Liver X Receptor (LXR) modulators

文档序号：1785618 发布日期：2019-12-06 浏览：31次中文

阅读说明：本技术 肝x受体(lxr)调节剂 (Liver X Receptor (LXR) modulators ) 是由 C·盖格 M·伯克尔 E·汉布鲁克 U·多伊施勒 C·克里莫瑟于 2018-04-10 设计创作，主要内容包括：本发明涉及含有磺酰胺、亚磺酰胺或亚胺基磺酰胺的化合物,其结合至肝X受体(LXRα和/或LXRβ)并且优选用作LXR的反向激动剂。(The present invention relates to compounds containing sulfonamides, sulfenamides or imidosulfonamides, which bind to liver X receptors (LXR α and/or LXR β) and are preferably useful as inverse agonists of LXR.)

1. A compound represented by formula (I), enantiomers, diastereomers, tautomers, N-oxides, solvates, prodrugs and pharmaceutically acceptable salts thereof,

Wherein

R1, R2 are independently selected from H and C1-4-alkyl,

Wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Or R1 and R2 together are oxo, 3-to 6-membered cycloalkyl, or 3-to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S,

wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Or R1 forms a saturated or partially saturated 5-to 8-membered cycloalkyl group with the adjacent residue from ring C, or a 5-to 8-membered heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from N, O and S,

wherein said cycloalkyl or said heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

R3, R4 are independently selected from H, C1-4-alkyl and halo-C1-4-alkyl;

Or R3 and R4 together are oxo, 3-to 6-membered cycloalkyl, or 3-to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S,

Wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Or R3 forms with the adjacent residue from ring B a partially saturated 5-to 8-membered cycloalkyl group, or a 5-to 8-membered heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from N, O and S,

Wherein said cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 51, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR51, C0-6-alkylene-NR 51S (O)2R51, C0-6-alkylene-S (O)2NR51R52, C0-6-alkylene-NR 51S (O)2NR51R52, C0-6-alkylene-CO 2R51, C0-6-alkylene-O-COR 51, C0-6-alkylene-CONR 51R52, C0-6-alkylene-NR 51-COR51, C0-6-alkylene-NR 51-CONR 52, C0-6-alkylene-O-CONR 51R52, C0-6-alkylene-NR 51-CO2R51 and C0-6-alkylene-NR 51R52,

wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of: halogen, CN, oxy, hydroxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

and wherein optionally two adjacent substituents on said aryl or heteroaryl moiety form a 5-to 8-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Selected from the group consisting of: 6-or 10-membered aryl, and 5-to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,

Wherein aryl and heteroaryl are substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 61, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR61, C0-6-alkylene-NR 61S (O)2R61, C0-6-alkylene-S (O)2NR61R62, C0-6-alkylene-NR 61S (O)2NR61R62, C0-6-alkylene-CO 2R61, C0-6-alkylene-O-COR 61, C0-6-alkylene-CONR 61R62, C0-6-alkylene-NR 61-COR61, C0-6-alkylene-NR 61-CONR61R62, C0-6-alkylene-O-CONR 61R62, C0-6-alkylene-NR 61-CO2R61 and C0-6-alkylene-NR 61R62,

Wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of: halogen, CN, oxy, hydroxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

And wherein optionally two adjacent substituents in said aryl or heteroaryl moiety form a 5-to 8-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 71, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR71, C0-6-alkylene-NR 71S (O)2R71, C0-6-alkylene-S (O)2NR71R72, C0-6-alkylene-NR 71S (O)2NR71R72, C0-6-alkylene-CO 2R71, C0-6-alkylene-O-COR 71, C0-6-alkylene-CONR 71R72, C0-6-alkylene-NR 71-COR71, C0-6-alkylene-NR 71R 71-CONR 72, C0-6-alkylene-O-CONR 71R72, C0-6-alkylene-NR 71-CO2R71, C0-6-alkylene-NR 71R72,

Wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 81, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR81, C0-6-alkylene-NR 81S (O)2R81, C0-6-alkylene-S (O)2NR81R82, C0-6-alkylene-NR 81S (O)2NR81R82, C0-6-alkylene-CO 2R81, C0-6-alkylene-O-COR 81, C0-6-alkylene-CONR 81R82, C0-6-alkylene-NR 81-COR81, C0-6-alkylene-NR 81-CONR 82R 82, C0-6-alkylene-O-CONR 81R82, C0-6-alkylene-NR 81-CO2R81 and C0-6-alkylene-NR 81R82,

And wherein optionally two adjacent substituents on said aryl or heteroaryl moiety form a 5-to 8-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

w is selected from O, NR11 or absent;

Residues X-Y-Z on Loop D are linked in a1, 3-orientation with respect to the linkage towards Loop C;

X is selected from the group consisting of a bond, C0-6-alkylene-S (═ O) n-, C0-6-alkylene-S (═ NR11) (═ O) -, C0-6-alkylene-S (═ NR11) -, C0-6-alkylene-O-, C0-6-alkylene-NR 91-, C0-6-alkylene-S (═ O)2NR91-, C0-6-alkylene-S (═ NR11) (═ O) -NR91-, and C0-6-alkylene-S (═ NR11) -NR 91-;

y is selected from C1-6-alkylene, C2-6-alkenylene, C2-6-alkynylene, 3-to 8-membered cycloalkylene, 3-to 8-membered heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, O and S,

Wherein alkylene, alkenylene, alkynylene, cycloalkylene, or heterocycloalkylene is unsubstituted or substituted with 1 to 6 substituents independently selected from: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, O-C1-4-alkyl and O-halo-C1-4-alkyl;

z is selected from-CO 2H, -CONH-CN, -CONHOH, -CONHOR90, -CONR90OH, -CONHs (═ O)2R90, -NR91CONHs (═ O)2R90, -CONHs (═ O)2NR91R92, -SO3H, -S (═ O)2NHCOR90, -NHS (═ O)2R90, -NR91S (═ O)2NHCOR90, -S (═ O)2NHR90, -P (═ O) (OH)2, -P (═ O) (NR91R92) OH, -P (═ O) H (OH), -b (OH) 2;

Or X-Y-Z is selected from-SO 3H and-SO 2NHCOR 90;

Or when X is not a bond, then Z may be additionally selected from-CONR 91R92, -S (═ O)2NR91R92,

R11 is selected from H, CN, NO2, C1-4-alkyl, C (═ O) -C1-4-alkyl, C (═ O) -O-C1-4-alkyl, halo-C1-4-alkyl, C (═ O) -halo-C1-4-alkyl, and C (═ O) -O-halo-C1-4-alkyl;

R51, R52, R61, R62, R71, R72, R81, R82 are independently selected from H and C1-4-alkyl,

Wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Or R51 and R52, R61 and R62, R71 and R72, R81 and R82, respectively, when taken together with the nitrogen to which they are attached form a 3-to 6-membered ring containing a carbon atom and optionally 1 or 2 heteroatoms independently selected from O, S or N; and wherein the newly formed ring is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, O-C1-4-alkyl and O-halo-C1-4-alkyl;

R90 is independently selected from C1-4-alkyl,

r91, R92 are independently selected from H and C1-4-alkyl,

Or R91 and R92, taken together with the nitrogen to which they are attached, form a 3-to 6-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein the newly formed ring is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, O-C1-4-alkyl and O-halo-C1-4-alkyl;

n and m are independently selected from 0 to 2.

2. The compound of claim 1, wherein

R1, R2, R3 and R4 are independently selected from H or Me;

W is O;

m is 1.

3. A compound according to claim 1 or 2, wherein

Selected from the group consisting of: 6-or 10-membered aryl, and optionally 5-to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,

Wherein the 6-membered aryl and 5-to 6-membered heteroaryl are substituted with 2 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -OC 1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl;

And wherein optionally two adjacent substituents in said aryl or heteroaryl moiety form a 5-to 6-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: fluorine, CN, oxy, OH, Me, CF3, CHF2, OMe, OCF3, and OCHF 2;

or wherein the 10-membered aryl and the 8-to 10-membered heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -O-C1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl.

4. a compound according to any one of claims 1 to 3, wherein

Selected from the group consisting of phenyl, pyridyl, pyrrolyl, thiazolyl, thiofuryl and furyl,

Wherein phenyl, pyridyl, pyrrolyl, thiazolyl, thiofuryl or furyl is substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, bromine, CN, C1-4-alkyl, -O-C1-4-alkyl, fluorine-C1-4-alkyl, -O-fluorine-C1-4-alkyl, CONH2, CONH (C1-4-alkyl), CONH (fluorine-C1-4-alkyl) and CON (C1-4-alkyl) 2.

5. The compound according to any one of claims 1 to 4, wherein

Selected from the group consisting of phenyl, thienyl, thiazolyl and pyridyl,

Wherein phenyl, thienyl, thiazolyl and pyridyl are unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, CN, C1-4-alkyl, -O-C1-4-alkyl, fluorine-C1-4-alkyl and-O-fluorine-C1-4-alkyl.

6. The compound according to any one of claims 1 to 5, wherein

Selected from the group consisting of phenyl, pyridyl, thienyl or thiazolyl,

Wherein phenyl, pyridyl, thienyl or thiazolyl are unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, CN, OH, C1-4-alkyl, -O-C1-4-alkyl, fluorine-C1-4-alkyl, -O-fluorine-C1-4-alkyl and C1-3-alkylene-OH.

7. The compound according to any one of claims 1 to 6, wherein

X is selected from the group consisting of a bond, O, S (═ O), and S (═ O) 2;

Y is selected from the group consisting of C1-3-alkylene, 3-to 6-membered cycloalkylene, and 3-to 6-membered heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, O and S,

Wherein alkylene, cycloalkylene, or heterocycloalkylene is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, CN, C1-4-alkyl, halo-C1-4-alkyl, OH, oxy, O-C1-4-alkyl and O-halo-C1-4-alkyl; and

Z is selected from the group consisting of-CO 2H and-CONHOH.

