EA041925B1 - INDAN DERIVATIVES FOR USE IN THE TREATMENT OF BACTERIAL INFECTION - Google Patents

Description

Technical field

The present invention relates to compounds that can be used to prevent or treat a bacterial infection. The invention also provides said compounds per se (lat.

as such) and pharmaceutical compositions containing them.

Prior Art

Cystic fibrosis (CF, cystic fibrosis) is a life-threatening disease that affects about 70,000 people worldwide. CF is one of the most common lethal hereditary diseases of white Caucasians caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The prevalence of CF in Europe is 1 in every 2000-3000 live births and in North America approximately 1 in every 3500 live births. There are approximately 9800 people with CF in the UK.

In the organs of people suffering from CF, as a rule, there are much thicker secretions. This, in turn, can lead to a number of pathological problems. For example, mucociliary clearance is usually impaired in people with CF, and the lungs of such patients are often colonized and infected with bacteria from an early age. These bacteria include Staphylococcus aureus, Haemophilus influenza, Pseudomonas aeruginosa, and Burkholderia cepacia. The bacterium Pseudomonas aeruginosa (PA) is the most common cause of chronic lung infection in individuals with CF, with chronic RA infection found in 9% of preschool children, 32% of children aged 10 to 15 years, and most (from 59 to 80%) of adults with CF, leading to progressive lung damage and early death.

As the lung of a person with CF is colonized by RA bacteria, the growth pattern of the bacteria changes and their ability to survive increases. In chronic infection, RA bacteria form biofilms on mucous or epithelial surfaces or in sputum and produce a large amount of alginate (the so-called mucoid phenotype), which reduces the effectiveness of phagocytosis and antibiotic therapy. This leads to chronic colonization of the lungs by RA, which is not eliminated by conventional antibiotic therapy.

Antibiotics are a wide range of substances that exhibit antibacterial activity. A large number of antibiotic compounds are known to exhibit antibacterial activity against a wide range of bacteria. However, currently available antibiotics are unable to control some bacterial infections. This is because the target bacteria acquire resistance to antibiotics, for example, through horizontal gene transfer, or because the target bacteria are in a state in which the effectiveness of antibiotics that would otherwise be highly active is reduced. One such condition is bacterial biofilm.

Bacteria in biofilms are enclosed in a matrix of extracellular biopolymer substances synthesized by them, which may contain polysaccharides, proteins and DNA (Eng. DNA, Deoxyribonucleic Acid - deoxyribonucleic acid). Bacteria in biofilms usually have properties that are different from those of free-living bacteria of the same species. These properties typically include increased resistance to antibiotics and detergents, as well as increased horizontal gene transfer. For example, bacteria in biofilms typically show 1000 times higher resistance to antibiotic use than their autonomous planktonic (free-living) counterparts.

Such limitation of the effectiveness of antibacterial compounds is especially important for people who, due to immunodeficiency or other diseases or conditions, cannot adequately fight a bacterial infection. These people include patients with cystic fibrosis.

CF patients colonized with RA are also characterized by a dramatic decline in lung function, a rapid worsening of chest radiographs, insufficient weight gain, an increased rate of hospitalizations, and an increased need for antibiotic therapy. At the same time, the average survival rate decreases, and mortality increases (the risk of death increases by 2.6 times). Most disease-related complications and deaths in CF are due to progressive lung disease resulting from bacterial infection and inflammation of the airways, which is primarily due to the consequences of chronic RA lung infection and the persistence of RA biofilms. Despite intensive antibiotic treatment, adaptive mechanisms such as biofilm formation allow RA bacteria to resist both immune and antibiotic exposure, leading to recurrent exacerbations and respiratory failure.

Pathogenic bacteria such as RA are not only relevant in the context of CF. For example, the opportunistic pathogen RA can also cause septic shock, especially in neutropenic patients, and can cause respiratory, urinary, gastrointestinal, skin, and soft tissue infections. RAs often colonize medical devices such as catheters, nebulizers, etc.

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Thus, there is a clear need for new antibiotic compounds and compositions, as well as adjuvant therapy for the treatment of bacterial infection.

Brief description of the essence of the invention

The inventors have surprisingly found that the compounds of formula (I) are potent inhibitors of the LasB elastase enzyme produced by the bacterium Pseudomonas aeruginosa and which plays an important role in the pathogenesis and persistence of Pseudomonas aeruginosa through biofilm formation.

LasB elastase is implicated in the pathology of bacterial diseases because secreted LasB degrades many host immune proteins and causes tissue damage. LasB, also known as pseudolysin, is largely secreted into the host environment, where it can proteolytically attack numerous host immune proteins (eg, immunoglobulins, cytokines, SP-A, antimicrobial peptides (eg, Trappin 2))) and tissue proteins (eg, elastin). There are no LasB homologues in mammals. The ability of LasB to attack host proteins favors immune evasion (eg, prevention of SP-A mediated phagocytosis and immunoglobulin degradation, degradation of antimicrobial peptides (eg, trappin 2)), while promoting tissue invasion and long-term colonization. Therefore, LasB inhibition will help the host cope with the immune attack.

LasB also plays an important intrasystemic role in the bacterial cell by cleaving nucleoside diphosphate kinase (NDK) to a smaller active form.

The active form of NDK leads to an increase in the levels of GTP (English Guanosine triphosphate - guanosine triphosphate) in the cell, increasing the production of alginate. Alginate is a polysaccharide that is the main component of the extracellular matrix of the biofilm and is necessary for the mobility of bacterial clusters. These two virulence phenotypes are associated with the persistence of bacteria in response to the effects of the immune system and antibiotics. It has also been shown that LasB elastase activity stimulates the production of rhamnolipids necessary for the formation/maturation of biofilms. Accordingly, inhibition of LasB will contribute to the disruption of biofilm formation and the destruction of the already existing biofilm. And this, in turn, is believed to help the antibiotics currently used to effectively fight infection.

In addition, LasB directly activates interleukin-1-β (IL-1e). IL-1e is a human protein and a key initiator of the inflammatory response. This pro-inflammatory cytokine is a clinical biomarker of inflammation and is upregulated during severe pulmonary exacerbations in CF patients. IL-1P is produced in an inactive form (pro-IL-1p) by host cells in response to pathogen detection and is activated by hydrolytic removal of the peptide fragment by the host's caspase-1. Recent studies have shown that Pseudomonas aeruginosa (PA) secreted LasB elastase can also cleave and activate IL-1e. This activation occurs via cleavage at an alternative and non-caspase-1 site. Since LasB directly activates IL-1e by hydrolysis of pro-IL-1 β, IL-1e, respectively, can be considered as a marker of LasB PA activity both in vitro and in vivo. The inventors have found that the ability of LasB to activate IL-1e leads to the use of LasB inhibitors in the treatment of inflammation and related conditions.

Accordingly, the invention provides the following aspects.

1. An indane compound of formula (I) or a pharmaceutically acceptable salt thereof (r ³ ) ''n

FORMULA (I) where R ¹ is selected from

NHOH, OH, OR ^1a and -OCH2OC(O)R ^1a where R ^1a is selected from an unsubstituted C to C4 alkyl group and phenyl; and in the case where the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O ^- so that the compound forms a zwitterion;

R ² is selected from H and unsaturated C1 to C ₂ alkyl;

each of the R ³ groups is independently selected from halogen, -OH, -NH2, methyl, and -CF ₃ ;

n is an integer from 0 to 4;

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R ⁴ is selected from H and unsaturated C ₁ to C ₂ alkyl;

L is selected from a bond and a C ₁ to C ₃ alkylene group, unsubstituted or substituted with one group selected from halo, -OH, -OMe, -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² and -CF ₃ ;

p is 0 or 1;

R ⁵ is selected from -OMe, -OH, halogen, -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² , -CF ₃ and R ⁶ ;

each R ⁶ is independently selected from

- R ^6a R ^A , -OR ^6a R ^A , -NR ²⁰ -R ^6a R ^A , -R ^6b R ^B , -OR ^6b R ^B and -NR ²⁰ -R ^6b R ^B ;

-R ^x R ^r , -OR ^x R ^r , -OR ^x -C(O)-R ^r , -R ^x -C(O)-R ^r , -NR ²⁰ -R ^x R ^r and -NR ²⁰ -R ^x -C(O)-R ^r ; And

- CN; -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^x R ^b ; -C(O)NR ⁴⁰ R ⁴¹ ; -SO2R ²⁰ ; -SO2-R ^X R ^B ; -SO2NR ²⁰ R ²¹ ; -SO2-NR ²⁰ R ^X R ^B and -SO2NR ⁴⁰ R ⁴¹ ;

where each R ^X is independently selected from R ^6a and R ^6b ;

each R ^6a is independently selected from C1 to C4 alkylene, C2 to C4 alkenylene, and C2 to C4 alkynylene; and each R ^6a is independently unsubstituted or substituted with one group selected from —OH, halo; -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ C(NR ²¹ )NR ²² R ²³ ; -NR ²⁰ C(N ⁺ R ²¹ R ²² )NR ²³ R ²⁴ ; -NR ²⁰ C(NR ²¹ )R ²² ; -NR ²⁰ C(N ⁺ R ²¹ R ²² )R ²³ ; -C(NR ²⁰ )NR ²¹ R ²² ; -C(N ⁺ R ²⁰ R ²¹ )NR ²² R ²³ ; -C(NR ²⁰ )R ²¹ and -C(N ⁺ R ²⁰ R ²¹ )R ²² ;

