, 2H), 7.01-6.99 (m, 3H), 4.75 ( s, 2H); MS: 515.1 (M+1) ⁺ .

Examples 27/1-27/3.

The following examples were prepared in the same manner as described for Example 27 using the appropriate starting material.

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27/1

27/2

27/3

¹ H-NMR (500 MHz, DMSO-de) b: 12.55 (brs, 1H), 8.26 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.55-7.34 (m, JH), 7.28 (d, J = 7.0 Hz, 2H), 6.98 (d, J = 5.0 Hz, 1H), 3.61 (s, 2H); MS: 499.1 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 13.18 (brs, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.17 (s, 1H), 8. 00 (d, J = 5.0 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.63- 7.52 (m, 4H), 7.45-7.32 (m, 7H), 6.97 (d, J = 5.0 Hz, 1H); MS:561.2 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 12.85 (brs, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 5.5 Hz, 1H), 7.54-7.51 (m, 1H), 7.44-7.32 (m, 8H), 7.00 (d, J = 5.0 Hz, 1H), 6.95 (d, J = 3.5 Hz, 1H), 3.91 (s, 2H); MS: 505.0 (M+1) ⁺ .

Example 28.

3-(4-(3-(2-Cyanothiophen-3-yl)-1-((4-methoxyphenyl)sulfonyl)-1H-indol-2-yl)phenyl)propanamide (28)

To a solution of compound 15/6 (200 mg, 0.40 mmol) in DMF (10 ml) was added EDCI (100 mg, 0.50 mmol), DMAP (60 mg, 0.50 mmol) and NH4C1 (70 mg, 0 .50 mmol) and stirred the mixture at room temperature for 12 hours, diluted with water (100 ml) and extracted with EA (3x100 ml). The combined organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 28 as a white solid. 1H-NMR (500 MHz, DMSO-66) δ: 8.26 (d, J=8.0 Hz, 1H), 7.98 (d, J=5.5 Hz, 1H), 7.50-7 .47 (m, 1H), 7.40-7.33 (m, 5H), 7.20 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.93 (d, J=5.0 Hz, 1H), 6.84 (s, 1H), 3.78 (s, 3H), 2.85 (t, J=8.0 Hz, 2H), 2.41 (t, J=8.0 Hz, 2H); MS: 542.1 (M+1) ⁺ .

Example 29.

Step 1: Methyl 2-chloro-3’-((2-((4-(difluoromethyl)phenyl)sulfonamido)-5-fluorophenyl)ethynyl)-[1,1’biphenyl]-4-carboxylate (29a)

Compound 29a was synthesized in the same manner as described in Example 1 in steps 1 and 2 using the appropriate building blocks.

Step 2: Methyl-2-chloro-3'-(1 -((4-(difluoromethyl)phenyl)sulfonyl)-5 -fluoro-1 H-indol-2-yl)-[1,1'biphenyl]-4 -carboxylate(29b)

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To a solution of compound 29a (400 mg, 0.70 mmol) in MeCN (12.0 ml) was added K ₂ CO ₃ (193 mg, 1.40 mmol) and Pd(PPh ₃ ) ₄ (81 mg, 70 μmol) in atmosphere N2. The mixture was stirred at 100°C for 2 hours, cooled to room temperature, poured into EA (200 ml) and washed with H ₂ O (2x20 ml) and brine (20 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified using FCC (EA:PE=1:4) to obtain compound 29b as a colorless oily substance.

Step 3: Methyl 3'-(3-bromo-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl)-2-chloro[1,1'-biphenyl ]-4-carboxylate (29c)

To a solution of compound 29b (150 mg, 0.26 mmol) in THF (15 ml) was added NBS (56 mg, 0.31 mmol). The mixture was stirred at room temperature overnight, poured into EA (200 ml) and washed with H ₂ O (2x20 ml) and brine (20 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by preparative TLC (EA:PE=1:4) to obtain compound 29c as a white solid.

Step 4: Methyl-2-chloro-3'-(1-((4-(difluoromethyl)phenyl)sulfonyl)-3-(2,6-dimethylphenyl)-5-fluoro1 H-indol-2-yl)-[ 1,1'-biphenyl]-4-carboxylate (29)

To a solution of compound 29c (150 mg, 0.23 mmol) in dioxane (8 ml) was added 2,6dimethylphenylboronic acid (45 mg, 0.30 mmol), Cs ₂ CO ₃ (176 mg, 0.46 mmol) and Pd( dppf)Cl ₂ (17 mg, 23 µmol) in an N ₂ atmosphere. The mixture was stirred at 90°C overnight, cooled to room temperature, poured into EA (200 ml) and washed with H ₂ O (2 x 20 ml) and brine (20 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by preparative TLC (EA:PE=1:4) to obtain compound 29 as a colorless oily substance.

Examples 29/1-29/3.

The following examples prepared the starting material(s).

No. in the same manner as described for Example 29, using the corresponding starting material(s) structure

29/1

29/2

29/3

oh oh

Example 30

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rac-( 1 R,2R)-2-(3-(3 -(2-Cyanothiophen-3-yl)-1 -tosyl-1 H-indol-2-yl)phenyl)cyclopropane-1 carboxylic acid (30)

To a solution of compound 1/56 (130 mg, 0.23 mmol) in MeOH (10 ml) was added LiOH H ₂ O (49 mg, 1.18 mmol) and the mixture was stirred at room temperature for 1 hour.

The mixture was then concentrated and adjusted to pH < 4 with 2N. aqueous HCl solution and extracted with EA (3x30 ml). The combined organic layer was washed with brine (10 mL), dried over Na ₂ SO ₄ , concentrated and purified by preparative HPLC to give compound 30 as a white solid. 1H-NMR (500 MHz, DMSO-66) δ: 12.36 (s, 1H), 8.27 (d, J=10.0 Hz, 2H), 8.01 (d, J=5.5 Hz , 1H), 7.52-7.48 (m, 1H), 7.41-7.26 (m, 8H), 7.10-7.08 (m, 1H), 7.02-6.98 (m, 1H), 6.88 (s, 1H), 2.38-2.33 (m, 1H), 2.31 (s, 3H), 1.73-1.68 (m, 1H), 1.44-1.39 (m, 1H), 1.25-1.18 (m, 1H), MS: 521 (M18+H)+.

Examples 30/1-30/16.

The following examples were prepared in the same manner as described for Example 30 using the appropriate starting materials.

No. starting material

structure

analytical data ¹ H-NMR (500 MHz, DMSO-de) b: 13.12 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 8.07 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7. 76 (d, J = 8.0 Hz, 1H), 7.63-7.60 (m, 1H), 7.55-7.47 (m, 2H), 7.42-7.37 (m, 4H), 7.31-7.25 (m, ZN), 7.07 (d, J = 5.0 Hz, 1H), 2.24 (s, ZN); MS: 574.8 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD3OD) b: 8.43 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 5.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.51-7.32 (m, 9H), 7.27 (d, J = 8.5 Hz, 2H), 7.22 (s, 1H), 7. 12 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 5.0 Hz, 1H), 2.22 (s, ZN), 1.62 (s, 6H); MS: 615.0 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 12.75 (s, 1H), 8.75 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8. 28 (d, J = 8.5 Hz, 1H), 8.05-8.02 (m, 2H), 7.84 (d, J = 7.5 Hz, 1H), 7.62 (s, 1H ), 7.547.25 (m, 9H), 7.11 (d, J = 5.0 Hz, 1H), 2.23 (s, ZN), 1.61 (s, 6H); MS: 618.1 (M+1) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 12.35 (s, 1H), 8.26 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 5.0 Hz, 1H), 7.61-7.44 (m, 5H), 7.42-7.08 (m, 4H), 7.07-7.06 (m, 1H), 7.00-6, 94 (m, 2H), 2.39-2.34 (m, 1H), 1.72 (s, 1H), 1.441.40 (m, 1H), 1.25-1.23 (m, 1H) ; MS: 540.8 (M+1) ⁺ .

- 118 045482

^1H -NMR (500 MHz, DMSO-de) b: 12.05 (s, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 5.0 Hz, 1H), 7.60-7.46 (m, 5H), 7.40-7.23 (m, 4H), 7.13 (d, J = 7.5 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 5.0 Hz, 1H), 2.56 (t, J = 8.0 Hz, 2H), 2.15 (t, J = 7.0 Hz , 2H), 1.741.70 (m, 2H); MS: 560.8 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD3OD) b: 8.34 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 5.0 Hz, 1H), 7.837.79 (m, 1H), 7.73 (d, J = 9.0 Hz, 2H), 7.62-7.58 (m, 1H), 7.53-7.42 (m, 4H), 7.23 (d , J = 5.0 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 7.0 Hz, 1H), 4.54-4.43 (m, 4H), 3.77-3.73 (m, 1H); MS: 574.7 (M+1) ⁺ .

¹ H-NMR (500 MHz, CD3OD) b: 8.38 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 5.0 Hz, 1H), 7.517.34 (m, 7H), 7.16 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 5.0 Hz, 1H), 6.65 (d, J = 7.5 Hz, 1H) , 6.55-6.53 (m, 1H), 6.23 (s, 1H), 4.013.97 (m, 2H), 3.91-3.88 (m, 2H), 3.54-3 .50 (m, 1H); MS: 574.1 (M+1) ⁺ .

¹ H-NMR (400 MHz, DMSO-de) b: 8.26 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 5.5 Hz, 1H), 7.64- 7.51 (m, 5H), 7.42-7.36 (m, 2H), 7.05 (d, J = 5.0 Hz, 1H), 7.02 (d, J = 5.0 Hz , 1H), 6.88 (d, J = 3.5 Hz, 1H), 2.52-2.45 (m, 1H), 1.78-1.75 (m, 1H), 1.48- 1.42 (m, 1H), 1.24-1.18 (m, 1H); MS: 582.1 (M+18) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 8.25 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 5.0 Hz, 1H), 7.60 ( d, J = 8.5 Hz, 2H), 7.55-7.47 (m, ZN), 7.42-7.36 (m, ZN), 7.10 (s, 1H), 7.05 (d, J = 5.0 Hz, 1H), 6.90 (s, 1H), 2.39-2.35 (m, 1H), 1.79-1.72 (m, 1H), 1 .43-1.38 (m, 1H), 1.25-1.20 (m, 1H); MS: 610.0 (M+18) ⁺ .