8. The compound according to any one of claims 1 to 6, wherein

X is selected from O, S (═ O) and S (═ O) 2;

Y is selected from the group consisting of C1-3-alkylene, 3-to 6-membered cycloalkylene, and 3-to 6-membered heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, O and S,

Z is selected from-CO 2H, -CONHOH, -CONR91R92, -S (═ O)2NR91R92,

r91, R92 are independently selected from H and C1-4-alkyl,

9. The compound according to any one of claims 1 to 8, wherein

is selected from

Is selected from

is selected from

XYZ is selected from

R1, R2, R3 and R4 are independently selected from H and Me;

W is O; and

m is selected from 1 and 2.

10. a compound according to any one of claims 1 to 9, wherein

Is selected from

is selected from

Is selected from

XYZ is selected from

R1, R2, R3 and R4 are independently selected from H and Me;

W is O; and

m is selected from 1 and 2.

11. A compound according to any one of claims 1 to 10, wherein

Is selected from

is selected from

Is selected from

is selected from

XYZ is selected from

r1, R2, R3 and R4 are independently selected from H and Me;

W is O; and

m is 1.

12. A compound according to any one of claims 1 to 11 selected from

13. a compound according to any one of claims 1 to 12 as a medicament.

14. A compound according to any one of claims 1 to 12 for use in the prevention and/or treatment of a disease mediated by LXR.

15. The compound for use according to claim 14, wherein the disease is selected from non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis, hepatitis c virus infection or complications thereof, and undesired side effects of long-term glucocorticoid therapy in diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma.

16. a pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier or excipient.

Technical Field

the present invention relates to novel compounds which are liver X receptor modulators and pharmaceutical compositions comprising the same. The invention further relates to the use of said compounds for the prevention and/or treatment of diseases which are associated with the modulation of liver X receptors.

Background

The liver X receptors LXR α (NR1H3) and LXR β (NR1H2) are members of the nuclear receptor protein superfamily. Both receptors form heterodimeric complexes with retinoid X receptors (RXR α, β or γ) and bind to LXR responsive elements (e.g., DR 4-type elements) located in the promoter regions of LXR responsive genes. Both receptors are transcription factors that are physiologically regulated by binding ligands in the cholesterol biosynthetic pathway, such as oxysterol (oxysterol), or intermediates, such as dehydrocholesterol (desmosteterol). In the absence of ligand, LXR-RXR heterodimers are believed to still bind to DR 4-type elements complexed with co-repressors (co-repressors), such as NCOR1, resulting in the inhibition of the corresponding target genes. Upon binding of an agonist ligand (endogenous ligand, such as the previously mentioned oxysterols or steroid intermediates; or synthetic pharmacological ligands), the conformation of the heterodimeric complex changes, resulting in the release of a co-repressor protein and in the recruitment of co-activator proteins (coactivator proteins), such as NCOA1(SRC1), resulting in transcriptional stimulation of the respective target genes. While LXR β is expressed in most tissues, LXR α is more selectively expressed in cells of liver, intestine, adipose tissue and macrophages. The relative expression of LXR α and LXR β at the mRNA or protein level may vary between different tissues in the same species or between different species in a given tissue. LXRs control reverse cholesterol transport, i.e., mobilization of tissue-bound peripheral cholesterol into HDL and thence into bile and stool, by transcriptional control of target genes such as ABCA1 and ABCG1 in macrophages and ABCG5 and ABCG8 in liver and intestine. This explains the anti-atherosclerotic activity of LXR agonists in the dietary LDLR-KO mouse model. However, LXRs also control the transcription of genes involved in adipogenesis (e.g., SREBF1, SCD, FASN, ACACA), which explains the hepatic steatosis observed after long-term treatment with LXR agonists.

Hepatic steatosis liability is considered a major obstacle to the development of non-selective LXR agonists for the treatment of atherosclerosis.

Nonalcoholic fatty liver disease (NAFLD) is considered to be a manifestation of metabolic syndrome in the liver and NAFLD has reached a prevalence worldwide (Marchesini et al, curr. The pathologies of NAFLD range from benign and reversible steatosis to steatohepatitis (nonalcoholic steatohepatitis, NASH), which can progress toward fibrosis, cirrhosis and potentially further toward hepatocellular carcinogenesis. Typically, a two-step model is employed to describe the progression of NAFLD to NASH, in which hepatic steatosis is the initial first step of sensitization to a second signal (exogenous or endogenous) that causes inflammation and liver damage (Day et al, Gastroenterology 1998; 114: 842).

Notably, LXR expression was shown to be associated with the extent of fat deposition in NAFLD patients as well as liver inflammation and fibrosis (Ahn et al, dig.dis.sci.2014; 59: 2975). Furthermore, serum and liver dehydrocholesterol levels are increased in patients with NASH, but not in people with simple hepatic steatosis. Dehydrocholesterol has been characterized as a potent endogenous LXR agonist (Yang et al, j.biol.chem.2006; 281: 27816). Thus, NAFLD/NASH patients may benefit from blocking the increased LXR activity observed in the liver of these patients by cleaving small molecule antagonists or inverse agonists of LXR activity. In this process, it is noted that such LXR antagonists or inverse agonists do not interfere with LXRs in peripheral tissues or macrophages, thereby avoiding disruption of LXR-mediated anti-atherosclerotic reverse cholesterol transport in these tissues or cells.

certain publications (e.g., Peet et al, Cell 1998; 93:693 and Schultz et al, Genes Dev.2000; 14:2831) emphasize the role of LXR α, particularly for stimulating adipogenesis, and thus establishing NAFLD in the liver. They indicate that mainly LXR α is responsible for hepatic steatosis, and therefore LXR α -specific antagonists or inverse agonists may be sufficient or desirable to just treat hepatic steatosis. However, these data were generated only by comparing LXR α, LXR β or double knockout with the susceptibility of wild type mice to undergo steatosis when they were on a high fat diet. They fail to account for the major differences in the relative expression levels of LXR α and LXR β in humans as opposed to murine livers. However, LXR α is the major LXR subtype in rodent liver, and LXR β is expressed at about the same level (even higher level) in human liver as compared to LXR α. This is exemplified by testing LXR β -selective agonists that cause induction of strong liver steatosis but show that they do not activate human LXR α in a human phase I clinical study (Kirchgessner et al, Cell metal.2016; 24: 223).

Thus, it can be postulated that LXR modulators designed for the treatment of NAFLD or NASH should be expected to have no strong preference for a particular LXR subtype. A degree of LXR subtype selectivity can be tolerated if the pharmacokinetic properties of such compounds clearly ensure sufficient liver exposure and residence time to cover both LXRs in clinical use.

In summary, treatment of diseases such as NAFLD or NASH would require LXR modulators that block LXR in a liver-selective manner, and this can be achieved by the hepatotropic pharmacokinetic and tissue distribution properties that must be built into such LXR modulators.

disclosure of Invention

the present invention relates to compounds according to formula (I), enantiomers, diastereomers, tautomers, N-oxides, solvates, prodrugs and pharmaceutically acceptable salts thereof,

wherein A, B, C, D, W, X, Y, Z, R1 to R4 and m are as defined in claim 1.

The inventors have surprisingly found that potent orally bioavailable LXR modulators with liver-selective properties can be obtained when a carboxylic acid or carboxylic acid isostere (see, e.g., balatore et al, chem med chem 2013; 8:385, Lassalas et al, j.med.chem.2016; 59:3183) is covalently linked to the methylsulfonyl moiety of (GSK2033) or the methylsulfonyl moiety of (GSK2033) is replaced by another carboxylic acid or carboxylic acid isostere-containing moiety. The compounds of the invention have similar or better LXR inverse agonistic, antagonistic or agonistic activity compared to known LXR modulators without acidic moieties. Furthermore, the compounds of the invention show a favourable liver/blood ratio after oral administration, so that disruption of the anti-atherosclerotic reverse cholesterol transport in peripheral macrophages, governed by LXR, can be avoided. In addition, the introduction of an acidic moiety (or its bioisoster) may improve other parameters such as microsomal stability, solubility, and lipophilicity in a beneficial manner.

thus, the present invention further relates to a pharmaceutical composition comprising a compound according to formula (I) and at least one pharmaceutically acceptable carrier or excipient.

the invention further relates to compounds according to formula (I) for the prevention and/or treatment of LXR mediated diseases.

accordingly, the present invention relates to the prevention and/or treatment of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, obesity, insulin resistance, type II diabetes, metabolic syndrome, cancer, viral myocarditis, and hepatitis c virus infection.