- C(O)NR ²⁰ R ²¹ ; -C(O)N ⁺ R ²⁰ R ²¹ R ²² ; -C(O)-R ²⁰ and methoxy unsubstituted or substituted with one, two or three halogen substituents;

each R ^6b is independently selected from [C1 to C3 alkylene]-C(R ^z )2R ^b , [C2 to C3 alkenylene]-C(R ^z )2R ^b and [C2 to C3 alkynylene]-C(R ^z )2R ^b ; where two R ^z groups are interconnected and together with the atom to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic group;

R ^a is selected from -NR ²⁰ R ³⁰ ; -N ⁺ R ²⁰ R ²¹ R ³⁰ ; -NR ²⁰ NR ²¹ R ²² ; -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ; -N ⁺ R ²⁰ R ²¹ NR ²² R ²³ ;

-NR ²⁰ C(NR ²¹ )NR ²² R ³⁰ ; -NR ²⁰ C(N ⁺ R ²¹ R ²² )NR ²³ R ³⁰ ; -C(NR ²⁰ )NR ²¹ R ²² and -C(N ⁺ R ²⁰ R ²¹ )NR ²² R ²³ ;

R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² ; -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ; -N ⁺ R ²⁰ R ²¹ NR ²² R ²³ ;

-NR ²⁰ C(NR ²¹ )NR ²² R ²³ ; -NR ²⁰ C(N ⁺ R ²¹ R ²² )NR ²³ R ²⁴ ; -C(NR ²⁰ )NR ²¹ R ²² and -C(N ⁺ R ²⁰ R ²¹ )NR ²² R ²³ ;

R ⁴⁰ and R ⁴¹ together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocyclic group, where any nitrogen atom in the ring is independently selected from secondary, tertiary and quaternary nitrogen atoms;

each RR is independently a 4- to 10-membered heteroaryl or heterocyclic group containing at least one nitrogen atom, said nitrogen atom(s) being independently selected from secondary, tertiary, and quaternary nitrogen atoms;

where each RR and each ring formed by -NR ⁴⁰ R ⁴¹ is independently unsubstituted or substituted with one, two or three groups independently selected from

i) halogen, -CN;

ii) oxo groups, provided that said RR group is a heterocyclic group;

iii) -R ²⁰ , -R7-OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ ; -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² ; -R ⁷ -NR ²⁰ C(NR ²¹ )NR ²² R ²³ ; -R ⁷ NR ²⁰ C(N ⁺ R ²¹ R ²² )NR ²³ R ²⁴ ; -R ⁷ -NR ²⁰ C(NR ²¹ )R ²² ; -R ⁷ -NR ²⁰ C(N ⁺ R ²¹ R ²² )R ²³ ; -R ⁷ -C(NR ²⁰ )NR ²¹ R ²² ; -R ⁷ C(N ⁺ R ²⁰ R ²¹ )NR ²² R ²³ ; -R ⁷ -C(NR ²⁰ )R ²¹ and -R ⁷ -C(N ⁺ R ²⁰ R ²¹ )R ²² ;

each R ⁷ is independently selected from a bond and unsubstituted C ₁ to C ₃ alkylene;

each of R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ is independently selected from H and C ₁ to C ₃ alkyl, unsubstituted or substituted with one —OH or —OMe group, or one, two or three halogens;

each R ³⁰ is independently selected from C ₂ to C ₃ alkyl, unsubstituted or substituted with one —OH or —OMe group, or one, two or three halogens.

2. A compound according to aspect 1 wherein R ⁵ is selected from -OMe and -OH.

3. A compound according to aspect 1, wherein p is 0.

4. Connection in accordance with any of the preceding aspects, where R ¹ is selected from OH and NHOH; or in the case where the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O ^- so that the compound forms a zwitterion.

5. A compound according to any of the preceding aspects, wherein R ² is selected from H and unsubstituted methyl.

6. A compound according to any of the preceding aspects, wherein R ⁴ is H.

7. A compound according to any of the preceding aspects, wherein n is an integer from 0 to 2.

8. A compound according to any of the preceding aspects, wherein each of the R ³ groups is independently selected from halo and —OH.

9. A compound according to any of the preceding aspects, wherein L is an unsubstituted C1 alkylene group.

10. A compound according to any of the preceding aspects 1 to 5, wherein each R ⁶ is independently selected from -R ^6a R ^A , -OR ^6a R ^A , -NR ²⁰ -R ^6a R ^A , -R ^6b R ^B , - OR ^6b R ^B , -NR ²⁰ -R ^6b R ^B , -R ^X RR, -OR ^X RR, -OR ^X C(O)-R ^r and -R ^x -C(O)-R ^r , where each R ^X represents the group R ^6a ;

each R ^6a group is independently a C ₁ to C ₄ alkylene group, and each group

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R ^6a is independently unsubstituted or substituted with one group selected from -OH, halo;

-NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; and an unsubstituted methoxy group;

each R ^6b is independently [C1 to C3 alkylene]-C(R ^z )2R ^b ; where two groups

R ^z are interconnected and together with the atom to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic group;

R ^a is selected from -NR ²⁰ R ³⁰ ; -N ⁺ R ²⁰ R ²¹ R ³⁰ ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ; R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

each RR is independently a 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclic group containing at least one nitrogen atom, said nitrogen atom(s) being independently selected from secondary, tertiary, and quaternary atoms nitrogen;

where each RR is independently unsubstituted or substituted with one, two or three groups independently selected from -R ²⁰ , -R7-OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² .

11. A compound according to any of the preceding aspects, wherein each R ⁶ is independently selected from -OR ^6a R ^A , -OR ^6b R ^B , -OR ^x R ^{r ,} and -OR ^x -C(O)-R ^r , where each R ^X represents the group R ^6a ;

each R ^6a group is independently an unsubstituted C1 to _C4 alkylene group;

each R ^6b is independently a [C1 to C3 αkylene]-C(R ^z )2R ^b group; where two R ^z groups are interconnected and together with the atom to which they are attached form a 5- or 6-membered heterocyclic group, preferably an oxane group;

R ^a is selected from -NR ²⁰ R ³⁰ ; -N ⁺ R ²⁰ R ²¹ R ³⁰ ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

each RR is independently a 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclic group containing at least one nitrogen atom, said nitrogen atom(s) being independently selected from secondary, tertiary, and quaternary atoms nitrogen;

where each RR is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² .

12. Connection in accordance with any of aspects 1 to 9, where each R ⁶ is independently selected from -CN; -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^x R ^b ; -C(O)NR ⁴⁰ R ⁴¹ ; -SO2R ²⁰ ; -SO2NR ²⁰ R ²¹ and -SO ₂ NR ⁴⁰ R ⁴¹ ;

where each R ^X represents a group R ^6a ;

each R ^6a group is independently a C1 to _C4 alkylene group; and each R ^6a group is independently unsubstituted or substituted with one group selected from —OH, halo; -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; and an unsubstituted methoxy group;

R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

each R ⁴⁰ and R ⁴¹ together with the nitrogen atom to which they are attached independently form a 4- to 6-membered heterocyclic group wherein any nitrogen atom in the ring is independently selected from secondary, tertiary and quaternary nitrogen atoms;

where each ring formed by -NR ⁴⁰ R ⁴¹ is independently unsubstituted or substituted with one, two or three groups independently selected from -R ²⁰ , -R ⁷ -OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ N ⁺ R ²⁰ R ²¹ R ²² .

13. Connection in accordance with any of aspects 1 to 9, where each R ⁶ is independently selected from -CN; -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^x R ^b ; -C(O)NR ⁴⁰ R ⁴¹ ; -SO2R ²⁰ ; -SO2NR ²⁰ R ²¹ and -SO ₂ NR ⁴⁰ R ⁴¹ ;

where each R ^X represents a group R ^6a ;

each R ^6a group is independently an unsubstituted C1 to C4 alkylene group;

R ^B is selected from -NR ²⁰ R ²¹ and -N ⁺ R ²⁰ R ²¹ R ²² ;

each R ⁴⁰ and R ⁴¹ together with the nitrogen atom to which they are attached independently form a 4- to 6-membered heterocyclic group wherein any nitrogen atom in the ring is independently selected from secondary, tertiary and quaternary nitrogen atoms;

where each ring formed by NR ⁴⁰ R ⁴¹ is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² .