^1H -NMR (500 MHz, DMSO-de) b: 12.29 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 5.5 Hz, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.46-7.34 (m, ZN), 7.25-7.19 (m, 2H), 7.147 .10 (m, 2H), 6.99 (d, J = 5.0 Hz, 1H), 3.65 (s, ZN), 2.37-2.35 (m, 1H), 1.82- 1.75 (m, 1H), 1.45-1.38 (m, 1H), 1.28-1.22 (m, 1H); MS: 529.2 (M+1) ⁺ .

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30/ zo/ zo/ 11 zo/

thirty/

thirty/

¹ H-NMR (400 MHz, DMSO-de) b: 8.328.28 (m, 1H), 7.94-7.88 (m, ZH), 7.65-7.24 (m, 12H), 7 .04-6.85 (m, 2H), 5.19 (shs, 1H), 1.23 (s, 6H); MS: 663.0 (M-1)Ή-NMR (500 MHz, DMSO-de) b: 12.49 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 7. 99 (d, J = 5.0 Hz, 1H), 7.58-7.40 (m, 5H), 7.40-7.32 (m, 2H), 7.16-7.13 (m, 1H), 6.98 (d, J = 5.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H) , 6.27 (s, 1H), 3.33-3.28 (m, 2H), 3.21-3.14 (m, ZN), 2.21-2.13 (m, 2H); MS: 587.8 (M+1) ⁺ .

Ή-NMR (500 MHz, DMSO-de) b: 12.35 (brs, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.52 -7.39 (m, ZN), 7.27-7.13 (m, 4H), 7.04 (d, J = 5.0 Hz, 1H), 2.88-2.83 (m, 1H ), 2.41 -2.36 (m, 1H), 1.75-1.72 (m, 1H), 1.431.39 (m, 1H), 1.28-1.25 (m, 1H), 0.99-0.94 (m, 4H); MS: 471.0 (M-18+N) ⁺ .

Ή-NMR (500 MHz, CD ₃ OD) b: 8.37 (d, J = 8.0 Hz, 1H), 7.46-7.42 (m, 1H), 7.33-7.30 ( m, 1H), 7.27-7.17 (m, 9H), 6.74 (s, 1H), 6.60 (d, J = 5.5 Hz, 1H), 2.40-2.36 (m, 1H), 2.35 (s, ZN), 1.76-1.72 (m, 1H), 1.51 -1.48 (m, 1H), 1.17-1.13 (m , 1H); MS: 548.0 (M+1) ⁺ .

^1H -NMR (500 MHz, DMSO-de) b: 12.38 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.49-7.45 (m, 1H ), 7.36-7.13 (m, 8H), 7.15 (d, J = 7.0 Hz, 1H), 6.96-6.92 (m, 2H), 6.48-6, 46 (m, 1H), 2.39-2.34 (m, 1H), 2.31 (s, ZN), 1.73-1.69 (m, 1H), 1.45-1.40 ( m, 1H), 1.27-1.23 (m, 1H); MS: 530.0 (M-1)-.

¹ H-NMR (500 MHz, DMSO-de) b: 12.35 (brs, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.887.85 (m, 1H), 7, 57-7.34 (m, 8H), 7.32-7.18 (m, ZN), 7.06 (s, 1H), 6.84 (s, 1H), 2.322.29 (m, 4H) , 1.64-1.61 (m, 1H), 1.43-1.39 (m, 1H), 1.19-1.16 (m, 1H); MS: 549.0 (MExample 31.

3-((6-(1-((4-Chlorophenyl)sulfonyl)-3-(2-cyanothiophen-3-yl)-1H-indol-2-yl)pyridin-2-yl)oxy)propanoic acid (31 )

A solution of compound 1/62 (110 mg, 0.19 mmol) in 4 N. HCl in dioxane (30 ml) was stirred at room temperature overnight. The solvent was removed, EA (20 ml) was added and the mixture was washed with water (10 ml) and brine (10 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by preparative HPLC to give compound 31 as a white solid. 1H-NMR (400 MHz, DMSO^) δ: 12.38 (s, 1H), 8.13 (d, J=8.5 Hz, 1H), 8.02 (d, J=5.0 Hz, 1H), 7.947.91 (m, 2H), 7.77-7.65 (m, 3H), 7.54-7.42 (m, 1H), 7.41-7.37 (m, 2H) , 7.13 (d, J=6.8 Hz, 1H), 7.00 (d, J=4.8 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 4 .32 (t, J=6.4 Hz, 2H), 2.67 (t, J=6.4 Hz, 2H); MS: 563.8 (M+1) ⁺ .

Example 32.

3'-(3-(2-Cyanothiophen-3-yl)-1-tosyl-1H-indol-2-yl)-N-(methylsulfonyl)-[1,1'-biphenyl]-3-carboxamide (32)

Cloudy solution of compound 30/1 (100 mg, 0.17 mmol), methanesulfonamide (17 mg, 0.17 mmol),

- 120 045482

DMAP (21 mg, 0.17 mmol) and EDCI (50 mg, 0.26 mmol) in DMF (4 ml) were stirred for 14 h at room temperature. The product was isolated from the mixture by preparative HPLC to give compound 32 as a white solid. 1H-NMR (500 MHz, DMSO-d ₆ ) δ: 12.30 (s, 1H), 8.31-7.92 (m, 4H), 7.83 (t, J=7.5 Hz, 2H ), 7.65-7.62 (m, 2H), 7.55-7.49 (m, 2H), 7.42-7.39 (m, 4H), 7.30-7.26 (m , 3H), 7.07 (d, J=2.5 Hz, 1H), 3.42 (s, 3H), 2.25 (s, 3H); MS: 652.1 (M+1)+.

Examples 32/1-32/5.

The following examples were prepared in the same manner as described for Example 32 using the appropriate starting materials.

analytical data ¹ H-NMR (500 MHz, DMSO-de) b: 12.09 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.01 (d, 3 = 5 ,0Hz, 1H), 7.627.59 (m, 2H), 7.54-7.23 (m, 7H), 7.10-6.96 (m, ZN), 3.28 (s, 1H), 2.46-2.42 (m, 1H), 2.09-2.06 (m, 1H), 1.51-1.46 (m, 1H), 1.35-1.32 (m, 1H ); MS: 658.0 (M+Na) ⁺ .

¹ H-NMR (500 MHz, DMSO-de) b: 8.27 (dd, J = 9.1,4.4 Hz, 1H), 7.98 (d, J = 5.1 Hz, 1H), 7.46-7.28 (m, 5H), 7.20-7.07 (m, 2H), 6.94 (d, J = 5.1 Hz, 1H), 6.57-6.48 ( m, 2H), 6.24 (s, 1H), 3.95 (t, J = 7.5 Hz, 2H), 3.89-3.80 (m, 1H), 3.72 (t, J = 6.2 Hz, 2H), 3.52 (s, ZN), 2.87 (s, ZN), 2.33 (s, ZN), 1.34 (s, 6H); MS: 685.0 (M+1) ⁺ .

starting material structure

Example 33.

^1H -NMR (500 MHz, DMSO-de) b: 12.32 (s, 1H), 8.31-8.28 (m, 1H), 8.11 (d, J = 1.5 Hz, 1H ), 8.03 (d, J = 5.0 Hz, 1H), 7.99-7.97 (m, 2H), 7.557.35 (m, 4H), 7.41-7.33 (m, ZN), 7.26-7.18 (m, ZN), 7.07-7.03 (m, 2N), 3.38 (s, ZN), 2.22 (s, ZN); MS: 701.9 (M-1)-.

¹ H-NMR (500 MHz, CD ₃ OD) b: 8.44 (dd, J = 9.0.4.0 Hz, 1H), 8.08-8.04 (m, ZH), 7.93 (dd, J = 8.5, 1.5 Hz, 1H), 7.73 (t, J = 8.3 Hz, 1H), 7.557.32 (m, 9H), 7.12 (s, 1H) , 6.95 (dd, J = 8.0.2.5 Hz, 1H), 6.69 (t, J = 55.5 Hz, 1H), 3.36 (s, ZN); MS: 756.8 (M-1)-.

Methyl 3'-(3-(2-cyanothiophen-3-yl)-5-fluoro-7-hydroxy-1-tosyl-1H-indol-2-yl)-[1,1'-biphenyl]-4carboxylate (33)

To a solution of compound 1/101 (120 mg, 0.19 mmol) in DCM (6 ml) at -78°C, BBg ₃ (10 ml, 1 M in DCM) was slowly added. The mixture was stirred at the indicated temperature for 40 minutes and at room temperature for 1 hour, quenched with H ₂ O (20 ml) and extracted with EA (2x100 ml). The combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by preparative TLC (EA:PE=1:1) to give compound 33 as a yellow oily substance.

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Example 34.

Step 1: Ethyl-2-((3'-(3 -(2-cyanothiophene-3-yl)-1 -tosyl-1 H-indol-2-yl)-5 -fluoro-4-(hydroxymethyl)[1 ,1'-biphenyl]-3-yl)sulfonyl)acetate (34a)

To a solution of compound 1 (290 mg, 0.54 mmol) in dioxane (15 ml) was added compound P3-1 (193 mg, 0.54 mmol), B ₂ Pin ₂ (166 mg, 0.65 mmol), Pd( dppf)Cl ₂ (39 mg, 0.05 mmol) and KOAc (107 mg, 1.09 mmol). The mixture was stirred at 100°C overnight. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (EA:PE=1:1) to obtain compound 34a as a yellow oily substance.

Step 2: 2-((3'-(3-(2-Cyanothiophen-3-yl)-1-tosyl-1H-indol-2-yl)-5-fluoro-4-(hydroxymethyl)-[1,1 'biphenyl]-3-yl)sulfonyl)acetic acid (34)

To a solution of compound 34a (90 mg, 0.12 mmol) in EtOH (10 ml) was added LiOH H ₂ O (26 mg, 0.62 mmol) and the mixture was stirred at room temperature for 1.5 hours. EtOH was then removed , water was added and the pH was adjusted to < 4 by adding 2 N. HCl. Extract the EA mixture (3x40 ml) and wash the combined organic layer with brine (10 ml), dry over Na ₂ SO ₄ , concentrate and purify by preparative HPLC to give 34 as a white solid. 1H-NMR (500 MHz, CD3OD) δ: 8.42 (d, J=8.5 Hz, 1H), 7.99 (s, 1H), 7.84 (d, J=4.5 Hz, 1H ), 7.75 (d, J=8.0 Hz, 1H), 7.64-7.30 (m, 9H), 7.20 (d, J=8.5 Hz, 2H), 7.03 (d, J=5.0 Hz, 1H), 5.11 (s, 2H), 4.50 (s, 2H), 2.29 (s, 3H); MS: 718.1 (M+18)+.