Detailed Description

the compounds, enantiomers, diastereomers, tautomers, N-oxides, solvates, prodrugs and pharmaceutically acceptable salts thereof, which follow the structural formula represented by formula (I), can be utilized to produce the desired properties of LXR modulators along with liver selectivity,

wherein

R1, R2 are independently selected from H and C1-4-alkyl,

wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Or R1 and R2 together are oxo, 3-to 6-membered cycloalkyl, or 3-to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S,

wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl, O-halo-C1-4-alkyl;

Wherein cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

R3, R4 are independently selected from H, C1-4-alkyl and halo-C1-4-alkyl;

wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl, O-halo-C1-4-alkyl;

Or R3 and R4 together are oxo, 3-to 6-membered cycloalkyl, or 3-to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S,

Wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

selected from the group consisting of: a 3-to 10-membered cycloalkyl group, a 3-to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from N, O and S, a 6-or 10-membered aryl group, and a 5-to 10-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O and S,

And wherein optionally two adjacent substituents on the aryl or heteroaryl moiety form a 5-to 8-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

selected from the group consisting of: 6-or 10-membered aryl, and 5-to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S,

And wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-to 8-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 71, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR71, C0-6-alkylene-NR 71S (O)2R71, C0-6-alkylene-S (O)2NR71R72, C0-6-alkylene-NR 71S (O)2NR71R72, C0-6-alkylene-CO 2R71, C0-6-alkylene-O-COR 71, C0-6-alkylene-CONR 71R72, C0-6-alkylene-NR 71-COR71, C0-6-alkylene-NR 71R 71-CONR 72, C0-6-alkylene-O-CONR 71R72, C0-6-alkylene-NR 71-CO2R71, C0-6-alkylene-NR 71R72,

And wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-to 8-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is optionally substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

W is selected from O, NR11 or absent;

Residues X-Y-Z on Ring D are linked in the 1, 3-orientation (orientation) with respect to the linkage toward Ring C;

Y is selected from C1-6-alkylene, C2-6-alkenylene, C2-6-alkynylene, 3-to 8-membered cycloalkylene, 3-to 8-membered heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, O and S,

Z is selected from-CO 2H, -CONH-CN, -CONHOH, -CONHOR90, -CONR90OH, -CONHs (═ O)2R90, -NR91CONHs (═ O)2R90, -CONHs (═ O)2NR91R92, -SO3H, -S (═ O)2NHCOR90, -NHS (═ O)2R90, -NR91S (═ O)2NHCOR90, -S (═ O)2NHR90, -P (═ O) (OH)2, -P (═ O) (NR91R92) OH, -P (═ O) H (OH), -b (OH) 2;

Or X-Y-Z is selected from-SO 3H and-SO 2NHCOR 90;

Or when X is not a bond, Z may additionally be selected from-CONR 91R92, -S (═ O)2NR91R92,

R11 is selected from H, CN, NO2, C1-4-alkyl, C (═ O) -C1-4-alkyl, C (═ O) -O-C1-4-alkyl, halo-C1-4-alkyl, C (═ O) -halo-C1-4-alkyl, and C (═ O) -O-halo-C1-4-alkyl;

R51, R52, R61, R62, R71, R72, R81, R82 are independently selected from H and C1-4-alkyl,

wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Or R51 and R52, R61 and R62, R71 and R72, R81 and R82, respectively, when taken together with the nitrogen to which they are attached form a 3-to 6-membered ring containing a carbon atom and optionally 1 or 2 heteroatoms independently selected from O, S or N; and wherein the newly formed ring is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, O-C1-4-alkyl and O-halo-C1-4-alkyl;

R90 is independently selected from C1-4-alkyl,

Wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, SO3H, O-C1-4-alkyl, and O-halo-C1-4-alkyl;

r91, R92 are independently selected from H and C1-4-alkyl,

Or R91 and R92, taken together with the nitrogen to which they are attached, form a 3-to 6-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein the newly formed ring is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, O-C1-4-alkyl and O-halo-C1-4-alkyl;

n and m are independently selected from 0 to 2.

In a preferred embodiment in combination with any of the above or below embodiments, R1 and R2 are independently selected from H and C1-4-alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Or R1 and R2 together are oxo, 3-to 6-membered cycloalkyl, or 3-to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Or R1 forms with an adjacent residue from ring C a saturated or partially saturated 5-to 8-membered cycloalkyl group, or a 5-to 8-membered heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from N, O and S, the cycloalkyl and heterocycloalkyl groups being unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

In a more preferred embodiment in combination with any of the above or below embodiments, R1 and R2 are independently selected from H and C1-4-alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

In a most preferred embodiment in combination with any of the above and below embodiments, R1 and R2 are independently selected from H or Me.

In a preferred embodiment in combination with any of the above or below embodiments, R3 and R4 are independently selected from H and C1-4-alkyl; wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl, O-halo-C1-4-alkyl;

Or R3 and R4 together are oxo, 3-to 6-membered cycloalkyl, or 3-to 6-membered heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Or R3 forms with an adjacent residue from ring B a partially saturated 5-to 8-membered cycloalkyl, or a 5-to 8-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

more preferably, in combination with any of the above and following embodiments, R3 and R4 are independently selected from H and C1-4-alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, OH, oxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

in a most preferred embodiment in combination with any of the above and below embodiments, R3 and R4 are independently selected from H or Me.

in preferred embodiments in combination with any of the above or below embodiments, W is selected from O, NR11 or is absent; more preferably, W is O.

In a preferred embodiment in combination with any of the above or below embodiments, m is selected from 0 to 2, more preferably m is 1 or 2. In a most preferred embodiment in combination with any of the above and below embodiments, m is 1.

In another preferred embodiment in combination with any of the above or below embodiments, R1, R2, R3, and R4 are independently selected from H or Me, and m is 1.

In another preferred embodiment in combination with any of the above or below embodiments, R1, R2, R3, and R4 are independently selected from H or Me, W is O, and m is 1.

In a preferred embodiment in combination with any of the above or below embodiments, R11 is selected from H, CN, NO2, Me, Et, C (═ O) -Me, C (═ O) -Et, C (═ O) -O-CMe 3.

In a more preferred embodiment in combination with any of the above or below embodiments, R11 is H.

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

Selected from the group consisting of: a 3-to 10-membered cycloalkyl group, a 3-to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from N, O and S, a 6-or 10-membered aryl group, and a 5-to 10-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 51, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR51, C0-6-alkylene-NR 51S (O)2R51, C0-6-alkylene-S (O)2NR51R52, C0-6-alkylene-NR 51S (O)2NR51R52, C0-6-alkylene-CO 2R51, C0-6-alkylene-O-COR 51, C0-6-alkylene-CONR 51R52, C0-6-alkylene-NR 51-COR51, C0-6-alkylene-NR 51-CONR 52, C0-6-alkylene-O-CONR 51R52, C0-6-alkylene-NR 51-CO2R51, C0-6-alkylene-NR 51R52, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from: halogen, CN, oxy, hydroxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl; and wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-to 8-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is optionally substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

In a preferred embodiment in combination with any of the above and below embodiments, selected from the group consisting of: a 6-or 10-membered aryl, and a 5-to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 51, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR51, C0-6-alkylene-NR 51S (O)2R51, C0-6-alkylene-S (O)2NR51R52, C0-6-alkylene-NR 51S (O)2NR51R52, C0-6-alkylene-CO 2R51, C0-6-alkylene-O-COR 51, C0-6-alkylene-CONR 51R52, C0-6-alkylene-NR 51-COR51, C0-6-alkylene-NR 51-CONR 52, C0-6-alkylene-O-CONR 51R52, C0-6-alkylene-NR 51-CO2R51, C0-6-alkylene-NR 51R52, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from: halogen, CN, oxy, hydroxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl; and wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-to 8-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

In a more preferred embodiment in combination with any of the above and below embodiments, selected from the group consisting of: a 6-or 10-membered aryl, and a 5-to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein the 6-membered aryl and the 5-to 6-membered heteroaryl are substituted with 2 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -O-C1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl; and wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-to 6-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: fluorine, CN, oxy, OH, Me, CF3, CHF2, OMe, OCF3, and OCHF 2; or therein

The 10-membered aryl and 8-to 10-membered heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -OC 1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl.

In an even more preferred embodiment in combination with any of the above and below embodiments, selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, naphthyl, benzo [ b ] thiophene, quinolinyl, isoquinolinyl, pyrazolo [1,5-a ] pyrimidinyl, and 1, 5-naphthyridinyl, wherein phenyl, pyridyl, and pyrimidinyl are substituted with 2 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -O-C1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl; and wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-to 6-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: fluorine, CN, oxy, OH, Me, CF3, CHF2, OMe, OCF3, and OCHF 2; or therein

Naphthyl, benzo [ b ] thiophene, quinolinyl, isoquinolinyl, pyrazolo [1,5-a ] pyrimidinyl, and 1, 5-naphthyridinyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -OC 1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl.

In an even more preferred embodiment in combination with any of the above and below embodiments, selected from the group consisting of phenyl, naphthyl, and quinolinyl, wherein phenyl is substituted with 2 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -O-C1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl; or wherein naphthyl or quinolinyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -OC 1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl.

in an even more preferred embodiment in combination with any of the above and below embodiments, is selected from

Even more preferably, selected from

In a most preferred embodiment in combination with any of the above and below embodiments, is selected from

In a further preferred embodiment in combination with any of the above or below embodiments, selected from the group consisting of 6-or 10-membered aryl and 5-to 10-membered heteroaryl, wherein aryl and heteroaryl are substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 61, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR61, C0-6-alkylene-NR 61S (O)2R61, C0-6-alkylene-S (O)2NR61R62, C0-6-alkylene-NR 61S (O)2NR61R62, C0-6-alkylene-CO 2R61, C0-6-alkylene-O-COR 61, C0-6-alkylene-CONR 61R62, C0-6-alkylene-NR 61-COR61, C0-6-alkylene-NR 61-CONR61R62, C0-6-alkylene-O-CONR 61R62, C0-6-alkylene-NR 61-CO2R61 and C0-6-alkylene-NR 61R62, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from: halogen, CN, oxy, hydroxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl; and wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-to 8-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

In a more preferred embodiment in combination with any of the above and below embodiments, selected from the group consisting of: phenyl, pyridyl, pyrrolyl, thiazolyl, thiofuranyl, or furanyl, wherein phenyl, pyridyl, pyrrolyl, thiazolyl, thiofuranyl, or furanyl is substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 61, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR61, C0-6-alkylene-NR 61S (O)2R61, C0-6-alkylene-S (O)2NR61R62, C0-6-alkylene-NR 61S (O)2NR61R62, C0-6-alkylene-CO 2R61, C0-6-alkylene-O-COR 61, C0-6-alkylene-CONR 61R62, C0-6-alkylene-NR 61-COR61, C0-6-alkylene-NR 61-CONR61R62, C0-6-alkylene-O-CONR 61R62, C0-6-alkylene-NR 61-CO2R61, C0-6-alkylene-NR 61R62, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from: halogen, CN, oxy, hydroxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl; and wherein optionally two adjacent substituents of the phenyl, pyridyl, pyrrolyl, thiazolyl, thiofuranyl or furanyl moiety form a 5 to 8 membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

in an even more preferred embodiment in combination with any of the above and below embodiments, selected from the group consisting of: phenyl, pyridyl, pyrrolyl, thiazolyl, thiofuranyl, or furanyl, wherein phenyl, pyridyl, pyrrolyl, thiazolyl, thiofuranyl, or furanyl is substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, bromine, CN, C1-4-alkyl, -O-C1-4-alkyl, fluorine-C1-4-alkyl, -O-fluorine-C1-4-alkyl, CONH2, CONH (C1-4-alkyl), CONH (fluorine-C1-4-alkyl) and CON (C1-4-alkyl) 2.