14. A compound according to any one of aspects 1 to 13 wherein each RR or each ring formed by -NR ⁴⁰ R ⁴¹ , if present, is independently selected from azetidine, morpholine, piperazine, piperidine, pyrrolidine, and triazole.

15. The compound according to aspect 1, wherein the compound is selected from

1) 2-[2-[(4-carbamoyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid;

2) 2-[2-[[4-(pyrrolidin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

3) 2-[2-[(4-pyrrolidin-1-ylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid;

4) 2-[2-[(4-sulfamoyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid;

5) 2-[2-[(4-piperazin-1-ylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic

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6) 2-[2-[[4-(3-Aminopyrrolidin-1-yl)sulfonyl-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid;

7) 2-[2-[(4-methylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid;

8) 2-[2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2 -yl]acetic acid;

9) 2-[2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

10) 2-[5,6-difluoro-2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

11) 2-[5,6-difluoro-2-[[6-methoxy-5-[(1-methyl-4-piperidyl)methoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan- 2-yl]acetic acid;

12) 2-[5,6-difluoro-2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl ]indan-2-yl]acetic acid;

13) 2-[5,6-difluoro-2-[[6-methoxy-5-[2-(4-methylmorpholin-4-ium-4-yl)ethoxy]-1,3-benzothiazol-2-yl] methylcarbamoyl]indan-2-yl]acetate;

14) 2-[2-[[5-[2-(4,4-dimethylpiperazin-4-ium-1-yl)-2-oxoethoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl ]-5,6-difluoroindan-2-yl]acetate;

15) 2-[5,6-difluoro-2-[[6-methoxy-5-[3-(4-methylmorpholin-4-ium-4-yl)propoxy]-1,3-benzothiazol-2yl]methylcarbamoyl] indan-2-yl]acetate;

16) 2-[2-[[6-methoxy-5-[3-(4-methylmorpholin-4-ium-4-yl)propoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2- yl]acetate;

17) 2-[2-[[5-[(1,1-dimethylpiperidin-1-ium-4-yl)methoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2- yl]acetate;

18) 2-[2-[[5-[3-[diethyl(methyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

19) 2-[5,6-difluoro-2-[[6-methoxy-5-[3-(1-methylpyrrolidin-1-ium-1-yl)propoxy]-1,3-benzothiazol-2yl]methylcarbamoyl] indan-2-yl]acetate;

20) 2-[2-[[5-[3-[2-hydroxyethyl(dimethyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

21) 2-[5,6-difluoro-2-[[5-[3-[2-hydroxyethyl(dimethyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan- 2-yl]acetate;

22) 2-[2-[[5-[3-[bis(2-hydroxyethyl)-methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate ;

23) 2-[2-[[5-[3-[bis(2-hydroxyethyl)-methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan- 2-yl]acetate;

24) 2-[2-[[5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

25) 2-[2-[[5-[2-(4-methylpiperazin-1-yl)ethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid;

26) 2-[2-[[6-[3-(dimethylamino)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan2-yl]acetic acid;

27) 2-[2-[[5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid;

28) 2-[2-[[5-[2-(dimethylamino)ethylcarbamoyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

29) 2-[2-[[6-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid;

30) 2-[2-[[6-[2-(dimethylamino)ethylcarbamoyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

31) 2-[2-[[5-[4-[3-(dimethylamino)propyl]piperazin-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

32) 2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan2-yl]acetic acid;

33) 2-[2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

34) 2-[5,6-difluoro-2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl ]acetic acid;

35) 2-[2-[[5-(4,4-dimethylpiperazin-4-ium-1-carbonyl)-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6- difluorindan-2-yl]acetate;

36) 2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

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37) 2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan-2-yl ]acetic acid;

38) 2-[2-[[5-[4-(dimethylamino)piperidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

39) 2-[2-[[6-methoxy-5-[4-(trimethylammonio)piperidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

40) 2-[2-[[5-[2-[(dimethylamino)methyl]morpholine-4-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acids;

41) 2-[2-[[6-methoxy-5-[2-[(trimethylammonio)methyl]morpholine-4-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate ;

42) 2-[2-[[6-methoxy-5-[3-(trimethylammonio)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

43) 2-[5,6-difluoro-2-[[6-methoxy-5-[3-(trimethylammonio)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2- yl]acetate;

44) 2-[2-[[5-[(1,1-dimethylpiperidin-1-ium-4-yl)methoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5 ,6-difluorindan-2-yl]acetate;

45) 2-[2-[[6-methoxy-5-(4-methylpiperazin-1-yl)sulfonyl-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

46) 2-[2-[[5-[[4-(dimethylamino)-1-piperidyl]sulfonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid ;

47) 2-[2-[[6-methoxy-5-[[4-(trimethylammonio)-1-piperidyl]sulfonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

48) 2-[2-[(6-cyano-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid;

49) 2-[2-[(5-cyano-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid;

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition containing (i) a compound according to any of the preceding aspects and (ii) at least one pharmaceutically acceptable carrier or diluent; and optionally also containing an antibiotic agent.

17. The pharmaceutical composition according to aspect 16 wherein the antibiotic agent is selected from tobramycin, neomycin, streptomycin, gentamicin, ceftazidime, ticarcillin, piperacillin, tazobactam, imipenem, meropenem, rifampicin, ciprofloxacin, amikacin, colistin, aztreonam, azithromycin and levofloxacin.

18. A combination of (i) a compound according to any of aspects 1 to 15 and (ii) an antibiotic agent.

19. The combination according to aspect 18, wherein the antibiotic agent is selected from tobramycin, neomycin, streptomycin, gentamicin, ceftazidime, ticarcillin, piperacillin, tazobactam, imipenem, meropenem, rifampicin, ciprofloxacin, amikacin, colistin, aztreonam, azithromycin, and levofloxacin.

20. Connection in accordance with any of aspects 1 to 15; a composition according to aspect 16 or 17 or a combination according to aspect 18 or 19 for use in medicine.

21. Connection in accordance with any of aspects 1 to 15; a composition according to aspect 16 or 17 or a combination according to aspect 18 or 19 for use in the treatment or prevention of a bacterial infection in a subject.

22. A compound for use, a composition for use, or a combination for use according to aspect 21, wherein the bacterial infection is caused by Bacillus, Pseudomonas, Staphylococcus, Streptococcus, Listeria, Burkholderia, or Escherichia bacteria.

23. A compound for use, a composition for use, or a combination for use according to aspect 22, wherein the bacterial infection is caused by Pseudomonas aeruginosa.

24. The use compound, use composition, or use combination according to any one of aspects 21 to 23, wherein the use compound, use composition, or use combination is for the treatment or prevention of pneumonia.

25. Connection in accordance with any of aspects 1 to 15; a composition according to aspect 16 or 17 or a combination according to aspect 18 or 19 for use in the treatment or prevention of inflammation in a subject.

26. A compound for use, a composition for use, or a combination for use according to aspect 25 for the treatment or prevention of airway inflammation in a subject.

27. A compound for use, a composition for use, or a combination for use according to aspect 25 or aspect 26, wherein the inflammation is caused by a bacterial infection.

28. A compound for use, a composition for use, or a combination for use according to any one of aspects 21 to 27 wherein the subject suffers from cystic fibrosis.

29. A compound for use, a composition for use, or a combination for use in

- 6 041925 in accordance with any of the aspects from 21 to 28, where the subject suffers from chronic obstructive pulmonary disease (eng. COPD), bronchiectasis and/or ventilator-associated pneumonia (eng.

VAP).

Brief description of graphic materials

In FIG. 1 shows the incidence of death versus survival and chronic colonization versus bacterial clearance in a mouse lung infection model 7 days after infection with wild-type RA strains and AlasB PA mutant strains. The results are discussed in example 50.

**p<0.01.

In FIG. 2 shows the quantitation of active IL-1e in lungs after infection with wild-type PAO1 and mutant AlasB PAO1 with and without treatment with the compounds of the invention in the lungs of mice 24 hours post-infection. The results are discussed in example 52.

**p<0.001, ****p<0.0001.

RU - relative light units, in this experiment, proportional to the levels of IL-1e.

In FIG. 3 shows the total number of colony forming units (CFU - Colony forming unit) PAO1 wild-type and mutant AlasB PAO1 with and without treatment with the compounds of the invention in the lungs of mice 24 hours after infection. The results are discussed in Example 52.

**p<0.01,***p<0.001.

Detailed description of the invention

Definitions

When used in this context from C 1 to C ₄ alkyl group is a linear or branched alkyl group containing from 1 to 4 carbon atoms. A C1 to C ₄ alkyl group is often a C1 to C ₃ alkyl group. Examples of C1 to _C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. A C1 to C ₃ alkyl group is typically a C1 to C ₂ alkyl group. A C1 to _C2 alkyl group is methyl or ethyl, typically methyl. For the avoidance of ambiguity, if two alkyl groups are present, such alkyl groups may be the same or different.