Example 35.

Step 1: Methyl 3'-((2-amino-5-fluorophenyl)ethynyl)-2-chloro-[1,1'-biphenyl]-4-carboxylate (35a)

To a solution of compound P5 (5.00 g, 15.4 mmol) in TEA (60 ml) was added Pd(PPh ₃ ) ₄ (710 mg, 0.61 mmol), CuI (175 mg, 0.92 mmol), PPh ₃ (241 mg, 0.92 mmol) and 2-ethynyl-4-fluoroaniline (2.70 g, 20.0 mmol). The mixture was stirred at 60°C under N2 atmosphere overnight. After cooling to room temperature, filter the mixture, concentrate the filtrate and purify the residue with FCC (PE:EA=2:1) to give compound 35a as a light yellow solid.

Step 2: Methyl 2-chloro-3'-((5-fluoro-2-(2,2,2-trifluoroacetamido)phenyl)ethynyl)-[1,1'-biphenyl]-4carboxylate(35b)

ATPA (199 mg, 0.95 mmol) and TEA (120 mg, 1.19 mmol) were added to a solution of compound 35a (300 mg, 0.79 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 15 min, then DCM (20 ml) was added and the mixture was washed with H ₂ O (2x10 ml) and brine (20 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness to obtain crude compound 35b as a yellow solid.

Step 3: Methyl-2-chloro-3'-(3-(2-cyanothiophen-3-yl)-5-fluoro-1H-indol-2-yl)-[1,1'-biphenyl]-4

- 122 045482 carboxylate (35c)

To a solution of compound 35b (320 mg, 0.67 mmol) in ACN (20 ml) was added 3-bromothiophene-2carbonitrile (190 mg, 1.01 mmol), K ₂ CO ₃ (185 mg, 1.34 mmol) and Pd (PPh ₃ ) ₄ (77 mg, 67 µmol) under N ₂ and stirred the mixture at 100°C for 2 hours, cooled to room temperature, poured into EA (20 ml) and washed with H ₂ O (2x20 ml) and saturated saline solution (20 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified with FCC (EA:PE=1:3) to give compound 35c as a yellow solid.

Step 4: Methyl-2-chloro-3'-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-((6-(trifluoromethyl)pyridin-3yl)sulfonyl)-1H-indol-2 -yl)-[1,1'-biphenyl]-4-carboxylate (35)

To a solution of compound 35c (200 mg, 0.41 mmol) in THF (8 ml) at 0°C was added NaH (60% in mineral oil, 50 mg, 1.23 mmol) and 6-(trifluoromethyl)pyridine-3- sulfonyl chloride (201 mg, 0.82 mmol). The mixture was stirred at room temperature for 1 hour and poured into cold saturated aqueous NH4Cl solution (50 ml). The mixture was extracted with EA (2x50 ml) and washed with brine (20 ml). The combined organic layer was dried over Na ₂ SO ₄ , concentrated and purified by preparative TLC (EA:PE=1:3) to give compound 35 as a yellow solid.

Examples 35/1-35/2.

The following examples were prepared in the same manner as described for Example 35 using the appropriate starting materials.

Example 36.

-(3 -(3 -(2-Cyanothiophen-3-yl)-5-fluoro-1-tosyl-1 H-indol-2-yl)phenyl)-4-methylpicolinic acid (36)

To a stirred solution of compound 2/13 (150 mg, 0.24 mmol) in THF (10 ml) at room temperature was added 1 N. LiOH (1 ml) and continued stirring at room temperature for 2 hours. The mixture was extracted with EA (100 ml), washed the organic layer with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 36 in as a white solid. 1H-NMR (500 MHz, DMSO-d ₆ ) δ: 8.39 (s, 1H), 8.28 (dd, J=10.0, 4.5 Hz, 1H), 8.05 (d, J =5.0 Hz, 1H), 8.01 (s, 1H), 7.57-7.51 (m, 2H), 7.42-7.36 (m, 4H), 7.27 (d, J=8.5 Hz, 2H), 7.20-7.18 (m, 1H), 7.13 (s, 1H), 7.06 (d, J=5.0 Hz, 1H), 2, 24 (s, 3H), 2.19 (s, 3H); MS: 606.0 (M-1) ^- .

Example 36/1.

The following example was prepared in the same manner as described for Example 36 using the appropriate starting material.

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Example 37.

3-(2-(2'-Chloro-4'-(1H-tetrazol-5-yl)-[1,Γ-biphenyl]-3-yl)-5-fluoro-1-tosyl-1H-indol-3 -yl)thiophene-2carbonitrile (37)

To a stirred solution of compound P2/15 (150 mg, 0.17 mmol) in acetone (10 ml) at room temperature was added 1 N. HCl (1 ml) and stirring continued for 2 hours. Water was added and the mixture was extracted with EA (100 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 37 as a white solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 8.31-8.28 (m, 1H), 8.19 (s, 1H), 8.11-8.09 (m, 1H), 8.03 (d, J=5.0 Hz, 1H), 7.59-7.56 (m, 3H), 7.47-7.20 (m, 7H), 7.11 (s, 1H) , 7.04 (d, J=5.0 Hz, 1H), 2.21 (s, 3H); MS: 649.0 (M-1)-.

Example 37/1.

The following example was prepared in the same manner as described for Example 37 using the appropriate starting material.

Example 38.

rel-methyl-(2R,4R)-1-(3-(3-(2-cyanothiophen-3-yl)-5-fluoro-1-tosyl-1H-indol-2-yl)phenyl)-2methylpiperidin-4 -carboxylate (38)

To a solution of compound 1 (500 mg, 0.91 mmol) in toluene (15 ml) was added rel-methyl-(2R,4R)-2methylpiperidine-4-carboxylate (215 mg, 1.36 mmol), Cs ₂ CO ₃ ( 869 mg, 2.27 mmol), Pd ₂ (dba) ₃ (83 mg, 90 µmol) and BINAP (113 mg, 0.18 mmol) under N2 atmosphere. The mixture was stirred at 100°C overnight, cooled to room temperature, poured into EA (200 ml) and washed with H ₂ O (30 ml) and brine (30 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by preparative TLC (EA:PE=1:1) to obtain compound 38 as a yellow oily substance.

Example 38/1.

The following example was prepared in the same manner as described for Example 38 using the appropriate starting materials.

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Example 39.

Methyl-2-chloro-3'-(1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-3-(2-(3-fluoroazetidin-3-yl)phenyl)1 H-indole-2 -yl)-[1,1'-biphenyl]-4-carboxylate (3 9)

To a solution of compound 1/114 (30 mg, 40 µmol) in DCM (2 ml) was added TFA (0.2 ml) and the mixture was stirred at room temperature for 4 hours. The mixture was poured into water and adjusted to pH 8 with a saturated aqueous solution _NaHCO3 . The mixture was then extracted with EA and washed the organic layer with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give compound 39 as a yellow solid.

Example 40.

Methyl 2-chloro-3'-(1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-3-(2-(3-fluoro-1-methyl-azetidin-3yl)phenyl)-1 N-indol-2-yl)-[1,1'-biphenyl]-4-carboxylate (40)

Formaldehyde (0.2 ml) was added to a solution of compound 39 (27 mg, 40 μmol) in MeOH (2 ml) and the mixture was stirred at room temperature for 1 hour. Then NaBH(OAc) ₃ (82 mg, 0.37 mmol) and stirred the mixture at room temperature overnight. Water (40 ml) was added and the mixture was extracted with DCM (3x20 ml). The combined organic layer was washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=1:1) to give compound 40 as a yellow solid.

Example 41/1 and example 41/2.

Isolated atropisomers 2-chloro-3'-(3-(2-cyano-6-methylphenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol-2-yl) -[1,1'-biphenyl]-4-carboxylic acid (41/1 and 41/2)

Compound 11/36 (300 mg) was separated using chiral HPLC (instrument: Gilson-281; column: IE 20*250, 10 μm; mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA) = 55:45; recording time per sample injection: 14 min; sample injection volume: 0.4 ml; sample solution: 75 mg in 3 ml MeOH) resulting in the first eluted isomer (retention time: 10.28 min) of compound 41/1 and as the second eluted isomer (retention time: 14.35 min) of compound 41/2. NMR corresponds to example 11/36; MS: 669.0 (M-1) ^- .

Example 42.

Step 1: Methyl 4-(N-(4-fluoro-2-iodophenyl)sulfamoyl)benzoate (42a)

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To a solution of 4-fluoro-2-iodoaniline (2.00 g, 8.43 mmol) in pyridine (10 ml) was added methyl 4(chlorosulfonyl) benzoate (2.20 g, 9.40 mmol). The mixture was stirred at room temperature overnight. Add brine (40 ml) and the resulting solid was filtered, washed with EA (30 ml) and water (30 ml). The crude product was lyophilized to give compound 42a as a white solid.

Step 2: N-(4-fluoro-2-iodophenyl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide (42b)

To a solution of compound 42a (3.50 g, 8.04 mmol) in THF (30 ml), a solution of MeMgBr (2.0 M in THF, 20 ml, 40.0 mmol) was added slowly over 20 min at -78 °C. The mixture was stirred at -78°C for 6 hours, then the mixture was allowed to warm to room temperature. A saturated aqueous solution of NH4Cl (50 ml) was added and the resulting mixture was extracted with EA (3x50 ml). The combined organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give 42b as a white solid.

Step 3: Methyl-2-chloro-3'-((5-fluoro-2-((4-(2-hydroxypropan-2-yl)phenyl)sulfonamido)phenyl)ethyl)-[1,1'-biphenyl ]-4-carboxylate (42c)

To a solution of compound 42b (1.30 g, 2.98 mmol) and compound P30 (740 mg, 2.74 mmol) in dry THF (20 ml) was added CuI (23 mg, 0.12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (130 mg) and TEA (830 mg, 8.22 mmol). The mixture was stirred at 0°C for 30 min under argon and then stirred at room temperature overnight, diluted with water (30 ml) and extracted with EA (3x40 ml). The combined organic layer was washed with brine (2x50 ml), dried over Na ₂ SO ₄ , filtered, concentrated and purified with FCC (PE:EA=5:1) to give compound 42c as a pale yellow solid.