in an even more preferred embodiment in combination with any of the above and below embodiments, is selected from

In an even more preferred embodiment in combination with any of the above and below embodiments, is selected from

In a more preferred embodiment in combination with any of the above and below embodiments, is selected from

In a most preferred embodiment in combination with any of the above and below embodiments is

in a further preferred embodiment in combination with any of the above or below embodiments, selected from the group consisting of: 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-or 10-membered aryl, and 5-to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 71, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR71, C0-6-alkylene-NR 71S (O)2R71, C0-6-alkylene-S (O)2NR71R72, C0-6-alkylene-NR 71S (O)2NR71R72, C0-6-alkylene-CO 2R71, C0-6-alkylene-O-COR 71, C0-6-alkylene-CONR 71R72, C0-6-alkylene-NR 71-COR71, C0-6-alkylene-NR 71R 71-CONR 72, C0-6-alkylene-O-CONR 71R72, C0-6-alkylene-NR 71-CO2R71, C0-6-alkylene-NR 71R72, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from: halogen, CN, oxy, hydroxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl; and wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-to 8-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

In a preferred embodiment in combination with any of the above and following embodiments, selected from the group consisting of phenyl, thienyl, thiazolyl and pyridyl, wherein phenyl, thienyl, thiazolyl and pyridyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 71, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR71, C0-6-alkylene-NR 71S (O)2R71, C0-6-alkylene-S (O)2NR71R72, C0-6-alkylene-NR 71S (O)2NR71R72, C0-6-alkylene-CO 2R71, C0-6-alkylene-O-COR 71, C0-6-alkylene-CONR 71R72, C0-6-alkylene-NR 71-COR71, C0-6-alkylene-NR 71R 71-CONR 72, C0-6-alkylene-O-CONR 71R72, C0-6-alkylene-NR 71-CO2R71, C0-6-alkylene-NR 71R72, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from: halogen, CN, oxy, hydroxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

In a more preferred embodiment in combination with any of the above and following embodiments, selected from the group consisting of phenyl, thienyl, thiazolyl and pyridyl, wherein phenyl, thienyl, thiazolyl and pyridyl are unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, CN, C1-4-alkyl, -OC 1-4-alkyl, fluorine-C1-4-alkyl and-O-fluorine-C1-4-alkyl.

In an even more preferred embodiment in combination with any of the above and below embodiments, is selected from

in a most preferred embodiment in combination with any of the above and below embodiments, is selected from

In a further preferred embodiment in combination with any of the above or below embodiments, selected from the group consisting of: 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-or 10-membered aryl, and 5-to 10-membered heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, NO2, C1-4-alkyl, C0-6-alkylene-OR 81, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR81, C0-6-alkylene-NR 81S (O)2R81, C0-6-alkylene-S (O)2NR81R82, C0-6-alkylene-NR 81S (O)2NR81R82, oxy, C0-6-alkylene-CO 2R81, C0-6-alkylene-O-COR 81, C0-6-alkylene-CONR 81R82, C0-6-alkylene-NR 81-COR81, C0-6-alkylene-NR 81-CONR81R82, C0-6-alkylene-O-CONR 81R82, C0-6-alkylene-NR 81-CO2R81, C0-6-alkylene-NR 81R82, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from: halogen, CN, oxy, hydroxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl; and wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-to 8-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: halogen, CN, oxy, OH, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

In an even more preferred embodiment in combination with any of the above and following embodiments, selected from the group consisting of phenyl, pyridyl, thienyl or thiazolyl, wherein the phenyl, pyridyl, thienyl or thiazolyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, CN, NO2, oxy, C1-4-alkyl, C0-6-alkylene-OR 81, C0-6-alkylene- (3-to 6-membered cycloalkyl), C0-6-alkylene- (3-to 6-membered heterocycloalkyl), C0-6-alkylene-S (O) nR81, C0-6-alkylene-NR 81S (O)2R81, C0-6-alkylene-S (O)2NR81R82, C0-6-alkylene-NR 81S (O)2NR81R82, oxy, C82-6-alkylene-CO 2R 82, C82-6-alkylene-O-COR 82, C82-6-alkylene-CONR 81R82, C82-6-alkylene-NR 82-COR 82, C82-6-alkylene-NR 82-CONR 81R82, C0-6-alkylene-O-CONR 81R82, C0-6-alkylene-NR 81-CO2R81, C0-6-alkylene-NR 81R82, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from: halogen, CN, oxy, hydroxy, C1-4-alkyl, halo-C1-4-alkyl, O-C1-4-alkyl and O-halo-C1-4-alkyl.

In an even more preferred embodiment in combination with any of the above and below embodiments, selected from the group consisting of phenyl or pyridyl, wherein phenyl or pyridyl is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, CN, OH, C1-4-alkyl, -OC 1-4-alkyl, fluorine-C1-4-alkyl, -O-fluorine-C1-4-alkyl and C1-3-alkylene-OH.

In an even more preferred embodiment in combination with any of the above and below embodiments, is selected from

In a most preferred embodiment in combination with any of the above and below embodiments, is selected from

in a further preferred embodiment in combination with any of the above or below embodiments, residues X-Y-Z on ring D are linked in a1, 3-orientation with respect to the linkage towards ring C;

Y is selected from C1-6-alkylene, C2-6-alkenylene, C2-6-alkynylene, 3-to 6-membered cycloalkylene, 3-to 6-membered heterocycloalkylene, wherein alkylene, alkenylene, alkynylene, cycloalkylene, or heterocycloalkylene is unsubstituted or substituted with 1 to 6 substituents independently selected from: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, C3-6-cycloalkyl, halo-C3-6-cycloalkyl, C3-6-heterocycloalkyl, halo-C3-6-heterocycloalkyl, OH, oxy, O-C1-4-alkyl, O-halo-C1-4-alkyl;

Or X-Y-Z is selected from-SO 3H and-SO 2NHCOR 90;

or when X is not a bond, Z may additionally be selected from-CONR 91R92, -S (═ O)2NR91R92,

r11 is selected from H, CN, NO2, C1-4-alkyl, C (═ O) -C1-4-alkyl, C (═ O) -O-C1-4-alkyl, halo-C1-4-alkyl, C (═ O) -halo-C1-4-alkyl, or C (═ O) -O-halo-C1-4-alkyl;

R90 is independently selected from C1-4-alkyl and halo-C1-4-alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, SO3H, O-C1-4-alkyl, and O-halo-C1-4-alkyl;

r91, R92 are independently selected from H and C1-4-alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, SO3H, O-C1-4-alkyl, and O-halo-C1-4-alkyl;

R91 and R92, when taken together with the nitrogen to which they are attached, form a 3-to 6-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein the newly formed ring is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, O-C1-4-alkyl and O-halo-C1-4-alkyl;

n is selected from 0 to 2.

In a more preferred embodiment in combination with any of the above and below embodiments, XYZ is selected from

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

X is selected from the group consisting of a bond, O, S (═ O), and S (═ O) 2;

y is selected from C1-3-alkylene, 3-to 6-membered cycloalkylene, and 3-to 6-membered heterocycloalkylene, wherein alkylene, cycloalkylene, or heterocycloalkylene is unsubstituted or substituted with 1 to 2 substituents independently selected from: fluorine, CN, C1-4-alkyl, halo-C1-4-alkyl, OH, oxy, O-C1-4-alkyl and O-halo-C1-4-alkyl;

z is selected from the group consisting of-CO 2H and-CONHOH.

In another preferred embodiment in combination with any of the above and below embodiments,

X is selected from the group consisting of a bond, S, S (═ O), and S (═ O) 2;

Y is selected from C1-3-alkylene or C3-cycloalkylene, wherein alkylene or cycloalkylene is unsubstituted or substituted with 1 to 2 substituents independently selected from halo or C1-4-alkyl; and

Z is-CO 2H, or an ester or pharmaceutically acceptable salt thereof.

in an even more preferred embodiment in combination with any of the above and below embodiments, XYZ is selected from

In a more preferred embodiment in combination with any of the above and below embodiments, XYZ is selected from

In an even more preferred embodiment in combination with any of the above and below embodiments, XYZ is a sum

in a most preferred embodiment in combination with any of the above and below embodiments, XYZ is

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

x is selected from O, S (═ O) and S (═ O) 2;

Y is selected from C1-3-alkylene, 3-to 6-membered cycloalkylene, and 3-to 6-membered heterocycloalkylene, wherein alkylene, cycloalkylene, or heterocycloalkylene is unsubstituted or substituted with 1 to 2 substituents independently selected from: fluorine, CN, C1-4-alkyl, halo-C1-4-alkyl, OH, oxy, O-C1-4-alkyl and O-halo-C1-4-alkyl;

Z is selected from-CO 2H, -CONHOH, -CONR91R92, -S (═ O)2NR91R92,

R91, R92 are independently selected from H, C1-4-alkyl and halo-C1-4-alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from: halogen, CN, C1-4-alkyl, halo-C1-4-alkyl, 3-to 6-membered cycloalkyl, halo- (3-to 6-membered cycloalkyl), 3-to 6-membered heterocycloalkyl, halo- (3-to 6-membered heterocycloalkyl), OH, oxy, SO3H, O-C1-4-alkyl, and O-halo-C1-4-alkyl;

n is selected from 0 to 2.