When used in this context, the alkoxy group, as a rule, is the specified alkyl group attached to an oxygen atom. Thus, a C ₂ to C ₄ alkoxy group is a C ₂ to C ₄ alkyl group attached to an oxygen atom. A C1 to _C3 alkoxy group is a C1 to _C3 alkyl group attached to an oxygen atom. Examples of C2 to C4 alkoxy groups include ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy. Examples of C1 to _C3 alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy. Typically, a C1 to C ₃ alkoxy group is a C1 to C ₂ alkoxy group such as a methoxy or ethoxy group. For the avoidance of ambiguity, if two alkoxy groups are present, such alkoxy groups may be the same or different.

When used in this context from ₂ to C ₄ alkenyl group is a linear or branched alkenyl group containing from 2 to 4 carbon atoms and having one or more double bonds, for example one or two double bonds, usually one double bond. Typically, a C2 to C4 alkenyl group is a C2 to C3 alkenyl group. Examples of C2 to C4 alkenyl groups include ethenyl, propenyl and butenyl. For the avoidance of ambiguity, if two alkenyl groups are present, such alkenyl groups may be the same or different.

When used in this context, from ₂ to C ₄ alkynyl group is a linear or branched alkynyl group containing from 2 to 4 carbon atoms and having one or more triple bonds, for example one or two triple bonds, usually one triple bond. Typically, a C ₂ to C ₄ alkynyl group is a C ₂ to C ₃ alkynyl group. Examples of C ₂ to C ₄ alkynyl groups include ethynyl, propynyl and butynyl. For the avoidance of ambiguity, if two alkynyl groups are present, such alkynyl groups may be the same or different.

Unless otherwise indicated, alkyl, alkoxy, alkenyl, or alkynyl groups, such as defined herein, may be unsubstituted or substituted as provided herein. Substituents on a substituted alkyl, alkenyl, alkynyl, or alkoxy group are themselves generally unsubstituted. If more than one substituent is present, they may all be the same or different.

When used in this context, halogen is typically chlorine, fluorine, bromine or iodine, and is preferably chlorine, bromine or fluorine, especially chlorine or fluorine.

A 4- to 10-membered carbocyclic group is a cyclic hydrocarbon containing 4 to 10 carbon atoms. The carbocyclic group may be saturated or partially unsaturated, but is generally saturated. 4- to 10-membered carbocyclic group

- 7 041925 may be a fused bicyclic group or bicyclic spiro group, as defined in this context. A 4- to 10-membered carbocyclic group may be saturated from 4- to

A 6-membered carbocyclic group, preferably a 5- or 6-membered carbocyclic group.

Examples of 4- to 6-membered saturated carbocyclic groups include cyclobutyl, cyclopentyl and cyclohexyl groups.

A 4- to 10-membered heterocyclic group is a cyclic group having 4 to 10 ring atoms selected from C, O, N, and S, including at least one heteroatom, typically one or two heteroatoms. The heteroatom or heteroatoms are typically selected from O, N and S, most commonly O and N, especially N. The heterocyclic group may be saturated or partially unsaturated, it is usually saturated. A 4- to 10-membered heterocyclic group may be a fused bicyclic group or a bicyclic spiro group, as defined herein. A 4 to 10 membered heterocyclic group may be a saturated 4 to 6 membered heterocyclic group, preferably a 5 or 6 membered heterocyclic group. Mentioned in this document, the heterocyclic group(s) includes its quaternized derivatives, as defined in this context. Preferred nitrogen-containing heterocyclic groups include azetidine, morpholine, 1,4-oxazepane, octahydropyrrolo[3,4-c]pyrrole, piperazine, piperidine, and pyrrolidine, including their quaternized derivatives, as defined herein.

When used in this context, from ₆ to C ₁₀ aryl group is a substituted or unsubstituted, monocyclic or fused polycyclic aromatic group containing in the ring part from 6 to 10 carbon atoms. Examples include monocyclic groups such as phenyl and fused bicyclic groups such as naftryl and indenyl. Phenyl (benzene) is preferred.

When used in this context, a 5- to 10-membered heteroaryl group is a substituted or unsubstituted monocyclic or fused polycyclic aromatic group containing from 5 to 10 atoms in the ring portion, including at least one heteroatom, for example 1, 2 or 3 heteroatoms, typically selected from O, S, and N. The heteroaryl group is typically a 5- or 6-membered heteroaryl group, or a 9- or 10-membered heteroaryl group. Preferably the heteroaryl group contains 1, 2 or 3, preferably 1 or 2 nitrogen atoms. As used herein, the heteroaryl group(s) includes its quaternized derivatives as defined herein. Preferred nitrogen-containing heteroaryl groups include imidazole, pyridine, pyrimidine, and pyrazine, including their quaternized derivatives, as defined herein.

When used in this context, a fused bicyclic group is a group containing two cyclic fragments having a common bond between two atoms. A bicyclic spiro group is a group containing two cyclic fragments having a common atom.

Carbocyclic, heterocyclic, aryl or heteroaryl groups may be unsubstituted or substituted as described herein. Substituents on a substituted carbocyclic, heterocyclic, aryl, or heteroaryl group are themselves generally unsubstituted unless otherwise indicated.

A number of compounds described in this work include heterocyclic or heteroaryl groups containing at least one nitrogen atom. In such compounds, said nitrogen atom(s) is(are) independently selected from secondary, tertiary, and quaternary nitrogen atoms. A quaternary nitrogen atom is present when the compound contains a quaternized derivative of one or more monocyclic groups or fused bicyclic groups. When used in this context, a quaternized derivative of a moiety, such as a cyclic moiety, is formed by bonding an additional alkyl group to a nitrogen atom in that moiety such that the valence of said nitrogen atom rises from 3 to 4 and the nitrogen atom becomes positively charged.

When used in this context, a pharmaceutically acceptable salt is a salt formed with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulfuric, phosphoric, pyrophosphoric, hydrobromic or nitric acid, and organic acids such as oxalic, citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, palmitic, benzoic, acetic, triphenylacetic, methanesulfonic, ethanesulfonic, 1-hydroxy-2-naphthenic, isethionic, benzenesulfonic or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium or magnesium) and zinc bases such as hydroxides, carbonates and bicarbonates, and organic bases such as alkylamines, aralkyl- (i.e. aryl-substituted alkyl-, for example, benzyl-)amines and heterocyclic amines.

In case the compound of formula (I) contains a positively charged nitrogen atom, such a compound may exist as a zwitterion, where R ¹ is O ^- , thereby forming a COO ^- group. These compounds may also be presented in the form of a pharmaceutically acceptable salt. Suitable salts include salts formed with pharmaceutically acceptable acids providing a proton for the COO ^- group and a counterion to balance the positive charge on the quaternary nitrogen atom. Suitable pharmaceutically acceptable acids include hydrochloric acid, sulfonic acids including methanesulfonic acid and toluenesulfonic acid, ascorbic acid and citric acid. Hydrochloric acid and sulfonic acids, in particular hydrochloric acid, are preferred. Alternatively, zwitterions can be combined with pharmaceutically acceptable bases as above, eg alkali metal (eg sodium or potassium) and alkaline earth metal (eg calcium or magnesium) hydroxides.

In formula (I), the stereochemistry is not limited. In particular, compounds of formula (I) containing one or more stereocenters (eg one or more chiral centers) may be used in enantiomerically or diastereoisomerically pure form, or in the form of a mixture of isomers. In addition, to avoid ambiguity, the compounds of the invention may be used in any tautomeric form. Typically, an agent or substance described herein contains at least 50%, preferably at least 60%, 75%, 90% or 95% of a compound of formula (I) that is enantiomerically or diastereomerically pure. Thus, the compound is preferably substantially optically pure.

To avoid ambiguity, the terms indanyl derivative and indan derivative may be used interchangeably and, unless otherwise indicated, refer to compounds of the invention, such as compounds of formula (I).

Compounds of the invention

Preferably in the invention, p is 0. Wherein, in embodiments of the invention in which p is 1, R ⁵ is preferably selected from -OMe, -OH, halogen, -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² and -CF3. More preferably R ⁵ is selected from -OMe and -OH. Most preferably R ⁵ is -OMe.

Preferably in the invention, L is an unsubstituted C1 alkylene group (ie a -CH ₂ - group).

Accordingly, according to the invention it is preferred that

L was an unsubstituted C ₁ alkylene group;

p was 0; or p was 1 and R ⁵ was -OMe; preferably p is 0.

Preferably R ¹ is selected from OH, NHOH and OR ^1a , or in the case where the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O ^- so that the compound forms a zwitterion. R ^1a is generally an unsubstituted C1 to C ₄ alkyl group, such as an unsubstituted C1 to C ₂ alkyl group. More preferably R ^1a is methyl or t-butyl.

More preferably, R ¹ is OH or NHOH, or in the case where the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O ^- , so that the compound forms a zwitterion. Even more preferably, R ¹ is OH or, in the case where the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O ^- so that the compound forms a zwitterion.