Step 4: Methyl-2-chloro-3'-(5-fluoro-1-((4-(2-hydroxypropan-2-yl)phenyl)sulfonyl)-3-iodo-1Hindol-2-yl)-[1 , 1'-biphenyl]-4-carboxylate (42d)

To a solution of compound 42c (500 mg, 0.86 mmol) and K2CO3 (368 mg, 2.67 mmol) in ACN (30 ml) was added NIS (608 mg, 2.67 mmol) at -10°C under argon. The mixture was allowed to warm to room temperature for 30 minutes and stirred overnight. The mixture was washed with saturated aqueous Na ₂ S ₂ O ₃ (3x20 ml) and extracted with DCM (2x20 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give 42d as a white solid.

Step 5: Methyl-2-chloro-3'-(3-(2-cyanophenyl)-5-fluoro-1-((4-(2-hydroxypropan-2-yl)phenyl)sulfonyl)-1 H-indol- 2-yl)-[1,1'-biphenyl]-4-carboxylate (42)

To a solution of compound 42d (350 mg, 0.49 mmol), (2-cyanophenyl)boronic acid (217 mg, 1.47 mmol) and K2CO3 (210 mg, 1.47 mmol) in a mixture of dioxane and H ₂ O (15 ml, 10:1) Pd(dppf)Cl ₂ (45 mg) was added under argon atmosphere. The mixture was stirred at 60°C for 4 hours, cooled, quenched with water (20 ml) and extracted with EA (3x20 ml). The combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative TLC (PE:EA=8:5) to give compound 42 as a yellow solid.

Example 43/1 and example 43/2.

Isolated isomers methyl-(1s,4s)-4-(3-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-fluoro-1H-indol- 2-yl)phenyl)cyclohexane-1-carboxylate (43/1) and methyl (1r,4r)-4-(3-(3-(2,6-dicyanophenyl)-1 -((4-(difluoromethyl) phenyl)sulfonyl)-5-fluoro-1 H-indol-2-yl)phenyl)cyclohexane-1-carboxylate (43/2)

To a solution of compound 8/4 (665 mg, 1.00 mmol) in MeOH (10 ml) was added Pd/C (100 mg). The mixture was stirred at room temperature for 16 hours under an H ₂ atmosphere. The catalyst was filtered and washed with MeOH (15 ml). The combined filtrates were concentrated. The residue was purified by preparative TLC (EA:PE=1:3) to give two isolated compounds 43/1 and 43/2 as white solids, respectively.

Example 44.

Step 1: Methyl 3'-((2-amino-4-fluoro-5-methoxyphenyl)ethynyl)-2-chloro-[1,1'-biphenyl]-4-carboxylate (44a)

To a solution of compound P30 (1.39 g, 5.10 mmol) in TEA (20 ml) was added Pd(PPh ₃ ) ₄ (237 mg, 205 μmol), CuI (78 mg, 0.41 mmol), PPh ₃ ( 108 mg, 0.41 mmol) and 2-bromo-5-fluoro-4-methoxyaniline (1.34 g, 6.12 mmol). The mixture was stirred at 60°C under N ₂ atmosphere overnight. The reaction mixture was cooled, filtered, concentrated and purified with FCC (PE:EA=1:1) to give compound 44a as a light yellow solid.

Step 2: Methyl-2-chloro-3'-((2-((4-(difluoromethyl)phenyl)sulfonamido)-4-fluoro-5-methoxyphenyl)ethynyl)-[1,1'-biphenyl]-4- carboxylate (44b)

To a solution of compound 44a (818 mg, 2.00 mmol) in DCM (10 ml) was added 4-(difluoromethyl)benzene1-sulfonyl chloride (542 mg, 2.40 mmol), pyridine (316 mg, 4.00 mmol) and DMAP (89 mg). The mixture was stirred at room temperature overnight, then DCM (20 ml) was added and the mixture was washed with 2N. aqueous HCl solution (2x20 ml) and saturated saline solution (40 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified using FCC (PE:DCM=1:1) to obtain compound 44b as a white solid.

Step 3: Methyl-2-chloro-3'-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-6-fluoro-5methoxy-1H-indole-2- yl)-[1,1'-biphenyl]-4-carboxylate (44c)

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To a solution of compound 44b (599 mg, 1.00 mmol) in dioxane (5 ml) was added 2-bromoisophthalonitrile (310 mg, 1.50 mmol), K ₂ CO ₃ (276 mg, 2.00 mmol) and Pd(PPh ₃ ) ₄ (47 mg, 40 µmol) in an atmosphere of N ₂ . The mixture was stirred at 90°C for 4 hours under N2 atmosphere. Once complete, the mixture was cooled to room temperature, poured into EA (20 ml) and washed with H ₂ O (2x20 ml) and brine (20 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified using FCC (EA:PE=1:1) to obtain compound 44c as a yellow solid.

Step 4: 2-Chloro-3'-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-6-fluoro-5-hydroxy-III-indol-2-yl )-[1,1'-biphenyl]-4-carboxylic acid (44)

To a solution of compound 44c (390 mg, 0.53 mmol) in CCl ₄ (10 ml) was added iodotrimethylsilane (5 ml) and Nal (159 mg, 1.06 mmol) and the mixture was stirred at 85°C overnight. The solvent was removed and the residue was divided between a saturated aqueous solution of NaS ₂ O ₃ and EA. The aqueous phase was again extracted with EA (3x20 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give compound 44 as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 8.12 (d, J=11.7 Hz, 1H), 8.10-7.93 (m, 4H), 7.70 (t, J=7, 9 Hz, 1H), 7.58-7.29 (m, 8H), 7.00 (s, 1H), 6.83-6.48 (m, 2H), MS: 696.0 (M-1 )-.

Example 45.

2-chloro-3'-(3-(2,6-dicyanophenyl)-1-((4-(difluoromethyl)phenyl)sulfonyl)-5-hydroxy-1H-pyrrolo[2,3-c]pyridine-2- yl)-[1,1'-biphenyl]-4-carboxylic acid (45)

Treatment of a solution of compound 29/3 in ACN (10 ml) with chlorotrimethylsilane and sodium iodide at reflux gives compound 45.

The following compounds can be prepared by the methods described above using appropriate building blocks:

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Initial solutions of compounds

Experimental compounds were typically dissolved, tested, and stored as 20 mM stock solutions in DMSO. Since sulfonylacetic acid derivatives undergo decarboxylation under these conditions, their stock solutions were prepared, tested, and stored as 20 mM stock solutions in DMSO containing 100 mM trifluoroacetic acid (5 eq.). Sulfonylacetic acid derivatives are stable when stored in solid form at room temperature for long periods of time, as described by Griesbrecht et al. (Synlett 2010:374) or Faucher et al. (J Med Chem 2004;47:18).

TR-FRETe activity assay

Recombinant ligand binding domain GST-LXRp (LBD; amino acids 156-461; NP009052; SEQ ID NO:4) was expressed in E. coli and purified by glutathione-Sepharose affinity chromatography. N-terminal biotinylated NCoA3 coactivator peptide (SEQ ID NO:7) was chemically synthesized (Eurogentec). Assays were performed in 384-well format (final assay volume 25 µl/well) in Tris/HCl buffer (pH 6.8) containing KCl, bovine serum albumin, Triton-X-100 and 1 µM 24(S)-25- epoxycholesterol as an LXR prestimulant agonist. Prepare assay buffer and titrate experimental compounds (potential LXR inverse agonists) to obtain final assay concentrations of 50 µM, 16.7 µM, 5.6 µM, 1.9 µM, 0.6 µM, 0.2 µM, 0.07 µM , 0.02 µM, 0.007 µM, 0.002 µM with one vehicle control. Finally, a detection mixture containing anti-GST-Tb cryptate (CisBio; 610SAXLB) and streptavidin-XL665 (CisBio; 610SAXLB) as fluorescent donor and acceptor, respectively, as well as coactivator peptide and LXRp-LBD protein (SEQ ID NO:4). The reaction mixture was thoroughly mixed, equilibrated for 1 h at 4°C, and the affinity of LXRP and the coactivator peptide was detected by measuring fluorescence in a multiplate reader (PerkinElmer Life Science) at an excitation wavelength of 340 nm and an emission wavelength of 615 and 665 nm. Analyzes were performed in triplicate.

Final analytical concentrations of components:

240 mM KCl, 1 μg/μl BSA, 0.002% Triton-X-100, 125 pg/μl anti-GST-Tb cryptate, 2.5 ng/μl streptavidin-XL665, coactivator peptide (400 nM), LXRP protein ( 530 µg/ml, i.e. 76 nM).

LXR Gal4 reporter transient transfection assay

The activity status of LXRa and LXRP was determined by detecting interactions with coactivator protein and corepressor protein in mammalian two-hybrid (M2H) experiments. To do this, full-length (FL) proteins LXRa (amino acids 1-447; NP005684; SEQ ID NO:1) or LXRp (amino acids 1-461; NP009052; SEQ ID NO:2) or ligand binding domains (LBD) were expressed by transient transfection. LXRa (amino acids 155-447 SEQ ID NO:3) or LXRp (amino acids 156-461; SEQ ID NO:4) from pCMV-AD (Stratagene) in the form of fusions with the NFkB transcriptional activation domain. Steroid receptor coactivator 1 (SRC1; amino acids 552-887; SEQ ID NO:5) or NCoR corepressor domains (amino acids 19062312; NP006302; SEQ ID NO:6) were expressed as cofactors in the form of hybrids with the DNA-binding domain of the yeast transcription factor GAL4 (from pCMV-BD; Stratagene). The interaction was determined by activation of a coexpressed firefly luciferase reporter gene under the control of a promoter containing repeated GAL4-responsive elements (vector pFRLuc; Stratagene). Transfection efficiency was controlled by cotransfection of the constitutively active Renilla reniformis luciferase repator pRLCMV (Promega). HEK293 cells were grown in minimal maintenance medium (MEM) with 2 mM L-glutamine and Earle's balanced salt solution supplemented with 8.3% fetal bovine serum, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, at 37°C in 5% CO ₂ . 3.5 x 10 ⁴ cells per well were placed in 96-well cell culture plates in a nutrient medium supplemented with 8.3% fetal bovine serum for 16-20 hours until ~90% confluence. For transfection, the medium was removed and LXR and cofactor expression plasmids and reporter plasmids were added in 30 μl of OPTIMEM medium per well containing polyethylenimine (PEI) as carrier. Typical amounts of transfected plasmids per well: pCMV-AD-LXR (5 ng), pCMV-BD-cofactor (5 ng), pFRLuc (100 ng), pRL-CMV (0.5 ng). Stock solutions of compounds were prepared in DMSO, pre-diluted in MEM to a total volume of 120 μl and added 4 h after adding the transfection mixture (the final vehicle concentration did not exceed 0.2%). Cells were incubated for an additional 16 h, lysed for 10 min in 1× passive lysis buffer (Promega), and firefly and Renilla luciferase activities in the same cell extract were measured sequentially using buffers containing D-luciferin and coelenterazine, respectively. Luminescence measurements were carried out in a BMG luminometer.