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

Is selected from

is selected from

XYZ is selected from

r1, R2, R3 and R4 are independently selected from H or Me;

w is O; and

m is selected from 1 or 2.

In an even more preferred embodiment in combination with any of the above and below embodiments, is selected from

Is selected from

XYZ is selected from

R1, R2, R3 and R4 are independently selected from H or Me;

W is O; and

m is selected from 1 or 2.

In an even more preferred embodiment in combination with any of the above and below embodiments, is selected from

is selected from

Is selected from

XYZ is selected from

r1, R2, R3 and R4 are independently selected from H or Me;

w is O; and

m is 1.

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

r1, R2, R3 and R4 are independently selected from H or Me; and

m is 1;

W is selected from O, NR11 or absent;

r11 is selected from H, CN, NO2, C1-4-alkyl, C (═ O) -C1-4-alkyl, C (═ O) -O-C1-4-alkyl, halo-C1-4-alkyl, C (═ O) -halo-C1-4-alkyl, and C (═ O) -O-halo-C1-4-alkyl;

selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, naphthyl, benzo [ b ] thiophene, quinolinyl, isoquinolinyl, pyrazolo [1,5-a ] pyrimidinyl, and 1, 5-naphthyridinyl, wherein phenyl, pyridyl, and pyrimidinyl are substituted with 2 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -O-C1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl; and wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-to 6-membered partially saturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is unsubstituted or substituted with 1 to 4 substituents independently selected from: fluorine, CN, oxy, OH, Me, CF3, CHF2, OMe, OCF3, and OCHF 2; or therein

naphthyl, benzo [ b ] thiophene, quinolinyl, isoquinolinyl, pyrazolo [1,5-a ] pyrimidinyl, and 1, 5-naphthyridinyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -OC 1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl;

selected from the group consisting of: phenyl, pyridyl, pyrrolyl, thiazolyl, thiofuranyl, or furanyl, wherein phenyl, pyridyl, pyrrolyl, thiazolyl, thiofuranyl, or furanyl is substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, bromine, CN, C1-4-alkyl, -O-C1-4-alkyl, fluorine-C1-4-alkyl, -O-fluorine-C1-4-alkyl, CONH2, CONH (C1-4-alkyl), CONH (fluorine-C1-4-alkyl) and CON (C1-4-alkyl) 2;

Selected from the group consisting of phenyl, thienyl, thiazolyl and pyridyl, wherein phenyl, thienyl, thiazolyl and pyridyl are unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, CN, C1-4-alkyl, -OC 1-4-alkyl, fluorine-C1-4-alkyl and-O-fluorine-C1-4-alkyl;

Selected from the group consisting of phenyl or pyridyl, wherein phenyl or pyridyl is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, CN, OH, C1-4-alkyl, -OC 1-4-alkyl, fluorine-C1-4-alkyl, -O-fluorine-C1-4-alkyl and C1-3-alkylene-OH;

x is selected from the group consisting of a bond, S, S (═ O), and S (═ O) 2;

Y is selected from C1-3-alkylene or C3-cycloalkylene, wherein alkylene or cycloalkylene is optionally substituted with 1 to 2 substituents independently selected from halo or C1-4-alkyl; and

z is-CO 2H, or an ester or pharmaceutically acceptable salt thereof.

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

r1, R2, R3 and R4 are independently selected from H or Me; and

m is 1;

w is selected from O, NR11 or absent;

R11 is selected from H, CN, NO2, C1-4-alkyl, C (═ O) -C1-4-alkyl, C (═ O) -O-C1-4-alkyl, halo-C1-4-alkyl, C (═ O) -halo-C1-4-alkyl, and C (═ O) -O-halo-C1-4-alkyl;

Selected from the group consisting of phenyl, naphthyl, and quinolinyl, wherein phenyl is substituted with 2 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -O-C1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl; or wherein naphthyl or quinolinyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: F. cl, CN, C1-4-alkyl, -OC 1-4-alkyl, fluoro-C1-4-alkyl and-O-fluoro-C1-4-alkyl;

Selected from the group consisting of: phenyl, pyridyl, pyrrolyl, thiazolyl, thiofuranyl, or furanyl, wherein phenyl, pyridyl, pyrrolyl, thiazolyl, thiofuranyl, or furanyl is substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, bromine, CN, C1-4-alkyl, -O-C1-4-alkyl, fluorine-C1-4-alkyl, -O-fluorine-C1-4-alkyl, CONH2, CONH (C1-4-alkyl), CONH (fluorine-C1-4-alkyl) and CON (C1-4-alkyl) 2;

selected from the group consisting of phenyl, thienyl, thiazolyl and pyridyl, wherein phenyl, thienyl, thiazolyl and pyridyl are unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, CN, C1-4-alkyl, -OC 1-4-alkyl, fluorine-C1-4-alkyl and-O-fluorine-C1-4-alkyl;

selected from the group consisting of phenyl or pyridyl, wherein phenyl or pyridyl is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: fluorine, chlorine, CN, OH, C1-4-alkyl, -OC 1-4-alkyl, fluorine-C1-4-alkyl, -O-fluorine-C1-4-alkyl and C1-3-alkylene-OH;

x is selected from the group consisting of a bond, S, S (═ O), and S (═ O) 2;

Y is selected from C1-3-alkylene or C3-cycloalkylene, wherein alkylene or cycloalkylene is unsubstituted or substituted with 1 to 2 substituents independently selected from halo or C1-4-alkyl; and

Z is-CO 2H, or an ester or pharmaceutically acceptable salt thereof.

in a most preferred embodiment in combination with any of the above and below embodiments, the compound is selected from

the invention also provides a compound of the invention for use as a medicament.

also provided are compounds of the invention for use in the prevention and/or treatment of diseases mediated by LXR.

Also provided are compounds of the invention for use in treating an LXR mediated disease selected from the group consisting of: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis, hepatitis c virus infection or complications thereof, and undesirable side effects of long-term glucocorticoid therapy in diseases such as rheumatoid arthritis, inflammatory bowel disease, and asthma.

Also provided are pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient.

In the context of the present invention, "C1-4-alkyl" means a saturated alkyl chain having from 1 to 4 carbon atoms, which may be straight or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

The term "halo-C1-4-alkyl" means that more than one hydrogen atom in the alkyl chain is replaced by a halogen. A preferred example thereof is CF 3.

"C0-6-alkylene" means that each group is divalent and connects the attached residue with the rest of the molecule. Furthermore, in the context of the present invention, "C0-alkylene" is intended to denote a bond, whereas C1-alkylene means a methylene linker, C2-alkylene means an ethylene linker or a methyl-substituted methylene linker, etc. In the context of the present invention, C0-6-alkylene preferably represents a bond, methylene, ethylene or propylene.

Similarly, "C2-6-alkenylene" and "C2-6-alkynylene" mean a divalent alkenyl or alkynyl group that links two parts of a molecule.

by 3-to 10-membered cycloalkyl is meant a saturated or partially unsaturated monocyclic, bicyclic, spirocyclic or polycyclic ring system comprising 3 to 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, spiro [3.3] heptyl, bicyclo [2.2.1] heptyl, adamantyl and pentalane [4.2.0.02,5.03,8.04,7] octyl. Thus, a 3-to 6-membered cycloalkyl group means a saturated or partially unsaturated monocyclic ring system, bicyclic ring system or spiroring system comprising 3 to 6 carbon atoms, and a 5-to 8-membered cycloalkyl group means a saturated or partially unsaturated monocyclic ring system, bicyclic ring system or spiroring system comprising 5 to 8 carbon atoms.

3-to 10-membered heterocycloalkyl means a saturated or partially unsaturated 3-to 10-membered carbon monocyclic, bicyclic, spirocyclic or polycyclic ring in which 1,2, 3 or 4 carbon atoms are replaced by 1,2, 3 or 4 heteroatoms, respectively, wherein the heteroatoms are independently selected from N, O, S, SO and SO 2. Examples thereof include epoxy group, oxetanyl group, pyrrolidinyl group, tetrahydrofuryl group, piperidinyl group, piperazinyl group, tetrahydropyranyl group, 1, 4-dioxanyl group, morpholinyl group, 4-quinuclidinyl group, 1, 4-dihydropyridinyl group, and 6-azabicyclo [3.2.1] octyl group. The heterocycloalkyl group may be attached to the rest of the molecule via a carbon atom, a nitrogen atom (e.g. in morpholine or piperidine) or a sulfur atom. An example of an S-linked heterocycloalkyl group is a cyclic imidosulfonamide (sulfonimimide)

a 5-to 10-membered monocyclic or bicyclic heteroaromatic ring system (also referred to herein as heteroaryl) means an aromatic ring system comprising up to 4 heteroatoms independently selected from N, O, S, SO and SO 2. Examples of monocyclic heteroaromatic rings include pyrrolyl, imidazolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, and thiadiazolyl. It further means bicyclic ring systems in which heteroatoms may be present in one or both rings including the bridgehead atom. Examples thereof include quinolyl, isoquinolyl, quinoxalyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl and pyrazolo [1,5-a ] pyrimidinyl. The nitrogen or sulfur atom of the heteroaryl system may also optionally be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. If not otherwise stated, the heteroaryl system may be attached via a carbon atom or a nitrogen atom. Examples of N-linked heterocycles are

a 6-to 10-membered monocyclic or bicyclic aromatic ring system (also referred to herein as aryl) means an aromatic carbocyclic ring such as phenyl or naphthyl.

The term "N-oxide" denotes a compound in which the nitrogen in a heteroaromatic system, preferably pyridyl, is oxidized. Such compounds can be obtained in a known manner by reacting a compound of the invention (for example in pyridyl) with H2O2 or a peracid in an inert solvent.