Preferably R ² is selected from H and C1 to C2 unsaturated alkyl; preferably R ² is selected from H and methyl. More preferably R ² is H. Preferably in the invention R ⁴ is selected from H and methyl. More preferably R ⁴ is H. Even more preferably R ² and R ⁴ are independently H or methyl, most preferably both are H.

Thus, preferably in the invention R ¹ is selected from OH, NHOH and OR ^1a ; or in the case where the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O ^- so that the compound forms a zwitterion; R ² is selected from H and unsaturated C ₁ to C ₂ alkyl; and R ⁴ is H.

Each of the R ³ groups is generally independently selected from halogen; -OH and -NH ₂ . More preferably, each of the R ³ groups is independently selected from halogen (eg, fluorine or chlorine) and —OH. Even more preferably, each of the R ³ groups is halo (eg fluorine or chlorine), most preferably fluorine. Typically, n is an integer from 0 to 2; more preferably n is 0 or 2; most preferably n is 0. Preferably, if more than one R ³ group is present, all R ³ groups are the same.

Thus, according to the invention, it is preferable

R ¹ is OH or NHOH, or in the case where the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O ^- so that the compound forms a zwitterion;

R ² is selected from H and methyl;

each of the R ³ groups is independently selected from halogen (eg fluorine or chlorine) and —OH;

n is an integer from 0 to 2; And

- 9 041925

R ⁴ is selected from H and methyl.

More preferably

R ¹ is OH or, in the case where the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O ^- so that the compound forms a zwitterion;

R ² is H;

each of the R ³ groups is independently halogen (eg fluorine or chlorine);

n is 0 or 2; And

R ⁴ is H.

According to the first embodiment of the invention, each R ⁶ is preferably independently selected from -R ^6a R ^A , -OR ^6a R ^A , -NR ²⁰ -R ^6a R ^A , -R ^6b R ^B , -OR ^6b R ^B , -NR ²⁰ -R ^6b R ^B , -R ^x R ^r , -OR ^x R ^r , -OR ^x -C(O)-R ^r and -R ^x -C(O)-R ^r More preferably each R ⁶ is independently selected from -OR ^6a R ^A , -NR ²⁰ -R ^6a R ^A , -OR ^6b R ^B , -NR ²⁰ -R ^6b R ^B , -OR ^X RR and -OR ^X -C(O)-RR Most preferably each R ⁶ is independently selected from -OR ^6a R ^A , -OR ^6b R ^B , -OR ^X RR and -OR ^X -C(O)-RR

According to this embodiment, each R ^X is preferably an R ^6a group. Each R ^6a group is preferably independently a C1 to C4 alkylene group and is independently unsubstituted or substituted with one group selected from —OH, halo; -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² and an unsubstituted methoxy group. Most preferably, each R ^6a group is independently an unsubstituted C1 to _C4 alkylene group; preferably an unsubstituted C1 to _C3 alkylene group.

According to this embodiment, each R ^6b is preferably independently [C1 to C3 alkylene]-C(R ^z )2R ^b ; where two R ^z groups are connected to each other and together with the atom to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic group. More preferably, the two R ^z groups are linked together and together with the atom to which they are attached form a 5- or 6-membered heterocyclic group, most preferably a piperidine or oxane group, preferably an oxane group. The carbocyclic or heterocyclic group formed by the two R ^z groups is preferably unsubstituted or substituted with one substituent selected from -CH ₃ , -OH and -OCH ₃ . Most preferably, the carbocyclic or heterocyclic group formed by the two R ^z groups is unsubstituted.

According to this embodiment, R ^A is preferably selected from -NR ²⁰ R ³⁰ ; -N ⁺ R ²⁰ R ²¹ R ³⁰ ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ . More preferably R ^A is selected from -NR ²⁰ R ³⁰ and -n ⁺ r ²⁰ r ²¹ r ³⁰ .

According to this embodiment, R ^B is preferably selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ . More preferably R ^B is selected from -NR ²⁰ R ²¹ and -N ⁺ R ²⁰ R ²¹ R ²² .

According to this embodiment, each RR is preferably independently a 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclic group containing at least one nitrogen atom, wherein said nitrogen atom(s) is independently selected(s) from secondary, tertiary and quaternary nitrogen atoms. More preferably, each RR is independently a 4- to 6-membered heterocyclic group, such as a 5- or 6-membered heterocyclic group, and contains at least one nitrogen atom, wherein said nitrogen atom(s) is(are) independently selected from a secondary , tertiary and quaternary nitrogen atoms. Most preferably, each RR is independently selected from azetidine, morpholine, piperazine, piperidine, pyrrolidine, and triazole. To avoid ambiguity, the nitrogen atom(s) in these groups may be quaternized(quaternized) as defined herein.

Preferably each RR is independently unsubstituted or substituted with one, two or three groups selected from -R ²⁰ , -R7-OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² . More preferably, each RR is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² . Even more preferably, each RR is independently unsubstituted or substituted with one or two -R ²⁰ groups.

Accordingly, in view of the above, according to this embodiment, each R ⁶ is preferably independently selected from -R ^6a R ^A , -OR ^6a R ^A , -NR ²⁰ -R ^6a R ^A , -R ^6b R ^B , -OR ^6b R ^B , -NR ²⁰ -R ^6b R ^B , -R ^X RR, -OR ^X RR, -OR ^X -C(O)-RR and -R ^X -C(O)-RR, where each R ^X is a group ^R6a ;

each of the R ^6a groups is independently a C1 to C4 alkylene group, and each of the R ^6a groups is independently unsubstituted or substituted with one group selected from —OH, halogen; -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; and an unsubstituted methoxy group;

each R ^6b is independently a [C to C3 αkylene]-C(R ^z )2R ^b group; where two R ^z groups are interconnected and together with the atom to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic group;

R ^a is selected from -NR ²⁰ R ³⁰ ; -N ⁺ R ²⁰ R ²¹ R ³⁰ ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

- 10 041925

R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

each RR is independently a 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclic group containing at least one nitrogen atom, said nitrogen atom(s) being independently selected from secondary, tertiary, and quaternary atoms nitrogen;

where each RR is independently unsubstituted or substituted with one, two or three groups independently selected from -R ²⁰ , -R ⁷ -OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² .

More preferably, in this embodiment, each R ⁶ is independently selected from -OR ^6a R ^A , -OR ^6b R ^B , -OR ^x R ^r , and -OR ^x -C(O) -R ^r , where each R ^X is an R group ^6a ;

each of the R ^6a groups is independently an unsubstituted Ci to C ₄ alkylene group; _bb each R ^6b is independently [C1 to C3 alkylene]-C(R ^z ) ₂ R ^b ; where two R ^z groups are interconnected and together with the atom to which they are attached form a 5- or 6-membered heterocyclic group, preferably an oxane group;

R ^a is selected from -NR ²⁰ R ³⁰ ; -N ⁺ R ²⁰ R ²¹ R ³⁰ ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

each RR is independently a 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclic group containing at least one nitrogen atom, wherein said nitrogen atom(s) is(are) independently selected from secondary, tertiary, and quaternary nitrogen atoms ;

where each RR is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² .

According to a second embodiment of the invention, each R ⁶ is preferably independently selected from -CN; -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^X R ^B ; -C(O)NR ⁴⁰ R ⁴¹ ; -SO2R ²⁰ ; -SO2NR ²⁰ R ²¹ and -SO2NR ⁴⁰ R ⁴¹ . More preferably, each R ⁶ is independently selected from -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^X R ^B ; -C(O)NR ⁴⁰ R ⁴¹ and -So2NR ⁴⁰ R ⁴¹ . Even more preferably, each R ⁶ is independently selected from -SO ₂ NR ⁴⁰ R ⁴¹ and -C(O)NR ⁴⁰ R ⁴¹ . Most preferably, each R ⁶ is independently a C(O)NR ²⁰ R ²¹ group.

According to this embodiment of the invention, each R ^X is preferably an R ^6a group. Each of the R ^6a groups is preferably independently a C1 to C4 alkylene group and is independently unsubstituted or substituted with one group selected from —OH, halo; -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; and an unsubstituted methoxy group. Most preferably, each of the R ^6a groups is independently an unsubstituted C1 to C4 alkylene group; preferably an unsubstituted C1 to _C3 alkylene group.

According to this embodiment, R ^B is preferably selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ . More preferably R ^B is selected from -NR ²⁰ R ²¹ and -N ⁺ R ²⁰ R ²¹ R ²² .

According to this embodiment, each R ⁴⁰ and R ⁴¹ together with the nitrogen atom to which they are attached preferably independently form a 4- to 6-membered heterocyclic group, for example a 4- or 6-membered heterocyclic group, wherein any nitrogen atom in the ring independently selected from secondary, tertiary and quaternary nitrogen atoms. Most preferably, each ring formed by -NR ⁴⁰ R ⁴¹ , if present, is independently selected from azetidine, morpholine, piperazine, piperidine, pyrrolidine and triazole. To avoid ambiguous interpretation, the nitrogen atom(s) in these groups may(may) be quaternized(quaternized), as defined in this context.