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Materials Company Cat. No. HEK293 cells DSMZ ACC305 MEM Sigma-Aldrich M2279 OPTIMEM LifeTechnologies 11058-021 FCS Sigma-Aldrich F7542 Glutamax Invitrogen 35050038 Penicillin/Straptavidin Sigma Aldrich P4333 Sodium pyruvate Sigma Aldrich S8636 Essential amino acids Sigma Aldrich M7145 Trypsin Sigma-Aldrich T3924 PBS Sigma Aldrich D8537 P.E.I. Sigma Aldrich 40.872-7 Passive lysis buffer (5x) Promega E1941 D-Luciferin PJK 260150 Coelenterazine PJK 26035

Table 1. LXR activity data

Ranges (EC50): -: no measurable activity; A: <10 µM, B: 1 µM - <10 µM, C: 100 nM - <1 µM, D: <100 nM; italics indicate that efficiency (compared to

GW2033) is less than 40%.

Example No. 1/23 1/26 1/27 1/28 1/39 1/40 1/41 1/42

1/122 1/139

2/1 2/2

2/16 2/18

3/1 3/2 3/3 3/4 3/5 3/6 3/7 3/8 3/9

3/10 3/11

3/12 3/13

3/14 3/15 3/16 3/17 3/18 3/19 3/20 3/21 3/22 3/23 3/24 3/25

3/26 3/27 3/28 3/29 3/30 3/31 3/32 3/33 3/34 3/35 3/36 3/37

3/38 3/39

FRETp LBD-M2H Gal4a LBD-M2H Gal4p FL-M2H Gal4a FL-M2H Gal4p

C B B B A B B B C C C C D C D C B B C C B B B B C B C B B B B B B C D C

B B B A B C S S

B C C C C C

D D D D

B C with D

D D

D C C D C

D C C C C C C

D D D C C D D D C D C D C C D

C C D

D C

S S S S

C D D

C D

D D D D C C C

D D D D D D C B

D C

C C

C C

C D

D C

D C D D D D C

D D D

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3/40 3/41 3/42 3/43 3/44 3/45 3/46 3/47 3/48 3/49 3/50 3/51 3/52 3/53 3/54 3/55 3/ 56 3/57 3/58 3/59 3/60 3/61 3/62 3/63 3/64 3/65 3/66 3/67 3/68 3/69 3/70 3/71 3/72 3 /73

4/1 4/2 4/3

5/1 5/2 5/3 5/4 5/5 5/6 5/7 5/8 5/9

5/10 6

6/1 6/2 6/3

8/1 8/3 8/7 8/8

10/1

B B B B B B C C S C B C D C C D C B D C C C D C C B C C C C D D D B B B B C C C C B C C C C C B C C s D C C C C D C D

C C

D

D

D C

D

D

C C D C D D D

D D

D D D C D D D D D

C D D D D D D D D C C D D D C C D C C D D D D C C D B B C

C C D C C C C D D D D C D C C D D D

C D D D D D D D D C D D D D C C D C C D D D C D C D B C C D D C D D C D C D D D D D D D D D C D

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10/2 D D D 10/3 D D D 10/4 D C D eleven D D D 11/1 D D D 11/2 D D D 11/3 D D D 11/4 C D D 11/5 D D D 11/6 D D D 11/7 D D D 11/8 D D D 11/9 D D D 11/10 D D D 11/11 D D D 11/12 D D D 11/13 D D D 11/14 D D D 11/15 D D D 11/16 C D D 11/17 D D D 11/18 C D D 11/19 C D D 11/20 C D D 11/21 D D D 11/22 D D D 11/23 D D D 11/24 C C C 11/25 C C D 11/26 D D D 11/27 D D D 11/28 D D D 11/29 D D D 11/30 D D D 11/31 D D D 11/32 D D D 11/33 D D D 11/34 D D D 11/35 D D D 11/36 D D D 11/37 D D D 11/38 D D D C11/39 C D D 11/40 C D D 11/41 D D D 11/42 A C C 11/43 C C C 11/44 D D D 11/45 D D D 11/46 D D D 11/47 C C C C11/48 D D D 11/49 D D D 11/50 D D D 11/51 D D D 11/52 D D D 11/53 D D D 11/54 D D D 11/55 D D D 11/56 D D D

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11/57 D 11/58 D 11/59 D 11/60 11/61 C 11/62 C 11/63 C 11/64 C 11/65 D 11/66 C 11/67 C 11/68 D 11/69 D 12 C 12/1 C 12/2 C 12/3 C 12/4 C 12/5 D 12/6 IN 12/7 C 12/8 IN 12/9 C 12/10 D 13 C D D 13/1 IN D D 15 A IN A 15/1 IN WITH WITH 15/2 A WITH WITH 15/3 A — — 15/4 IN With D 15/5 IN D D 15/6 IN — WITH 17 A — IN 19 A — — 20 C D D 20/2 IN WITH D 20/3 C D D 20/4 IN D D 20/5 IN WITH WITH 20/6 WITH WITH D 20/7 IN WITH D 20/11 WITH D D 20/12 IN D D 20/13 WITH D D 20/14 WITH D D 20/15 WITH — WITH 20/16 IN WITH WITH 20/17 — WITH 20/18 — WITH D 20/19 A With WITH 20/20 IN V WITH 20/21 IN With D 20/22 WITH With WITH 20/23 IN With WITH 21 A — IN 21/1 IN V IN 21/2 IN V IN 21/3 D 22 IN With WITH

D D D D D D D D D D D D D D D D D D D C C C C D

D D D D D D D D D D D D D D D D D D D B C C C D

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23/1 23/2 23/3

25

26/1

27/1 27/2 27/3

30/1 30/2 30/3 30/4 30/5 30/6 30/7 30/8 30/9

30/10 30/11 30/12 30/13 30/14 30/15 30/16

32/1 32/2 32/4 32/5

36/1

37/1 41/1 41/2

A B C C B B C B in in A B C C B

B B B c c c A C B C B c c c c c D D B C C C D D C

B D C C C C C C D C C

S B S S S

S S S

WITH

D

D D

D D

D D

D D

WITH

C D D C C D D C D C D

D C D C C

WITH

C C D

C D D C D D C D D D

C D D

C D D

C D D D

Pharmacokinetics

The pharmacokinetics of the compounds were assessed in mice after single dosing and oral administration. Contents in blood/plasma and liver were measured using LC-MS.

Below is the research plan:

Animals: Males C57/bl6/J (Janvier)

Food: standard rodent food

Dose: 20 mg/kg

Animal management: animals were left without food for at least 12 hours before administration

Design: single dose oral administration, n=3 animals per group

Euthanasia: at the indicated time (4, 12 or 24 hours) after administration

Bioanalytical methods: LC-MS of liver and blood/plasma samples

Table 2. Study results

Ranges:

content in blood/plasma: A: >1 µM, B: 300 nM -< <1 µM, C: 100 nM - <300 nM, D: <100 nM;

content in the liver: A: <300 nM, B: 300 nM - <1 µM, C: 1 µM - <3 µM, D: >3 µM; attitude

content in liver/plasma: A: <3, B: : 3 -<10, C: 10 -<30, D: >30; Example No. moment contents in contents in attitude time blood/plasma liver contents in (h.) liver/plasma GSK2033 I below NLQ below NLQ (comparative example) 4 (14.4 ng/ml) (9.6 ng/ml) SR9238 (comparative example) 4 below NLQ below NLQ - 3/24 4 D WITH D 3/48 12 below LOQ (1.2 ng/ml) A - 5/3 4 WITH WITH WITH 8 4 IN D IN 23/2 4 V D WITH 30/4 4 With WITH With 30/7 4 D IN D

We have confirmed that the structurally unrelated LXR inverse agonists GSK2033 and SR9238 are not orally bioavailable. The compounds of the present invention have been found to be orally bioavailable and the compounds effectively reach the target liver tissue, which may minimize systemic exposure, which is undesirable.

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Mouse model of short-term HFD

The in vivo transcriptional regulation of several LXR target genes by LXR modulators in mice was assessed.

For this purpose, C57BL/6J mice, 8 weeks old, were purchased from Elevage Janvier (Rennes, France). After acclimatization for two weeks, the animals were pre-fed a high-fat diet (HFD) (Ssniff Spezialdiaten GmbH, Germany, Surwit EF D12330 mod, cat. no. E15771-34), in which 60% of kcal comes from fat, with an additional cholesterol content 1 % (w/w) (Sigma-Aldrich, St. Louis, MO) for 5 days. Animals were maintained on the indicated diet throughout treatment with LXR modulators. Experimental compounds were formulated in 0.5% hydroxypropyl methylcellulose (HPMC) and administered in three doses (1.5 to 20 mg/kg each) via gastric tube according to the following schedule: on the first day, animals received the drug in the morning and evening (approx. 17:00), on the second day the animals received the last dose of the drug in the morning after 4 hours of no access to food, and after 4 hours they were euthanized. Work with animals was carried out in accordance with the national rules for the care and use of animals in Germany.