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

Any formula or structure given herein is also intended to represent an unlabeled form of the compound as well as an isotopically labeled form. Isotopically-labeled compounds have the structure shown by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 125I. Various isotopically-labeled compounds of the present disclosure, for example, those incorporating a radioactive isotope such as 3H, 13C, and 14C. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution analysis, or in the radiation treatment of patients. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes below, or in the examples and preparations, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The disclosure also includes "deuterated analogs" of the compounds of formula (I) wherein 1 to n hydrogens attached to a carbon atom are replaced with deuterium, wherein n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism when administered to a mammal, such as a human, and thus may be used to extend the half-life of any compound of formula (I). See, e.g., Foster, Trends Pharmacol. Sci.1984: 5; 524. such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens are replaced with deuterium.

Deuterium labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties that are associated with distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or improved therapeutic index. The 18F-labeled compounds can be used for PET or SPECT studies.

The concentration of such heavier isotopes, in particular deuterium, can be defined by an isotopic enrichment factor (isotopic enrichment factor). In the compounds of the present disclosure, any atom that is not specifically designated as a particular isotope is intended to mean any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

Furthermore, the compounds of the invention are partly subject to tautomerism. For example, if a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxyl group on a carbon atom adjacent to the nitrogen atom, the following tautomerism may occur:

The cycloalkyl or heterocycloalkyl group can be a straight or spiro ring attached, for example when cyclohexane is substituted with a heterocycloalkyl oxetane, the following structures are possible:

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

those skilled in the art will appreciate that when a list of optional substituents includes members that cannot be used to replace a particular group due to their valence requirements or other reasons, that list is intended to be read by the knowledge of those skilled in the art to include only those members of the list that are suitable for replacing the particular group.

The compounds of the present invention may be in the form of prodrug compounds. By "prodrug compound" is meant a derivative which is converted into a compound according to the present invention by a reaction with an enzyme or gastric acid or the like under physiological conditions in an organism, for example, by oxidation, reduction or hydrolysis or the like, each of which is carried out enzymatically. Examples of prodrugs are compounds wherein an amino group in a compound of the invention is acylated, alkylated or phosphorylated to form, for example, eicosanoylamino, alanylamino, pivaloyloxymethylamino, or wherein a hydroxyl group is acylated, alkylated, phosphorylated or converted to a boronic ester, for example, acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, alanyloxy, or wherein a carboxyl group is esterified or amidated. These compounds can be produced from the compounds of the present invention according to known methods. Other examples of prodrugs are compounds (referred to herein as "ester prodrugs") wherein the carboxylic acid ester in the compounds of the invention is converted, for example, to an alkyl ester, aryl ester, arylalkylene ester, amino ester, choline ester, acyloxyalkyl ester, 1- ((alkoxycarbonyl) oxy) -2-alkyl, or linolenyl ester.

Exemplary structures of prodrugs of carboxylic acids are

Ester prodrugs can also be formed when a carboxylic acid forms a lactone with a hydroxyl group from the molecule. An illustrative example is

The term "-CO 2H or esters thereof" is intended to mean carboxylic acids and alkyl esters, e.g.

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

Where tautomerism (e.g., keto-enol tautomerism) of the compounds of the present invention or their prodrugs can occur, the individual forms (e.g., keto and enol forms) as well as mixtures thereof in any proportion are each within the scope of the present invention. The same applies to stereoisomers, such as enantiomers, cis/trans isomers and conformational isomers, and the like.

If desired, isomers may be separated by methods well known in the art, for example by liquid chromatography. The same applies to enantiomers by using, for example, a chiral stationary phase. Furthermore, enantiomers can be separated by: they are converted into diastereomers, i.e. coupled with enantiomerically pure auxiliary compounds, the resulting diastereomers are subsequently separated and the auxiliary residues are cleaved. Alternatively, any enantiomer of a compound of the invention may be obtained from stereoselective synthesis using optically pure starting materials. Another way to obtain pure enantiomers from racemic mixtures would be to use enantioselective crystallization with chiral counter ions.

The compounds of the invention may be in the form of pharmaceutically acceptable salts or solvates. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, especially their pharmaceutically acceptable salts. Thus, the compounds of the invention containing acidic groups may be present on these groups and may be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium, potassium, calcium, magnesium, or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine, or amino acids. The compounds of the invention containing one or more basic groups, i.e. groups which can be protonated, may be present and may be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, napadisylic acid, oxalic 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 invention contain both acidic and basic groups in the molecule, the invention also includes internal salts or betaines (zwitterions) in addition to the salt forms mentioned. The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these with organic or inorganic acids or bases in solvents or dispersants, or by anion exchange or cation exchange with other salts. The invention also includes all salts of the compounds of the invention which are not directly suitable for use in medicine due to low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

Furthermore, the compounds of the present invention may exist in the form of solvates, including, for example, those that are water solvates or pharmaceutically acceptable solvates such as alcohols, particularly ethanol.

in addition, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate 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 make up a carrier, and any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Thus, the pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may additionally comprise one or more other compounds as active ingredients, such as prodrug compounds or other nuclear receptor modulators.

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

The compounds of the invention are useful as LXR modulators.

ligands for nuclear receptors, including LXR ligands, may act as agonists, antagonists or inverse agonists. Agonist in this context means a small molecule ligand that binds to a receptor and stimulates its transcriptional activity as determined by, for example, an increase in mRNA or protein transcribed under the control of an LXR responsive element. Transcriptional activity can also be measured in biochemical or in vitro cell assays that employ only the ligand binding domain of LXR α or LXR β, but use interactions with cofactors (i.e., co-repressors or co-activators), potentially in combination with genetic DNA binding elements such as the Gal4 domain, to monitor agonistic, antagonistic, or inverse agonistic activity.

Whereas agonists under this definition stimulate LXR-or LXR-Gal 4-driven transcriptional activity, antagonists are defined as small molecules that bind to LXR and thereby inhibit transcriptional activation that would otherwise occur via endogenous LXR ligands.

Inverse agonists differ from antagonists in that they not only bind to LXRs and inhibit transcriptional activity, but they also actively shut down transcription directed by LXRs even in the absence of endogenous agonists. Whereas it is difficult to distinguish LXR antagonistic activity from inverse agonistic activity in vivo, biochemical or cellular reporter assays can more clearly distinguish between the two activities given that there is always some level of endogenous LXR agonist present. At the molecular level, inverse agonists do not allow recruitment of co-activator proteins or active parts thereof, however they should lead to active recruitment of co-repressor proteins or active parts thereof. An LXR antagonist in this context will be defined as an LXR ligand that causes neither co-activator nor co-repressor recruitment, but rather acts only by replacing an LXR agonist. Thus, it is mandatory to use assays such as Gal 4-mammalian-two-hybrid assays to distinguish LXR compounds that recruit co-activators or co-repressors (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 not clear but are smooth, the term "LXR modulator" has been created to encompass all compounds that are not explicit LXR agonists but show a degree of co-repressor recruitment and reduced LXR transcriptional activity. Thus, LXR modulators encompass LXR antagonists and LXR inverse agonists, and it should be noted that even weak LXR agonists can act as LXR antagonists if the weak LXR agonist prevents full transcriptional activation of the full agonist.

figure 1 will show the differences between LXR agonists, antagonists and inverse agonists, here distinguished by their different abilities to recruit co-activators or co-repressors.

FIG. 1: differences between LXR agonists, antagonists and inverse agonists.

the compounds are useful for the prevention and/or treatment of diseases mediated by LXR. Preferred diseases are all disorders associated with steatosis, i.e. the accumulation of tissue fat. Such diseases encompass the full spectrum of non-alcoholic fatty liver diseases including non-alcoholic steatohepatitis, liver inflammation and liver fibrosis, in addition to insulin resistance, metabolic syndrome and cardiac steatosis. LXR modulator-based drugs are also useful in the treatment of hepatitis c virus infection or its complications, and in the prevention of the undesirable side effects of long-term glucocorticoid therapy in diseases such as rheumatoid arthritis, inflammatory bowel disease, and asthma.

A different set of applications of LXR modulators can be used to treat cancer. LXR antagonists or inverse agonists can be used to counteract the so-called Warburg effect associated with the transition from normally differentiated to cancerous cells (see Liberti et al Trends biochem. Sci.2016; 41: 211; Ward & Thompson, Cancer Cell 2012; 21: 297-308). In addition, LXRs are known to modulate various components of the innate and adaptive immune systems. Oxysterols, known as endogenous LXR agonists, were identified as modulators of LXR-dependent immunosuppressive effects found in the tumor microenvironment (Traversari et al, eur.j.immunol.2014; 44: 1896). Therefore, it is reasonable to assume that LXR antagonists or inverse agonists are capable of stimulating the immune system and antigen presenting cells, in particular eliciting anti-tumor immune responses. The latter effect of LXR antagonists or inverse agonists can be used for the treatment of advanced cancers, typically and in particular those types of cancer solid tumors that show an adverse immune response and highly elevated signs of Warburg metabolism.

More specifically, the anti-Cancer activity of the LXR inverse agonist SR9243 was shown to be mediated by interfering with the Warburg effect and adipogenesis in SW620 colon tumor cells in different tumor cells in vitro and in athymic mice (see Flaveny et al, Cancer cell.2015; 28: 42; Steffensen, Cancer Cell 2015; 28: 3).

LXR modulators, preferably LXR inverse agonists, can counteract the diabetogenic effects of glucocorticoids without compromising the anti-inflammatory effects of glucocorticoids and can therefore be used for preventing the undesired side effects of long-term glucocorticoid therapy in diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma (Patel et al, Endocrinology 2017: in press; doi: 10.1210/en.2017-00094).

LXR modulators, preferably LXR inverse agonists, may be used to treat hepatitis C virus mediated hepatic steatosis (see Garcia-Mediavilla et al, Lab invest.2012; 92: 1191).