Preferably, each ring formed by -NR ⁴⁰ R ⁴¹ is independently unsubstituted or substituted with one, two or three groups independently selected from -R ²⁰ , -R ⁷ -OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² . More preferably, each ring formed by NR ⁴⁰ R ⁴¹ is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² . Most preferably, each ring formed by NR ⁴⁰ R ⁴¹ is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ and -R ⁷ -NR ²⁰ R ²¹ .

Accordingly, in view of the above, according to this embodiment of the invention, each R ⁶ is preferably independently selected from -CN; -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^X R ^B ; -C(O)NR ⁴⁰ R ⁴¹ ; -SO2R ²⁰ ; -SO2NR ²⁰ R ²¹ and -SO2NR ⁴⁰ R ⁴¹ ; where each R ^X represents a group R ^6a ;

each of the R ^6a groups is independently a C1 to _C4 alkylene group; and each of the R ^6a groups is independently unsubstituted or substituted with one group selected from —OH, halo; -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; and an unsubstituted methoxy group;

R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

each R ⁴⁰ and R ⁴¹ together with the nitrogen atom to which they are attached independently form a 4- to 6-membered heterocyclic group wherein any nitrogen atom in the ring is independently selected from secondary, tertiary and quaternary nitrogen atoms;

where each ring formed by -NR ⁴⁰ R ⁴¹ is independently unsubstituted or substituted with one, two or three groups independently selected from -R ²⁰ , -R ⁷ -OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ _n + r20r21r22.

More preferably, according to this embodiment, each R ⁶ is independently selected from -CN; -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^x R ^b ; -C(O)NR ⁴⁰ R ⁴¹ ; -SO2R ²⁰ ; -SO2NR ²⁰ R ²¹ and -SO ₂ NR ⁴⁰ R ⁴¹ ; where each R ^X represents a group R ^6a ;

each of the R ^6a groups is independently an unsubstituted C to C ₄ alkylene group;

R ^B is selected from -NR ²⁰ R ²¹ and -N ⁺ R ²⁰ R ²¹ R ²² ;

each R ⁴⁰ and R ⁴¹ together with the nitrogen atom to which they are attached independently form a 4- to 6-membered heterocyclic group wherein any nitrogen atom in the ring is independently selected from secondary, tertiary and quaternary nitrogen atoms;

where each ring formed by NR ⁴⁰ R ⁴¹ is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² .

Thus, in particularly preferred compounds of the invention

R ¹ is OH or NHOH, or in the case where the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O ^- so that the compound forms a zwitterion;

R ² is selected from H and methyl;

each of the R ³ groups is independently selected from halogen (eg fluorine or chlorine) and —OH;

n is an integer from 0 to 2;

R ⁴ is selected from H and methyl;

L is an unsubstituted C alkylene group;

p is 0; or p is 1 and R ⁵ is -OMe; preferably p is 0;

each R ⁶ is preferably independently selected from

A:

-R ^6a R ^A , -OR ^6a R ^A , -NR ²⁰ -R ^6a R ^A , -R ^6b R ^B , -OR ^6b R ^B , -NR ²⁰ -R ^6b R ^B , -R ^x R ^r -OR ^x R ^r , -OR ^x -C(O)-R ^r and -R ^X C(O)-R ^r , where each R ^X is an R ^6a group;

each of the R ^6a groups is independently a C ₁ to C ₄ alkylene group, and each R ^6a group is independently unsubstituted or substituted with one group selected from —OH, halogen; -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; and an unsubstituted methoxy group;

each R ^6b is independently [C to C3 αkylene]-C(R ^z )2R ^b ; where two R ^z groups are interconnected and together with the atom to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic group;

R ^a is selected from -NR ²⁰ R ³⁰ ; -N ⁺ R ²⁰ R ²¹ R ³⁰ ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

each RR is independently a 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclic group containing at least one nitrogen atom, wherein said nitrogen atom(s) is(are) independently selected from secondary, tertiary, and quaternary nitrogen atoms ;

where each RR is independently unsubstituted or substituted with one, two or three groups independently selected from -R ²⁰ , -R ⁷ -OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² ; And

IN:

-CN; -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^x R ^b ; -C(O)NR ⁴⁰ R ⁴¹ ; -SO2R ²⁰ ; -SO2NR ²⁰ R ²¹ and -SO ₂ NR ⁴⁰ R ⁴¹ ; where each R ^X represents a group R ^6a ;

each of the R ^6a groups is independently a C1 to C4 alkylene group; and each of the R ^6a groups is independently unsubstituted or substituted with one group selected from —OH, halo; -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; and an unsubstituted methoxy group;

R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

each R ⁴⁰ and R ⁴¹ together with the nitrogen atom to which they are attached independently form a 4- to 6-membered heterocyclic group wherein any nitrogen atom in the ring is independently selected from secondary, tertiary and quaternary nitrogen atoms;

where each ring formed by -NR ⁴⁰ R ⁴¹ is independently unsubstituted or substituted with one, two or three groups independently selected from -R ²⁰ , -R ⁷ -OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ N ⁺ R ²⁰ R ²¹ R ²² .

In even more preferred compounds of the invention

R ¹ is OH or, in the case where the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O ^- so that the compound forms a zwitterion;

R ² is H;

each of the R ³ groups is independently halogen (eg fluorine or chlorine);

n is 0 or 2;

R ⁴ is H;

L is an unsubstituted C ₁ alkylene group;

p is 0; or p is 1 and R ⁵ is -OMe; preferably p is 0;

- 12 041925 each R ⁶ is preferably independently selected from

A:

-OR ^6a R ^A , -OR ^6b R ^B , -OR ^x R ^r and -OR ^x -C(O)-R ^r , where each R ^X is an R ^6a group;

each of the R ^6a groups is independently an unsubstituted C ₁ to C ₄ alkylene group;

each R ^6b is independently [C ₁ to C ₃ alkylene]-C(R ^z )2R ^b ; where two R ^z groups are interconnected and together with the atom to which they are attached form a 5- or 6-membered heterocyclic group, preferably an oxane group;

R ^a is selected from -NR ²⁰ R ³⁰ ; -N ⁺ R ²⁰ R ²¹ R ³⁰ ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ;

each RR is independently a 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclic group containing at least one nitrogen atom, wherein said nitrogen atom(s) is(are) independently selected from secondary, tertiary, and quaternary nitrogen atoms ;

where each RR is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² ; And

IN:

-CN; -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^x R ^b ; -C(O)NR ⁴⁰ R ⁴¹ ; -SO2R ²⁰ ; -SO2NR ²⁰ R ²¹ and -SO2NR ⁴⁰ R ⁴¹ ; where each R ^X represents a group R ^6a ;

each of the R ^6a groups is independently an unsubstituted C _i to C ₄ alkylene group;

R ^B is selected from -NR ²⁰ R ²¹ and -N ⁺ R ²⁰ R ²¹ R ²² ;

each R ⁴⁰ and R ⁴ⁱ together with the nitrogen atom to which they are attached independently form a 4- to 6-membered heterocyclic group wherein any nitrogen atom in the ring is independently selected from secondary, tertiary and quaternary nitrogen atoms;

where each ring formed by NR ⁴⁰ R ⁴¹ is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² .

Preferably in the invention R ⁷ is selected from a bond and an unsubstituted C ₁ alkylene; more preferably R ⁷ is a bond.

Preferably in the invention, each of R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ is independently selected from H and C1 to C2 alkyl which is unsubstituted or substituted with one OMe group. More preferably, R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are each independently selected from H and unsubstituted C1 to C ₂ alkyl; most preferably, R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are each independently selected from H and methyl.

Preferably in the invention, each R ³⁰ is independently C2 or C3 alkyl which is unsubstituted or substituted with one OMe group. More preferably, each R ³⁰ is independently C2 alkyl which is unsubstituted or substituted with one OMe group. Most preferably, each R ³⁰ is independently unsubstituted C2 alkyl.

Preferred compounds according to the invention are presented in the examples.