Once completed, the livers were collected, immersed in ice-cold PBS for 30 s, and cut into suitable pieces. The resulting pieces were quickly frozen in liquid nitrogen and stored at -80°C. For clinical chemistry analysis, plasma alanine aminotransferase (ALT, IU/mL), cholesterol (CHOL, mg/dL) and triglycerides (TG, mg/dL) were determined using a fully automated benchtop analyzer (Respons®910, DiaSys Greiner GmbH, Flacht , Germany) with system kits provided by the manufacturers.

Analysis of gene expression in liver tissue. To obtain total RNA from frozen liver tissue, samples (25 mg liver tissue) were first homogenized with RLA buffer (4 M guanidine thiocyanate, 10 mM Tris, 0.97% w/v β-mercaptoethanol). RNA was prepared using the SV 96 Total RNA Isolation System (Promega, Madison, WI, USA) according to the manufacturer's instructions. cDNA was synthesized from 0.8–1 μg of total RNA using All-in-One Supermix cDNA reverse transcriptase (Absource Diagnostics, Munich, Germany). qPCR and analysis were performed using a Prime time gene expression master mix (Integrated DNA Technologies, Coralville, Iowa, USA) and an ABI 7900HT 384-well sequence detection system (Applied Biosystems, Foster City, USA). The expression of the following genes was analyzed: Stearoyl-CoA desaturase 1 (Scd1), fatty acid synthetase (Fas), and sterol regulatory element binding protein 1 (Srebp1). Specific primer and probe sequences (commercially available) are listed in Table. 3. qPCR was performed at 95°C for 3 min, followed by 40 cycles at 95°C for 15 s and 60°C for 30 s. All samples obtained in one RT reaction were tested in duplicate. Gene expression was expressed in arbitrary units and normalized to housekeeping gene TATA box binding protein (Tbp) mRNA using the comparative Ct method.

Table 3. Primers used for quantitative PCR

Gene Direct primer Reverse primer Probe sequence CCCCTCTGTTAATTGGC TTGTGGAAGTGCAGGTT CAGGCTCAGGGTGTCCC Fasn TCC (SEQ ID NO:8) AGG (SEQ ID NO:9) ATGTT (SEQ ID NO: 10) CTGACCTGAAAG CCGAG AGAAGGTGCTAACGAA TGTTTACAAAAGTCTCGC Scd1 AAG CAGG CCCAGCA (SEQ ID NO:11) (SEQ ID NO: 12) (SEQ ID NO: 13) Srebplc CCATCGACTACATCCGC GCCCTCCATAGACACAT TCTCCTGCTTGAGCTTCT TTC (SEQ ID NO: 14) CTG (SEQ ID NO: 15) GGTTGC (SEQ ID NO: 16) CACCAATGACTCCTATG CAAGTTTACAGCCAAGA ACTCCTGCCACACCAGC Tbp ACCC TTCACG CTC (SEQ ID NO: 17) (SEQ ID NO: 18) (SEQ ID NO: 19)

Table 4. Study results Ranges:

plasma content: A: >1 µM, B: 300 nM - <1 µM, C: 100 nM - <300 nM, D: <100 nM; content in the liver: A: <300 nM, B: 300 nM - <1 µM, C: 1 µM - <10 µM, D: >10 µM; liver/plasma ratio: A: <5, B: 5 -<30, C: 30 -<100, D: >100;

gene suppression: A: >0.9, B: 0.6-<0.9, C: 0.3-<0.6, D: <0.3;

No. example dose [mg/kg] plasma content 4 hours. content in the liver 4 hours liver/plasma ratio 4 hours 3/48 20 D WITH WITH 3/59 20 WITH WITH IN 3/64 20 WITH D D

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3/73 10 D IN C 5/3 20 D C IN 8/8 10 WITH IN IN 10/1 10 D IN WITH 10/2 10 D D IN 11/11 20 D D D 11/12 20 D C WITH 11/13 20 A C A 11/16 20 C C IN 11/17 20 C D WITH 11/23 20 C C IN 11/26 10 C C WITH 11/27 20 D C WITH 11/33 20 C C WITH 11/37 10 D C WITH 11/49 20 D C D 11/51 10 D C WITH 11/53 10 D C WITH 11/62 10 C C IN 11/63 10 D C IN 11/65 10 D C WITH 21/3 10 D C D 23/2 20 C A A 32/5 10 D IN IN Example No. Fasn suppression compared to vehicle Srebplc suppression compared to vehicle Suppression of Scd1 compared to vehicle 3/48 20 D D D 3/59 20 C D WITH 3/64 20 IN IN D 3/73 10 A D D 5/3 20 D C WITH 8/8 10 D D D 10/1 10 D D D 10/2 10 C C WITH 11/11 20 C D D 11/12 20 C D D 11/13 20 C D D 11/16 20 A IN WITH 11/17 20 C D D 11/23 20 C D D 11/26 10 D D WITH 11/27 20 C A D 11/33 20 IN D D 11/37 10 D D D 11/49 20 C C D 11/51 10 D D D 11/53 10 D D D 11/62 10 D D D 11/63 10 C D WITH 11/65 10 D D D 21/3 10 C D D 23/2 20 C D D 32/5 10 C C WITH

Oral dosing of mice three times over two days (morning and evening of the first day, morning of the second day) of the compounds of the present invention results in high hepatic exposure with a favorable liver/plasma ratio. Hepatic LXR target genes were effectively downregulated. These genes are involved in the transcriptional regulation of hepatic de-novo lipogenesis (Wang et al., Nat. Rev. Mol. Cell Biol. 2015; 16:678). Suppression of these genes leads to a decrease in liver fat (liver triglycerides).

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Claims (19)