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

LXR modulators, preferably LXR inverse agonists, may be useful for the treatment of insulin resistance (see Zheng et al, PLoS One 2014; 9: e 101269).

experimental part

the compounds of the present invention may be prepared by a combination of methods known in the art including the procedures described in schemes I and II below.

Scheme I: synthesis of sulfonamides

In the case when W is not an oxygen atom, the compounds of the invention may be prepared as outlined in scheme II: sulfonyl chloride II-a can be converted to sulfinic acid II-b. Activation with oxalyl chloride to the corresponding sulfinyl chloride followed by coupling with an amine (see Zhu et al, Tetrahedron: Asymmetry 2011; 22:387) gives an intermediate which can be processed as outlined in scheme I above to give the final sulfinamide II-c.

Sulfenamide II-d can be protected with Boc2O to tert-butyl carbamate II-e (see Maldonado et al, Tetrahedron 2012; 68:7456), activated with N-chlorosuccinimide and coupled with an amine (see Battula et al, Tetrahedron Lett. 2014; 55:517) to give an intermediate which can be treated as outlined in scheme I above to give the imidosulfonamide II-f.

Sulfonyl chloride II-a can be converted to R11 substituted sulfinamide II-g and then activated with tert-butyl hypochlorite similarly as outlined in US 20160039846. Coupling with amines gives intermediates which can be processed as outlined in scheme I above to finally give substituted imidoyl sulfonamides II-h.

Scheme II: synthesis of sulfenamides and imidosulfonamides

abbreviations

ac acetyl group

ACN acetonitrile

BINAP 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl

B2Pin 24, 4,4',4',5,5,5',5' -octamethyl-2, 2' -di-1, 3, 2-dioxaborolane

Boc N-tert-butoxycarbonyl

br width (signal in NMR)

m-CPBA m-chloroperbenzoic acid

dba dibenzylidene acetone

DCM dichloromethane

DMF N, N-dimethylformamide

dppf 1,1' -bis (diphenylphosphino) ferrocene

EA Ethyl acetate

FCC flash column chromatography (on SiO 2)

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

pin pinacol (OCMe2CMe2O)

PE Petroleum Ether

Pd/C palladium on carbon

rt Room temperature

sat, saturation

s-phos 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl

TBS tert-butyldimethylsilyl group

TEA Triethylamine

Tf trifluoromethanesulfonate (CF3SO3-)

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl group

X-phos 2-dicyclohexylphosphino-2 ',4', 6' -triisopropylbiphenyl

The example beginning with "C" (e.g., "C3/2") is a comparative example.

Preparation P1

2- ((3-bromophenyl) sulfonyl) propionic acid methyl ester (P1)

To a suspension of methyl 2- ((3-bromophenyl) sulfonyl) acetate (500mg, 1.71mmol) and K2CO3(354mg, 2.57mmol) in acetone (20mL) was added MeI (0.11mL, 1.71mmol) at room temperature. The reaction mixture was stirred at 30 ℃ overnight and filtered. The filtrate was concentrated to give crude compound P1 as a yellow oil. MS: 307(M +1) +.

Preparation P2

2- ((3-bromophenyl) sulfonyl) -2-methylpropanoic acid methyl ester (P2)

A suspension of 2- ((3-bromophenyl) sulfonyl) acetate (500mg, 1.71mmol) and NaH (152mg, 60% on oil, 3.8mmol) in anhydrous DMF (10mL) was stirred at 0 ℃ for 0.5h, then MeI (0.7mL, 3.77mmol) was added to the solution at 0 ℃. The mixture was stirred at room temperature for 2H, diluted with H2O and extracted with EA (3 ×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give crude compound P2 as a yellow oil. MS: 321(M +1) +.

Preparation P3

Step 1: 4-bromo-2, 6-difluorobenzoic acid tert-butyl ester (P3a)

a mixture of 4-bromo-2, 6-difluorobenzoic acid (25.0g, 110mmol), Boc2O (50.0g, 242mmol) and 4-dimethylaminopyridine (1.3g, 11mmol) in tert-BuOH (200mL) was stirred at 40 ℃ overnight, concentrated and purified by FCC (PE: EA ═ 50:1) to give compound P3a as a yellow oil. MS: 292(M +1) +.

Step 2: 4-bromo-2-fluoro-6- ((2-methoxy-2-oxyethyl) thio) benzoic acid tert-butyl ester (P3b)

To a solution of methyl 2-mercaptoacetate (11.2g, 106mmol) in anhydrous DMF (50mL) at 0 deg.C was added NaH (5.1g, 60%, 127 mmol). The mixture was stirred for 30 min. A solution of compound P3a (31g, 106mmol) in anhydrous DMF (100mL) was then added to the mixture. The mixture was stirred at room temperature for 2H, diluted with H2O (1000mL) and extracted with EA (3 ×). The combined organic layers were washed with H2O and brine, concentrated and purified by FCC (PE: EA ═ 10:1) to give compound P3b as a yellow oil. MS: 378(M +1) +.

and step 3: 4-bromo-2-fluoro-6- ((2-methoxy-2-oxyethyl) thio) benzoic acid (P3c)

A solution of compound P3b (18g, 47.5mmol) and TFA (30mL) in DCM (60mL) was stirred overnight at room temperature, concentrated in vacuo, diluted with Et2O and stirred for 30 min. The mixture was filtered to give compound P3c as a white solid.

And 4, step 4: methyl 2- ((5-bromo-3-fluoro-2- (hydroxymethyl) phenyl) thio) acetate (P3d)

To a solution of compound P3c (12g, 37.3mmol) in THF (100mL) at 0 deg.C was added TEA (10 mL). Isobutyl chloroformate (5.5g, 41.0mmol) was then slowly added to the reaction mixture at 0 ℃. The mixture was stirred at 0 ℃ for 30min, filtered and washed with THF (100 mL). The filtrate was cooled to 0 ℃ and NaBH4(2.8g, 74.6mmol) was added slowly. The mixture was allowed to warm to room temperature and held for 3 h. Saturated NH4Cl (1000mL) was added and the solution was extracted with EA (2 × 200 mL). The combined organic layers were washed successively with water (500mL) and brine (200mL), dried over Na2SO4, filtered, concentrated and purified by FCC (PE/EA ═ 10:1) to give the title compound P3d as a white solid. 1H-NMR (CDCl3, 300MHz): δ 7.43(t, J ═ 1.6Hz,1H),7.19(dd, J ═ 1.6,8.4Hz,1H),4.85(d, J ═ 2.0Hz,2H),3.73(s,2H),3.72(s,3H),2.59(br s,1H) MS: 306.9/308.9(M +1) +.

And 5: methyl 2- ((2- (acetoxymethyl) -5-bromo-3-fluorophenyl) thio) acetate (P3)

A solution of compound P3d (3.5g, 11.4mmol) in DCM (100mL) was treated with a catalytic amount of 4- (dimethylamino) -pyridine (140mg, 1.1mmol) under N2. TEA (1.7g, 17.1mmol) and Ac2O (1.4g, 13.7mmol) were added to the mixture and the mixture was stirred at room temperature for 1h, washed with 1N HCl (100mL), water and brine, dried over Na2SO4, filtered and concentrated to give crude compound P3 as a white solid which was used in the next step without further purification.

Preparation P4

Step 1: 4- (trifluoromethyl) thiazole-2-carboxylic acid ethyl ester (P4a)

A solution of 3-bromo-1, 1, 1-trifluoropropan-2-one (6.2mL, 35mmol) and ethyl 2-amino-2-thioacetate (8.0g, 60mmol) in EtOH (150mL) was stirred at 85 deg.C overnight. The mixture was concentrated, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by FCC (PE: EA ═ 100:1 to 50:1) to give compound P4a as a yellow oil.

Step 2: (4- (trifluoromethyl) thiazol-2-yl) methanol (P4b)

To a solution of compound P4a (7.53g, 33mmol) in MeOH (30mL) at 0 deg.C was added NaBH4(2.5g, 66 mmol). The mixture was stirred at 0 ℃ for 2h, concentrated, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by FCC (PE: EA ═ 20:1 to 5:1) to give compound P4b as a yellow solid.

And step 3: 2- (chloromethyl) -4- (trifluoromethyl) thiazole (P4)

A solution of compound P4b (1.0g, 5.5mmol), PPh3(2.15g, 8.2mmol) and CCl4(10mL) in toluene (30mL) was stirred at 120 ℃ overnight, concentrated and purified by FCC (PE: EA ═ 10:1) to give compound P4 as a yellow solid.

preparation P5

4- (chloromethyl) -2- (trifluoromethyl) thiophene (P5)

To a solution of (5- (trifluoromethyl) thiophen-3-yl) methanol (500mg, 2.74mmol) in DCM (10mL) was added SOCl2(0.60mL, 8.22mmol) at room temperature. The mixture was stirred at room temperature for 8h and adjusted to pH about 8 with 1N Na2CO 3. The organic layer was dried over Na2SO4, concentrated and purified by FCC (PE: EA ═ 20:1) to give compound P5 as a yellow oil.

Preparation P6

Step 1: (4-bromobenzyl) sulfamic acid (P6a)

to a solution of (4-bromophenyl) methylamine (5.0g, 26.9mmol) in DCM (50mL) at 0 ℃ was added HSO3Cl (1.89g, 16.2mmol) and the mixture was stirred at room temperature under N2 for 0.5h, filtered and the residue was washed with concentrated HCl. The solid was dried to give crude product P6a as a white solid.