More preferred compounds of the invention are selected from

2-[2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acids;

2-[2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

2-[5,6-difluoro-2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan2-yl]acetic acid;

2-[5,6-difluoro-2-[[6-methoxy-5-[(1-methyl-4-piperidyl)methoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl] acetic acid;

2-[5,6-difluoro-2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2 -yl]acetic acid;

2-[5,6-difluoro-2-[[6-methoxy-5-[2-(4-methylmorpholin-4-ium-4-yl)ethoxy]-1,3-benzothiazol-2yl]methylcarbamoyl]indan- 2-yl]acetate;

2-[2-[[5-[2-(4,4-dimethylpiperazin-4-ium-1-yl)-2-oxoethoxy]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]-5, 6-difluorindan-2-yl]acetate;

2-[5,6-difluoro-2-[[6-methoxy-5-[3-(4-methylmorpholin-4-ium-4-yl)propoxy]-1,3-benzothiazol-2yl]methylcarbamoyl]indan- 2-yl]acetate;

2-[2-[[6-methoxy-5-[3-(4-methylmorpholin-4-ium-4-yl)propoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl] acetate;

2-[2-[[5-[(1,1-dimethylpiperidin-1-ium-4-yl)methoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl] acetate;

2-[2-[[5-[3-[diethyl(methyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

2-[5,6-difluoro-2-[[6-methoxy-5-[3-(1-methylpyrrolidin-1-ium-1-yl)propoxy]-1,3-benzothiazol-2-13 041925 yl] methylcarbamoyl]indan-2-yl]acetate;

2-[2-[[5-[3-[2-hydroxyethyl(dimethyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

2-[5,6-difluoro-2-[[5-[3-[2-hydroxyethyl(dimethyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl] acetate;

2-[2-[[5-[3-[bis(2-hydroxyethyl)-methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

2-[2-[[5-[3-[bis(2-hydroxyethyl)-methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan-2- yl]acetate;

2-[2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid;

2-[5,6-difluoro-2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

2-[2-[[5-(4,4-dimethylpiperazin-4-ium-1-carbonyl)-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan-2- yl]acetate;

2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-

5,6-difluorindan-2-yl]acetic acid;

2-[2-[[5-[4-(dimethylamino)piperidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

2-[2-[[5-[2-[(dimethylamino)methyl]morpholine-4-carbonyl]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetic acid;

2-[2-[[6-methoxy-5-[2-[(trimethylammonio)methyl]morpholine-4-carbonyl]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetate;

2-[5,6-difluoro-2-[[6-methoxy-5-[3-(trimethylammonio)azetidine-1-carbonyl]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetate;

2-[2-[[5-[(1,1-dimethylpiperidin-1-ium-4-yl)methoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan -2-yl]acetate;

2-[2-[[6-methoxy-5-(4-methylpiperazin-1-yl)sulfonyl-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

2-[2-[[5-[[4-(dimethylamino)-1-piperidyl]sulfonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid and

2-[2-[[6-methoxy-5-[[4-(trimethylammonio)-1-piperidyl]sulfonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

or his(her) pharmaceutically acceptable salt.

Even more preferred compounds of the invention are selected from

2-[2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid;

2-[5,6-difluoro-2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan2-yl]acetic acid;

2-[5,6-difluoro-2-[[6-methoxy-5-[(1-methyl-4-piperidyl)methoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl] acetic acid;

2-[2-[[6-methoxy-5-[3-(4-methylmorpholin-4-ium-4-yl)propoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl] acetate;

2-[2-[[5-[3-[diethyl(methyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

2-[5,6-difluoro-2-[[6-methoxy-5-[3-(1-methylpyrrolidin-1-ium-1-yl)propoxy]-1,3-benzothiazol-2yl]methylcarbamoyl]indan- 2-yl]acetate;

2-[2-[[5-[3-[2-hydroxyethyl(dimethyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

2-[5,6-difluoro-2-[[5-[3-[2-hydroxyethyl(dimethyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl] acetate;

2-[2-[[5-[3-[bis(2-hydroxyethyl)-methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate;

2-[2-[[5-[3-[bis(2-hydroxyethyl)-methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan-2- yl]acetate;

2-[2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid;

2-[5,6-difluoro-2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]

- 14 041925 indan-2-yl]acetic acid;

2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]5,6-difluoroindan-2-yl]acetic acid ;

2-[2-[[5-[(1,1-dimethylpiperidin-1-ium-4-yl)methoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan -2-yl] acetate;

or his(her) pharmaceutically acceptable salt.

The most preferred compounds of the invention are selected from

2-[2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid;

2-[5,6-difluoro-2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan2-yl]acetic acid;

2-[5,6-difluoro-2-[[6-methoxy-5-[(1-methyl-4-piperidyl)methoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl] acetic acid;

2-[5,6-difluoro-2-[[6-methoxy-5-[3 -(1-methylpyrrolidin-1-ium-1-yl)propoxy]-1,3-benzothiazol-2yl]methylcarbamoyl]indan- 2-yl] acetate;

2-[5,6-difluoro-2-[[5-[3-[2-hydroxyethyl(dimethyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl] acetate;

2-[2-[[5-[3-[bis(2-hydroxyethyl)-methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan-2- yl] acetate;

2-[5,6-difluoro-2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid;

2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]5,6-difluoroindan-2-yl]acetic acid ;

2-[2-[[5-[(1,1-dimethylpiperidin-1-ium-4-yl)methoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan -2-yl] acetate;

or his(her) pharmaceutically acceptable salt.

Synthesis

The compounds of the invention may be prepared by any suitable method. For example, as will be described in more detail below, deprotonation of commercially available ethyl esters (1) with a strong base (such as sodium hexamethyldisilazide) followed by alkylation of the anion with t-butyl bromoacetates gives the diester (2) (Bell, IM and Stump, C.A. , WO 2006/29153; Robinson, RP et al., Bioorganic and Medicinal Chemistry Letters, 1996, 1719). Alkaline hydrolysis of an ethyl ester in the presence of a tert-butyl ester gives compound (3). Formation of the amide with the appropriate 2-aminomethylbenzothiazole followed by treatment with TFA (Trifluoroacetic acid) to remove the tert-butyl ester provides the desired acids. Examples of suitable conditions for the formation of aminomethylbenzothiazoles (4) are shown below. For example, R ₅ and R 6 substituents can be introduced by converting commercially available halogen-substituted triazoles (eg, halogen substitution) or OH-substituted triazoles (eg, alkylation at the hydroxyl position). Acids can be converted to esters (R ¹ = OR ^1a ) or other prodrugs (R ¹ = OCH ₂ OC(O)R ^1a ) by methods known to those skilled in the art.

There are many approaches to the preparation of hydroxamic acids (for a review, see Ganeshpurkar, A., et al., Current Organic Syntheses, 2018, 15, 154-165), a fairly reliable method is the addition reaction between acids and O-(oxane-2- yl)hydroxylamine under peptide binding conditions,

- 15 041925 leading to the formation of protected hydroxamates, followed by removal of the protective group with TFA to obtain hydroxamic acids (see, for example, Ding, C., et al., Bioorg. Med. Chem.

Lett, 2017, 25, 27-37).

Compositions and combinations

The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of the invention together with a pharmaceutically acceptable carrier or diluent. Typically, the composition contains up to 85% by weight of a compound of the invention. More often, the composition contains up to 50% by weight of a compound of the invention. Preferred pharmaceutical compositions are sterile and pyrogen-free. In addition, in the case where the pharmaceutical compositions of the invention contain a compound of the invention that is optically active, the compound of the invention will typically be a substantially pure optical isomer.

The composition of the invention may be presented in the form of a kit containing instructions for using the kit in the methods described in this context, or details as to which subjects this method can be used for.

As mentioned above, the compounds of the invention can be used to treat or prevent a bacterial infection. In particular, they can be used as inhibitors of the LasB enzyme, in particular the LasB of the bacterium Pseudomonas aeruginosa (PA). The compounds can be used alone or in combination therapy with antibiotic agents to enhance the action of the antibiotic agent.

Thus, the present invention also provides a combination comprising (i) a compound of the invention as described herein, and (ii) an antibiotic agent. The combination may also include one or more additional active agents. The compound of the invention and the antibiotic agent may be presented as a single preparation, or they may be prepared separately. When manufactured separately, the two agents may be administered simultaneously or separately. They may be presented in the form of a kit, optionally together with instructions for their use.

When formulated as a single preparation, the two active agents may be in the form of a pharmaceutical composition containing (i) a compound of the invention as described herein and (ii) an additional antibacterial compound; and (iii) a pharmaceutically acceptable carrier or diluent.

Preferably, the antibiotic agent is effective against Pseudomonas infection. Most preferably, the antibiotic is tobramycin, neomycin, streptomycin, gentamicin, ceftazidime, ticarcillin, piperacillin, tazobactam, imipenem, meropenem, rifampicin, ciprofloxacin, amikacin, colistin, aztreonam, azithromycin, or levofloxacin. More preferably, the antibiotic is tobramycin, neomycin, streptomycin, gentamicin, ceftazidime, ticarcillin, piperacillin, tazobactam, imipenem, meropenem, rifampicin, ciprofloxacin, amikacin, colistin, aztreonam, or levofloxacin.

A compound or combination of the invention may be administered in a variety of dosage forms. For example, they can be administered orally, for example, in the form of tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules. They can also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion. The compound or combination may also be administered in the form of a suppository. Preferably, the compound or combination can be administered by inhalation (aerosol) or intravenous route, most preferably by inhalation (aerosol) administration.