Comparative examples Example 302 Comparative Example C3'29 -RET 1,551 nM (-98%) ^RETS 4,228 nM (-102%) LBD-M2H Gal4« Ш nH (W'3%) -НМ2Н Gal4r. inactive LBD-M2F З14|1 13 nН (81%) -L-M2H G?l4;i inactive Example 1103 ^C RET,I 19 nM (-99%) Ch.-M2N Gal4u 13nMI64%) Ch -M2H GahlH 1 7 NM (130%) Comparative example C11’48 FRET0 49 nN (-96%) FL-M24 Ga!4u 62 ΗM (118%) P-M7Ch GaK|i 37 nN (173%) Comparative example C1109 FRETh OKnM (-91%) FL-M2HGdl4u 14 nM (117%) FL-M2H Gal4|l 14 nH., 140% I Comparative examples illustrate that an advantage can be provided if the cyclic moiety at the 3-position of the indole (or analog) has at least one substituent in the 1,2 orientation (ortho substituent). CLAIM 1. The compound represented by formula (I) its conjugate with glycine, tauroconjugate, enantiomer, diastereomer, tautomer and pharmaceutically acceptable salt, where it is an annulated 5-6-membered ring forming a 6-membered aryl or 5-6-membered heteroaryl containing from 1 to 3 heteroatoms independently selected from N , O and S, wherein said ring is unsubstituted or substituted with 1-4 substituents independently selected from the group consisting of halogen, CN, SF5, NO ₂ , C ₁ _ ₆ alkyl, oxo, C ₀ _ ₆ alkylene-OR ¹¹ , C ₀ - ₆ alkylene-(3-6-membered cycloalkyl), C ₀ - ₆ alkylene-(3-6-membered heterocycloalkyl), C ₀ - ₆ alkylene-S(O) _n R ¹¹ , С ₀ _ ₆ αlkylene-NR ¹¹ S(O)2R ¹¹ , C0-6alkylene-S(O) ₂ NR ¹¹ R ¹² , C0_6alkylene-NR ¹¹ S(O)2NR ¹¹ R ¹² , С0_6alkylene-CO2R ¹¹ , O-C1_ _{6 alkylene} -CO ₂ R ¹¹ , C0_6αalkylene-O-COR ¹¹ , C0_ ₆ alkylene-CONR ¹¹ R ¹² , _{C0_6} alkylene-NR ¹¹ -COR ¹¹ , C ₀ _ ₆ αlkylene-NR ¹¹ -CONR ¹¹ R ¹² , C0_6 alkylene-O-CONR ¹¹ R ¹² , C0_ ₆ αlkylene-NR ¹¹ -CO2R ¹¹ and C0_ ₆ alkylene-NR ¹¹ R ¹² , where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO ₂ H, CO ₂ -C1- ₄ alkyl, CONHCH ₂ CO ₂ H, CONH(CH ₂ ) ₂ SO ₃ H, C ₁ _ ₄ αlkyl, halogen-C1_ ₄ alkyl, O-C1- ₄ alkyl and O-halogen-C ₁ _ ₄ alkyl; wherein optionally two adjacent substituents on the aryl or heteroaryl fragment form a 5-8-membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and the newly formed ring is unsubstituted or substituted 1- 3 substituents independently selected from halogen, CN, C ₁ - ₄ alkyl, ^halo -C 1 - ₄ alkyl, 3-6 membered cycloalkyl, halogen-(3-6 membered cycloalkyl), 3-6 membered heterocycloalkyl, halogen-(3-6-membered heterocycloalkyl), OH, oxo, CO ₂ H, CO ₂ -C1- ₄ alkyl, CONHCH ₂ CO ₂ H, CONH(CH ₂ ) ₂ SO ₃ H, O-C1- ₄ alkyl and O-haloC1- ₄ alkyl; ® is selected from the group consisting of 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from N, O and S, 6-14 membered aryl and 5-14 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, SF5, NO ₂ , oxo, C ₁ _ ₄ αlkyl, C ₀ _ ₆ alkylene-OR ²¹ , C0-6alkylene-(3-6-membered cycloalkyl), C0-6alkylene-(3-6-membered heterocycloalkyl), C0_6αalkylene-S(O)R ²¹ , C0_ ₆ alkylene-NR ²¹ S(O)2R ²¹ , C0- ₆ alkylene-S(O) ₂ NR ²¹ R ²² , _C0 - ₆ alkylene-139 045482 NR ²¹ S(O)2NR ²¹ R ²² , C0. ₆ alkylene-СО2R ²¹ , О-С1.6alkylene-СО2R ²¹ , С0-6alkylene-O-COR ²¹ , _{С0_6} alkyleneCONR ²¹ R ²² , Co-balkylene-NR ²¹ -COR ₂₁ , Co-balkylene-NR ^{21 -} CONR ²¹ R ²² , Co-balkylene-O-CONR ²¹ R ²² , C _0-b alkylene-NR ²¹ -CO2R ²¹ and C0-balkylene-NR ²¹ R ²² , where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-b substituents independently selected from halogen, CN, oxo, hydroxy, CO ₂ H, CO ₂ -C _1-4 alkyl, CONHCH ₂ CO ₂ H, CONH(CH ₂ ) ₂ SO ₃ H, C _1-4 alkyl, halogen-C _1-4 alkyl, OC _1-4 alkyl and O- halogen-C _1-4 αlkyl, and optionally two adjacent substituents on the aryl or heteroaryl fragment form a 5-8-membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms, independently selected from O, S or N, and at the same time said additional ring is unsubstituted or substituted with 1-4 substituents independently selected from halogen, CN, oxo, OH, CO ₂ H, CO ₂ -C _1-4 alkyl, CONHCH ₂ CO ₂ H, CONH(CH ₂ ) ₂ SO ₃ H, C ₁ . ₄ αlkyl, halogen-C ₁ . ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C ₁ . ₄ alkyl, and optionally two adjacent substituents on the cycloalkyl or heterocycloalkyl moiety form a 5-membered unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, wherein said additional ring is unsubstituted or substituted 1-4 substituents independently selected from halogen, CN, oxo, OH, CO ₂ H, CO ₂ -C _1-4 alkyl, CONHCH ₂ CO ₂ H, CONH(CH ₂ ) ₂ SO ₃ H, C ₁ _ ₄ α alkyl , halogen-C ₁ _ ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C ₁ _ ₄ alkyl; selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl containing from 1 to 3 heteroatoms independently selected from N, O and S, wherein the aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of halogen, CN, SF ₅ , NO ₂ , oxo, C ₁ . ₄ alkyl, C ₀ . _b αlkylene-OR ³¹ , C0-6alkylene-(3-6-membered cycloalkyl), C0-6alkylene-(3-6-membered heterocycloalkyl), C0_6alkylene-(6-membered aryl), C0-6alkylene-(5-6-membered heteroaryl ), C0.6alkylene-S(O)nR ³¹ , C0-6alkyleneNR ³¹ S(O)2R ³¹ , _{C0_6} αalkylene-S(O)2NR ³¹ _R ³² , C0_6alkylene-NR ³¹ S(O) ^{2NR 31} _R ³² , С0_6alkylene-CO2R ³¹ , О-С1- ₆ alkylene-CO ₂ R ³¹ , С0_6alkylene-О-COR ³¹ , С0_ ₆ alkylene-CONR ³¹ R ³² , C0_6alkylene-NR ³¹ -COR ³¹ , С0_ ₆ alkylene-NR ³¹ CONR ³¹ R ³² , С0_6alkylene-О-CONR ³¹ R ³² , C0_ ₆ alkylene-NR ³¹ -CO2R ³¹ and С0_ ₆ αlkylene-NR ³¹ R ³² , where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted 1- 6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO2C _1-4 alkyl, CONHCH ₂ CO ₂ H, CONH(CH ₂ ) ₂ SO ₃ H, C ₁ . ₄ alkyl, halogen-C1_ ₄ alkyl, OC ₁ . ₄ alkyls and Ohalo-C1-4alkyls; and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO ₂ H, CO ₂ -C _1-4 alkyl, CONHCH ₂ CO ₂ H, CONH(CH ₂ ) ₂ SO ₃ H, C ₁ _ ₄ α alkyl, halogen-C ₁ _ ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C ₁ _ ₄ alkyl; ® is selected from the group consisting of 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from N, O and S, 6-14 membered aryl and 5-14 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, SF ₅ , NO ₂ , oxo , C ₁ . ₄ αlkyl, C ₀ . ₆ alkylene-OR ²¹ , C0-6alkylene-(3-6-membered cycloalkyl), C0-6alkylene-(3-6-membered heterocycloalkyl), C0.6alkylene-S(O)nR ²¹ , C0. ₆ alkylene-NR ²¹ S(O)2R ²¹ , C0. ₆ alkylene-S(O) ₂ NR ²¹ R ²² , C0.6alkyleneNR ²¹ S(O)2NR ²¹ R ²² , C0-6αalkylene-CR ⁴¹ (=N-OR ⁴¹ ), C0. ₆ alkylene _- CO ₂ R ²¹ , O-C1.6αalkylene-CO2R ²¹ , C0- ₆ ^alkyleneO -COR ²¹ , C0_6alkylene-CONR ²¹ R ²² , C0_ 6alkylene-NR ²¹ -COR 21 , C0_6αalkylene-NR ²¹ -CONR ²¹ R ²² , C0- ₆ alkylene-ОCONR ²¹ R ²² , C0_6alkylene-NR ²¹ -CO2R ²¹ and C0- ₆ αlkylene-NR ²¹ R ²² , where alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO ₂ H, CO ₂ -C _1-4 alkyl, CONHCH ₂ CO ₂ H, CONH(CH ₂ ) ₂ SO ₃ H, CO-OC ₁ _ ₄ alkyl, C ₁ . ₄ alkyl, halo-C _{1_4} alkyl, O-C _1-4 alkyl and O-halo-C _1-4 alkyl _; and wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO ₂ H, CO ₂ -C _1-4 alkyl, CONHCH ₂ CO ₂ H, CONH(CH ₂ ) ₂ SO ₃ H, C ₁ . ₄ αlkyl, halogen-C _1-4 alkyl, OC ₁ . ₄ αlkyl and O-halogen-C ₁ . ₄ alkyl; and optionally two adjacent substituents on the cycloalkyl or heterocycloalkyl fragment form a 5-6-membered unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, - 140 045482 wherein said additional ring is unsubstituted or substituted with 1-4 substituents independently selected from halogen, CN, oxo, OH, CO2H, CO ₂ -C1. ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, C ₁ . ₄ αlkyl, halogen-C ₁ . ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C ₁ . ₄ alkyl; 1(d) 1 t OO _x O has a substituent of the above in position 1,2 relative to the bond with n or has an annulated additional ring in position 1, 2; L is selected from the group consisting of the bond, C ₁ . ₆ αalkylene, C ₂ balkenylene, C ₂ balkynylene, 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene containing from 1 to 4 heteroatoms independently selected from N, O and S, 6- or 10-membered arylene and 5 -10-membered heteroarylene containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene are unsubstituted or substituted with 1-6 substituents independently selected from the group, consisting of halogen, CN, SF ₅ , NO2, oxo, C ₁ . ₄ αlkyl, C ₀ . ₆ αlkylene-OR ⁴¹ , C0_6alkylene-(3-6-membered cycloalkyl), C0_6alkylene-(3-6-membered heterocycloalkyl), C0.6alkylene-S(O)nR ⁴¹ , C0_ ₆ alkyleneNR ⁴¹ S(O)2R ⁴¹ , Co-6alkylene-S(O)2NR ⁴¹ R ⁴² , Co-6alkylene-NR ⁴¹ S(O)2NR ⁴¹ R ⁴² , Co.6alkylene-CO2R ⁴¹ , O-C^alkylene-cO2R ⁴¹ , C0. ₆ alkylene-O-COR ⁴¹ , C0.6 alkylene-CONR ⁴¹ R ⁴² , C0. ₆ alkylene-NR ⁴¹ -COR ⁴¹ , C ₀ - ₆ alkylene-NR ⁴¹ CONR41R ⁴² , Co.6alkylene-O-CONR ⁴¹ R ⁴² , Co-6alkylene-NR ⁴¹ -CO2R ⁴¹ and Co.6alkylene-NR ⁴¹ R ⁴² , where alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO ₂ H, CO ₂ -C1_ ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H , C ₁ . ₄ alkyl, halogen-C1_ ₄ alkyl, OC ₁ . ₄ alkyls and O-halo-C ₁ . ₄ αlkyl; and wherein optionally two adjacent substituents on the arylene and heteroarylene moieties form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO ₂ H, CO ₂ -C1_ ₄ alkyl, C ₁ . ₄ alkyl, haloC1_ ₄ alkyl, OC ₁ . ₄ alkyl and O-halo-C ₁ . ₄ αlkyl; R ¹ is selected from the group consisting of H, halogen, CN, SF5, NO2, oxo, C1_4alkyl, C0.6αalkylene-OR ⁴¹ , Y-C0. ₆ alkylene-(3-6-membered cycloalkyl), Y-C ₀ . ₆ alkylene-(3-6-membered heterocycloalkyl), Y-C ₀ . ₆ alkylene-(6-membered aryl), Y-C ₀ . ₆ αalkylene-(5-6-membered heteroaryl), C ₀ . ₆ alkylene-S(=O)(-R ⁴¹ )=NR ⁷⁵ , XC1.6alkylene-S(=O)(-R ⁴¹ )=NR ⁷⁵ , C0. ₆ alkylene- ^S (O) _nR41 , X-C1.6alkylene-S(O) ^nR41 , C0. ₆ alkylene-S(=NR ⁷¹ )R ⁴¹ , X-C1.6alkylene-S(=NR ⁷¹ )R ⁴¹ , C0. ₆ alkylene-S(O)(=NR ⁷¹ )R ⁴¹ , X-C1.6alkylene-S(O)(=NR ⁷¹ )R ⁴¹ , C0_ ₆ alkyleneS(=NR ⁷¹ )2R ⁴¹ , X-C1.6αalkylene- S(=NR ⁷¹ )2R ⁴¹ , Co.6alkylene-NR ⁴¹ S(O)2R ⁴¹ , X-C1.6αalkylene-NR ⁴¹ S(O)2R ⁴¹ , Co.6alkylene-S(o)2NR ⁴¹ R ⁴² , X-C1. ₆ alkylene-S(O) ₂ NR ⁴¹ R ⁴² , С0.6alkylene-NR ⁴¹ S(O)2NR ⁴¹ R ⁴² , X-C1.6alkyleneNR ⁴¹ S(O)2Nr ⁴¹ R ⁴² , С0.6αalkylene-SO3R ⁴¹ , X-C1. ₆ alkylene-SO ₃ R ⁴¹ , Co.6alkylene-CO2R ⁴¹ , X-C1. ₆ alkylene-CO ₂ R ⁴¹ , C0.6αalkylene-O-COR ⁴¹ , X-C1. ₆ alkylene-O-COR ⁴¹ , C0.6alkylene-CONR ⁴¹ R ⁴² , X-C1. ₆ alkylene-CONR ⁴¹ R ⁴² , C0.6alkylene-CONR ⁴¹ OR ⁴¹ , X-C1. ₆ alkylene-CONR ⁴¹ OR ⁴¹ , C0.6alkylene-CONR ⁴¹ SO2R ⁴¹ , X-C1.6alkyleneCONR41SO2R ⁴¹ , Co.6αalkylene-NR ⁴¹ -COR ⁴¹ , X-C1.6Co.6alkylene-NR ⁴¹ -COR ⁴¹ , Co. 6alkylene-NR ⁴¹ -CONR ⁴¹ R ⁴² , XC1. ₆ alkylene-NR ⁴¹ -CONR ⁴¹ R ⁴² , C0.6alkylene-O-CONR ⁴¹ R ⁴² , X-C1. ₆ alkylene-O-CONR ⁴¹ R ⁴² , C0.6alkylene-NR ⁴¹ CO2R ⁴¹ , X-C1. ₆ alkylene-NR ⁴¹ -CO2R ⁴¹ , C0. ₆ alkylene-NR ⁴¹ R ⁴² , XC ₁ . ₆ alkylene-NR ⁴¹ R ⁴² where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-6 substituents independently selected from halogen, CN, oxo, hydroxy, CO2H, CO2C1. ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, C ₁ . ₄ alkyl, halogen-C1_ ₄ alkyl, OC ₁ . ₄ alkyl and Ohalogen-C1_ ₄ alkyl; and wherein optionally two adjacent substituents on the aryl and heteroaryl moieties form a 5-8 membered partially unsaturated ring, optionally containing from 1 to 3 heteroatoms independently selected from O, S or N, and wherein said additional ring is unsubstituted or substituted 1 -4 substituents independently selected from halogen, CN, oxo, OH, CO ₂ H, CO ₂ -C1_ ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, C ₁ . ₄ αlkyl, halogen-C1_ ₄ alkyl, OC ₁ . ₄ αlkyl and O-halogen-C ₁ . ₄ alkyl; R ¹¹ , R ¹² , R ²¹ , R ²² , R ³¹ , R ³² , R ⁴¹ , R ⁴² , R ⁵¹ are independently selected from H and C ₁ . ₄ alkyl, wherein the alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halogen, CN, C ₁ . ₄ alkyl, halogen-C1_ ₄ alkyl, 3-6-membered cycloalkyl, halogen-(3-6-membered cycloalkyl), 3-6-membered heterocycloalkyl, halogen-(3-6-membered heterocycloalkyl), OH, oxo, CO ₂ H, CO ₂ -C1. ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, SO ₃ H, OC ₁ . ₄ alkyl and O-halo-C1_ ₄ alkyl; or R ¹¹ and R ¹² , R ²¹ and R ²² , R ³¹ and R ³² , R ⁴¹ and R ⁴² , respectively, together with the nitrogen atom to which they are attached, complete a 3-6 membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms independently selected from O, S or N; and wherein the newly formed ring is unsubstituted or substituted with 1-3 substituents independently selected from halogen, CN, C ₁ . ₄ alkyl, halogen-C1_ ₄ alkyl, 3-6-membered cycloalkyl, halogen-(3-6-membered cycloalkyl), 3-6-membered heterocycloalkyl, halogen-(3-6-membered heterocycloalkyl), OH, oxo, CO ₂ H, CO ₂ -C1. ₄ alkyl, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, SO ₃ H, OC ₁ . ₄ alkyl and Ohalo-C1_ ₄ alkyl; - 141 045482 R ⁷¹ is independently selected from H, CN; NO2, C _1-4 alkyl and C(O)-OC _1-4 alkyl, wherein the alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halogen, CN, C ₁ . ₄ alkyl, halogen-C1. ₄ alkyl, 3-6-membered cycloalkyl, halogen-(3-6-membered cycloalkyl), 3-6-membered heterocycloalkyl, halogen-(3-6-membered heterocycloalkyl), OH, oxo, СО2Н, СО2- _См alkyl, CONHCH2CO2H, СОХШЧСШ^ОзН, SO3H, O-Smalkyl and O-halogen-С _m alkyl; R ⁷⁵ is independently selected from C1_ ₄ alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-membered aryl and 5-6 membered heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted 1 -3 substituents independently selected from halogen, CN, Me, Et, CHF2, CF3, OH, oxo, CO ₂ H, CONHCH2CO2H, CONH(CH ₂ ) ₂ SO ₃ H, SO3H, OMe, OEt, OCHF2 and OCF3; X is independently selected from O, NR ⁵¹ , S(O) _n , S(=NR ⁷¹ ), S(O)(=NR ⁷¹ ) and S(=NR ⁷¹ )2; Y is independently selected from the bond, O, NR ⁵¹ , S(O)n, S(=NR ⁷¹ ), S(O)(=NR ⁷¹ ) and S(=NR ⁷¹ )2; n independently selected from 0 to 2; and provided that the following structures are excluded: 2. A compound according to claim 1, wherein it is selected from: wherein it is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, oxo, C1. ₄ alkyl, halogen-C1. ₄ alkyl, OC ₁ . ₄ alkyl, O-halo-C ₁ . ₄ alkyl, NH2, NHC ₁ _ ₄ alkyl, N(C ₁ . ₄ alkyl) ₂ , SO ₂ -C ₁ . ₄ alkyl and SO ₂ -halogen-C ₁ _ ₄ alkyl. 3. A compound according to claim 1 or 2, in which ® is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidinyl, thiophenyl, thiazolyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl , bicyclo[2.2.1]heptyl, pentacyclo[4.2.0.0 ^2.5 .0 ^3.8 .0 ^4.7 ]octyl and piperidinyl, wherein said ring is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting from F, Cl, Br, CN, OH, oxo, C _1-4 alkyl, halogen-C1. ₄ alkyl, OC ₁ . ₄ alkyl, O-halo-C ₁ _ ₄ alkyl, C1. ₄ alkyl-OH and halogen-C1_ ₄ alkyl-OH; and optionally two adjacent substituents on the phenyl ring together form the group -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, -OCF2O- and -OCH2O-. 4. A compound according to any one of claims 1-3, in which © is selected from phenyl, pyridyl and thiophenyl; wherein phenyl, pyridyl and thiophenyl are unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of F, Cl, CN, OH, oxo, C1. ₄ alkyl, halogen-C1. ₄ alkyl, OC ₁ . ₄ alkyl and O-halo-C ₁ . ₄ alkyl; and at the same time the remainder t π 1 „ _ „ 1 o _ _ „ YaO -L-R is bonded at position 1,3 relative to the bond to ν, and L is not a connection. 5. The connection according to any one of claims 1-4, in which -LR ¹ selected from wherein said ring is unsubstituted or additionally substituted with 1-4 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, oxo, C1. ₄ alkyl, halogen-C1. ₄ alkyl, O-C1_ ₄ alkyl, O-halo-C1_ ₄ alkyl, C1_ ₄ alkyl-OH, halogen-C1_ ₄ alkyl-OH, SO ₂ -C _{1_ 4} alkyl and SO ₂ -haloC1. ₄ alkyl; and optionally two adjacent substituents on the phenyl ring together form the group -(CH2)3-, -(CH2)4-, -OCF2O- and -OCH2O-. - 142 045482 6. The connection according to any one of claims 1-5, in which R ¹ is selected from CO ₂ H, tetrazole, CH ₂ CO ₂ H, OCH ₂ CO ₂ H, SO ₂ CH ₂ CO ₂ H, CHMeCO ₂ H, CMe ₂ CO ₂ H, C(OH)MeCO ₂ H, CONHSO ₂ Me and CONH(OH); and optionally its glycine and tauroconjugate. and optionally its glycine and tauroconjugate. 8. A compound according to any one of claims 1 to 7, wherein ® is selected from the group consisting of where R ² is selected from Me, F, Cl, CN, Me, CHO, CHF ₂ , CF3, SO ₂ Me, and is optionally further substituted with 1-2 substituents selected from the group consisting of F, Cl, CN, Me, OMe, CHO, CHF2 and CF3. 9. The compound according to any one of claims 1 to 8, in which it is selected from the group consisting of 10. A compound according to any one of claims 1 to 9, in which formula (I) contains a substituent selected from the group consisting of CO ₂ H, tetrazole, CONHSO ₂ Me and CONH(OH); and optionally its glycine and tauroconjugate. 11. The connection according to any one of claims 1-10, in which R ¹ LR ¹ represents > wherein said ring is unsubstituted or further substituted with 1-4 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, oxo, C _1-4 alkyl, halogen-C1- ₄ alkyl, OC ₁ _ ₄ alkyl, O-halo-C1_ ₄ alkyl, C ₁ _ ₄ alkyl-OH, halogen-C1_ ₄ alkyl-OH, SO ₂ -C _{1_4} alkyl and SO ₂ -halogen- _{C 1_4 alkyl ;} and optionally two adjacent substituents on the phenyl ring together form the group -( _CH2 )3-, -( _CH2 ) _4- , -OCF2O- and -OCH2O-. 12. The connection according to any one of claims 1-11, in which R ¹ represents C0_6alkylene-CO2R ⁴¹ or _{C0_6} alkylene-CONR ⁴¹ R ⁴² , or its glycine and tauroconjugate. 13. A compound according to any one of claims 1 to 12, in which R ¹ represents COOH, or a glycine and tauroconjugate thereof. 14. A compound according to any one of claims 1 to 12, in which R ¹ represents C ₀ _ ₆ alkylene-CONR ⁴¹ R ⁴² . 15. A compound according to claim 14, wherein R ⁴¹ and R ⁴² are independently selected from H and _C1-4 alkyl, wherein the _C1-4 alkyl is unsubstituted or substituted with CO ₂ H. 16. The compound according to any one of claims 1-11, in which o Uon fl /=/ Cl LR ¹ is either its glycine and tauroconjugate. 17. A compound according to any one of claims 1 to 16, wherein said compound is a glycine conjugate. 18. The connection according to any one of claims 1-17, which is 19. The connection according to any one of claims 1-17, which is or its glycine conjugate. 20. The connection according to any one of claims 1 to 17, selected from - 144 045482 or a glycine or tauroconjugate thereof; and an enantiomer, diastereomer, tautomer and pharmaceutically acceptable salt thereof. 21. Use of a compound according to any one of claims 1 to 20 as a medicine. - 145 -