Step 2: (4-bromobenzyl) sulfamoyl chloride (P6b)

To a solution of crude compound P6a (5.0g) in toluene (30mL) was added PCl5(1.96g, 9.43mmol) and the mixture was stirred at 120 ℃ for 1.5h, cooled and filtered. The filtrate was concentrated in vacuo and used directly in the next step.

and step 3: n- (4-bromobenzyl) -1,3, 3-trimethyl-6-azabicyclo [3.2.1] octane-6-sulfonamide (P6)

To a solution of 1,3, 3-trimethyl-6-azabicyclo [3.2.1] octane (600mg, 3.92mmol) in DCM (20mL) was added TEA (400mg, 3.92mmol) and crude compound P6 b. The mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated and purified by FCC (PE: EA ═ 5:1) to give compound P6 as a white solid.

Preparation examples P7 and P7-1

Step 1: 4-bromo-2- (bromomethyl) -1-toluene (P7a)

To a solution of (5-bromo-2-methylphenyl) methanol (2.7g, 13.4mmol) in THF (50mL) was added PBr3(0.6mL, 6.7mmol) with ice bath cooling. The mixture was stirred at 0 ℃ for 2h, diluted with water (100mL), basified with saturated NaHCO3 to pH 7 and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (100mL), dried over Na2SO4, filtered and concentrated to give compound P7a as a yellow oil.

Step 2: 2- (5-bromo-2-methylphenyl) acetonitrile (P7b)

to a solution of compound P7a (3.5g, 13.3mmol) in DMF (50mL) was added NaCN (715mg, 14.6mmol) at room temperature. The mixture was stirred at 60 ℃ for 5h, diluted with water (100mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with water (2 × 100mL) and brine (100mL), dried over Na2SO4, filtered and concentrated to give crude compound P7b as a white solid.

and step 3: 2- (5-bromo-2-methylphenyl) acetic acid (P7c)

to a solution of compound P7b (1.6g, 7.6mmol) in water (50mL) and EtOH (50mL) was added KOH (4.3g, 76mmol) at room temperature. The mixture was stirred at reflux overnight, then EtOH was evaporated, and the solution was acidified to pH3 with 1N HCl and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (100mL), dried over Na2SO4, filtered and concentrated to give crude compound P7c as a white solid.

And 4, step 4: 2- (5-bromo-2-methylphenyl) acetic acid methyl ester (P7d)

To a solution of compound P7c (1.5g, 6.6mmol) in MeOH (50mL) at room temperature was added concentrated H2SO4(0.3 mL). The mixture was stirred at reflux overnight, evaporated and dissolved in EA (50mL) and water (20 mL). The mixture was basified with saturated NaHCO3 to pH 7 and extracted with EA (2 × 50 mL). The combined organic layers were washed with brine (100mL), dried over Na2SO4, filtered and concentrated to give crude compound P7d as a yellow oil.

And 5: 2- (5-bromo-2-methylphenyl) -2-methylpropanoic acid methyl ester (P7e)

to a solution of compound P7d (9.5g, 39.1mmol) in anhydrous DMF (100mL) was added NaH (3.9g, 60%, 98mmol) with ice bath cooling. The mixture was stirred at 0 ℃ for 10min, then 18-crown-6 (1.1g, 7.8mmol) and MeI (12.2mL, 196mmol) were added. The mixture was stirred at room temperature overnight, diluted with water (200mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with water (2 × 200mL) and brine (100mL), dried over Na2SO4, filtered and evaporated. The process was repeated again, and the obtained residue was then purified by FCC (PE: EA ═ 20:1) to give crude compound P7e as a yellow oil.

Step 6: 2- (5-bromo-2- (bromomethyl) phenyl) -2-methylpropanoic acid methyl ester (P7f)

To a solution of compound P7e (9.0g, 33.2mmol) in CCl4(150mL) at room temperature under N2 was added NBS (6.5g, 36.5mmol) and benzoyl peroxide (799mg, 3.3 mmol). The mixture was stirred at reflux overnight and concentrated. The residue was dissolved in EA (200mL), washed with water (100mL) and brine (100mL), dried over Na2SO4, filtered and concentrated to give crude compound P7f as a yellow oil.

And 7: 2- (2- (Acetoxymethyl) -5-bromophenyl) -2-methylpropanoic acid methyl ester (P7g)

To a solution of compound P7f (11.0g, 31.4mmol) in DMF (100mL) at room temperature was added KOAc (6.2g, 63mmol) and KI (50mg, 0.3 mmol). The mixture was stirred at room temperature for 2h, diluted with water (200mL) and extracted with EA (3X 100 mL). The combined organic layers were washed with water (2 × 200mL) and brine (100mL), dried over Na2SO4, filtered, concentrated and purified by FCC (PE: EA ═ 10:1) to give compound P7g as a yellow oil.

And 8: 6-bromo-4, 4-dimethylisochroman-3-one (P7)

to a solution of compound P7g (5.5g, 16.7mmol) in MeOH (50mL) and water (50mL) was added KOH (3.7g, 63mmol) at room temperature. The mixture was stirred at room temperature for 5h and then concentrated. The residue was acidified with 1N HCl to pH 5, stirred at room temperature for 1h and then filtered. The filter cake was washed with PE/EA (20mL, 10/1) to give compound P7 as a white solid. 1H-NMR (CDCl3, 400MHz): δ 7.50(d, J ═ 2.0Hz,1H),7.42(dd, J ═ 8.0,1.6Hz,1H),7.05(d, J ═ 8.0Hz,1H),5.36(s,2H),1.58(s,6H) MS: 255(M +1) +.

And step 9:4, 4-dimethyl-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isochroman-3-one (P7-1)

To a solution of compound P7(900mg, 3.53mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (986mg, 3.88mmol) and KOAc (1.04g, 10.6mmol) in 1, 4-dioxane (20mL) was added pd (dppf) Cl2(284mg, 0.35mmol) at room temperature under N2. The mixture was stirred at 100 ℃ overnight, cooled, filtered, concentrated and purified by FCC (PE: EA ═ 20:1) to give compound P7-1 as a white solid.

Preparation P8

5-bromo-2- (bromomethyl) -3-chlorothiophene (P8)

A mixture of (3-chlorothien-2-yl) methanol (500mg, 3.36mmol) in AcOH (30mL) was stirred at 15 ℃. Br2(644mg, 4.03mmol) was then added dropwise to the mixture. The mixture was diluted with water and extracted with EA (3 ×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give compound P8 as a yellow oil.

Preparation P9

step 1: (5- (trifluoromethyl) furan-2-yl) carbamic acid tert-butyl ester (P9a)

A solution of 5- (trifluoromethyl) furan-2-carboxylic acid (1.0g, 5.5mmol), diphenylphosphoryl azide (2.4mL, 11mmol) and TEA (0.8mL, 11mmol) in tert-butanol (15mL) was refluxed overnight, concentrated and purified by FCC (PE: EA ═ 40:1) to give compound P9a as a yellow oil.

(P9b)step 2: (2,4, 6-Trimethylphenylsulfonyl) (5- (trifluoromethyl) furan-2-yl) carbamic acid tert-butyl ester (P9b)

To a suspension of NaH (180mg, 60%, 4.4mmol) in anhydrous DMF (15mL) was added compound P9a (550mg, 2.2 mmol). After stirring the mixture for 30min, 2,4, 6-trimethylbenzenesulfonyl chloride (480mg, 2.2mmol) was added. The mixture was stirred at room temperature for 2H, diluted with H2O (100mL) and extracted with EA (3 ×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and purified by FCC (PE: EA ═ 100:1) to give compound P9b as a yellow solid.

And step 3: 2,4, 6-trimethyl-N- (5- (trifluoromethyl) furan-2-yl) benzenesulfonamide (P9)

To a mixture of compound P9b (138mg, 0.32mmol) in DCM (20mL) was added TFA (1.5 mL). The mixture was stirred at room temperature for 2h and concentrated to give compound P9 as a yellow oil, which was used in the next step without further purification.

Preparation P10

Step 1: (E) -2- (2-nitrovinyl) furan (P10a)

to a solution of furan-2-carbaldehyde (50g, 0.52mol) in MeOH (100mL) at 0 deg.C was added nitromethane (70mL, 1.30mol) and 1N NaOH (1.3L) dropwise. Ice/water (250mL) was then added. The mixture was stirred at 0 ℃ for 30 min. The mixture was slowly added to 8.0M HCl (500mL) at 0 ℃ until the reaction was complete. The mixture was filtered to give compound P10a as a yellow solid.

step 2: 2- (Furan-2-yl) ethan-1-amine (P10)

To a solution of compound P10a (63.0g, 0.45mol) in anhydrous THF (400mL) at 0 deg.C was added LiAlH4(69g, 1.81 mol). The mixture was stirred at 0 ℃ for 2 h. To the mixture were added H2O (69mL), 10% NaOH (69mL), and H2O (207mL) at 0 ℃. The mixture was filtered, concentrated and purified by FCC (PE: EA ═ 5:1 to 1:1) to give compound P10 as a yellow oil.

Preparation P11

(P11a)Step 1: n- (4-bromobenzyl) -N- ((5-formylfuran-2-yl) methyl) -2,4, 6-trimethylbenzenesulfonamide (P11a)

To a solution of 5- (chloromethyl) furan-2-carbaldehyde (310mg, 2.14mmol) and compound 1a (786mg, 2.14mmol) in ACN (20mL) was added K2CO3(591mg, 4.28mmol) and KI (355mg, 2.14mmol) at room temperature. The mixture was stirred at 80 ℃ under N2 overnight, cooled, filtered, concentrated and purified by FCC (PE: EA ═ 20:1 to 10:1) to give compound P11a as a yellow solid.

Step 2: n- (4-bromobenzyl) -N- ((5- (difluoromethyl) furan-2-yl) methyl) -2,4, 6-trimethylbenzenesulfonylamine (P11)

To a solution of compound P11a (600mg, 1.3mmol) in DCM (20mL) was added diethylaminosulfur trifluoride (1.6mL, 12.6mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5h, then at 30 ℃ overnight, quenched with NaHCO3 and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by FCC (PE: EA ═ 20:1) to give compound P11 as a yellow solid.

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