A compound or combination of the invention is generally formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain diluents along with the active compound, for example lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disaggregating agents, for example starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; dyes; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates; and, in most cases, non-toxic and pharmacologically inactive substances used in pharmaceutical compositions. Such pharmaceutical preparations may be prepared in a manner known per se, for example using mixing, granulating, tableting, enrobing or film coating processes.

The compound or combination of the invention may be formulated for inhalation (aerosol) administration as a solution or suspension. The compound or combination of the invention can be administered using a metered dose inhaler (MDI) or a nebulizer such as an electronic or jet nebulizer. Alternatively, a compound or combination of the invention may be formulated for inhalation administration as a powdered drug, such formulations may be administered from a dry powder inhaler (DPI). When formulated for inhalation administration, a compound or combination of the invention may be delivered in the form of particles having a mass median aerodynamic diameter (MMAD) of 1 to 100 µm, preferably 1 to 50 µm, more preferably 1 to 20 µm, such as 3 up to 10 µm, for example from 4 to 6 µm. When delivering a compound or combination of the invention as an aerosol spray, reference to particle diameters refers to the MMAD of the aerosol droplets. MMAD can be measured by any suitable method, such as laser diffraction.

Liquid dispersions for oral administration may be syrups, emulsions and suspensions. Syrups as carriers may contain, for example, sucrose or sucrose with glycerol and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol as carrier. The suspension or solutions for intramuscular injection or inhalation may contain, in addition to the active compound, a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol and, if necessary, a suitable amount of lidocaine hydrochloride.

Solutions for inhalation, injection or infusion may contain, for example, sterile water as a carrier, or preferably they may be in the form of sterile aqueous isotonic saline solutions. Pharmaceutical compositions suitable for delivery by needleless injection, for example transdermally (percutaneously), may also be used.

Therapeutic efficacy

The compounds, compositions and combinations of the present invention are therapeutically acceptable. Thus, the present invention provides compounds, compositions and combinations as described herein for use in medicine. The present invention provides compounds as described herein for use in the treatment of a human or animal body. To avoid ambiguity, the agent may include a compound of the invention in solvate form.

The compounds, compositions and combinations of the invention may be used in the treatment or prevention of a bacterial infection. Thus, the present invention provides a compound, combination or composition as described herein for use in a method of treating or preventing a bacterial infection in a subject in need thereof. Also provided is a method for treating or preventing a bacterial infection in a subject in need thereof, the method comprising administering to said subject an effective amount of a compound, combination or composition as described herein. Also provided is the use of a compound, combination or composition as described herein in the manufacture of a medicament for use in the treatment or prevention of a bacterial infection in a subject.

The compounds described herein can be used as inhibitors of LasB elastase, in particular the LasB of the bacterium Pseudomonas aeruginosa (PA). Inhibition of LasB in bacteria prevents LasB secreted by bacteria from hydrolyzing host tissue and host immune response proteins, thereby maintaining the subject's natural response to bacterial infection and inflammation. Thus, the compounds described herein can be used as stand-alone supplements in antibiotic therapy, for example, in a chemotherapy setting. In addition, the compounds can be used to inhibit the formation of biofilms and/or to destroy biofilms. This activity to prevent the formation of biofilms or break down biofilms already formed helps the antibiotic agents eliminate the bacterial infection. It also helps the host's own immune system fight off bacterial infection. Therefore, the compounds can be used as independent antibacterial agents.

Alternatively, the compounds described herein may be used in combination with antibiotic agents to enhance the action of the antibiotic agent. Thus, a compound of the invention as described herein is also provided for use in a method for treating or preventing a bacterial infection by administering it together with an antibiotic agent. Also provided is a method for treating or preventing a bacterial infection in a subject in need thereof, the method comprising co-administering to said subject an effective amount of a compound as described herein and an antibiotic agent. Also provided is the use of a compound as described herein in the manufacture of a medicament for use in the treatment or prevention of a bacterial infection by co-administration with an antibiotic agent.

In one aspect, the subject is a mammal, in particular a human. However, the subject may not refer to a person. Preferred non-human animals include, but are not limited to, primates such as marmosets or monkeys, farm animals such as horses, cows, sheep or pigs, and domestic animals such as dogs,

- 17 041925 cats, mice, rats, guinea pigs, ferrets, gerbils or hamsters. The subject can be any animal capable of contracting the bacterium.

The compounds, compositions and combinations described herein can be used in the treatment of a bacterial infection resulting from recurrence after antibiotic treatment. Thus, the compounds and combinations can be used in the treatment of a patient previously treated with antibiotics for a (same episode) bacterial infection.

The bacterium causing the infection can be any bacterium that expresses LasB or its analogue. Typically, the bacterium causing the infection expresses LasB. The bacterium can be, for example, any bacterium capable of forming a biofilm. The bacterium can be gram positive or gram negative. According to a preferred example, the bacterium is Gram negative. In particular, the bacterium may be a pathogenic bacterium.

A bacterial infection can be caused by Bacillus, Pseudomonas, Staphylococcus, Streptococcus, Listeria, Escherichia, or Burkholderia bacteria. For example, the bacterium may be a bacterium selected from Staphylococcus aureus, Haemophilus influenza, Pseudomonas aeruginosa, and Burkholderia cepacia.

According to one preferred example, the bacterium may be a bacterium selected from a bacterium of the family Pseudomonadaceae (pseudomonas). For example, the bacterium may be selected from one of the following genera: Pseudomonas, Azomonas, Azomonotrichon, Azorhizophilus, Azotobacter, Cellvibrio, Mesophilobacter, Rhizobacter, Rugamonas, and Serpens. Preferably the bacterium is Pseudomonas, in particular when the compound to be treated is pneumonia. The bacterium may be an opportunistic pathogen. The bacterium may be selected from Pseudomonas aeruginosa, Pseudomonas oryzihabitans and Pseudomonas plecoglossicida, and most preferably the bacterium is Pseudomonas aeruginosa (PA).

A compound, composition or combination of the invention may be used to treat or prevent infections and conditions caused by any one or combination of the bacteria mentioned above. In particular, a compound or combination of the invention may be used to treat or prevent pneumonia. The compound or combination may also be useful in the treatment of septic shock, urinary tract infection, and gastrointestinal, skin, or soft tissue infections.

The compounds, compositions and combinations described herein may also be used to treat or prevent inflammation in a subject. Without being bound by any theory, it is possible that this versatility is due to the activity of the compounds in inhibiting the activation of the pro-inflammatory cytokine interleukin-1-β (IL-1e), for example, by inhibiting the activity of LasB enzymes (such as LasB PA) to activate IL. -1e by hydrolysis of proIL-113 at a site other than caspase-1. Accordingly, the compounds, compositions and combinations described herein are particularly well suited for the treatment of inflammation caused by or associated with IL-1e activation in a subject. The compounds, compositions and combinations described herein are particularly well suited for the treatment or prevention of bacterial inflammation caused by or associated with IL-II activation in a subject, particularly when the bacteria causing the infection express one or more LasB enzymes or analogs thereof. .

In general, the compounds, compositions, and combinations described herein are particularly well suited for the treatment or prevention of airway inflammation in a subject. Airway inflammation can be inflammation of any part of the airways, in particular the lower airways (eg, inflammation of the trachea, bronchi or lungs). The compounds described herein are particularly well suited for the treatment or prevention of pneumonia in a subject. Inflammation of the airways (eg, pneumonia) is typically caused by a bacterial infection, in particular an infection caused by bacteria expressing one or more LasB enzymes or analogues thereof, as described above. In some aspects, airway inflammation (eg, pneumonia) is caused by an infection with a bacterium of the Pseudomonadaceae family, such as a Pseudomonas aeruginosa (PA) infection.

The compounds, compositions and combinations described herein can be used to treat or prevent inflammation in a subject in need thereof. As described in more detail below, the compounds, compositions and combinations described herein can be used in the treatment of patients suffering from cystic fibrosis. The compounds, compositions and combinations described herein may also be used in the treatment of patients suffering from other conditions associated with bacterial inflammation, such as chronic obstructive pulmonary disease (COPD), bronchiectasis and/or ventilator associated pneumonia (VAP).

The compounds and combinations are particularly useful in the treatment of patients suffering from cystic fibrosis. Preferably, a compound or combination of the invention may be used to treat or prevent pneumonia in a subject suffering from cystic fibrosis. For example, a subject may have any of the six classes of CFTR (Cystic Fibrosis Transmembrane conductance Regulator) mutations and/or may be infected or chronically colonized with RA. The compounds and combinations of the invention can also be used in the treatment of neutropenic patients.

A compound or combination of the invention may be administered to a subject to prevent the onset or recurrence of one or more symptoms of a bacterial infection. This introduction is prophylactic. In this embodiment, the subject may be asymptomatic. Typically, the subject is a subject exposed to the bacterium. Such a subject is administered a prophylactically effective amount of the agent or drug. A prophylactically effective amount is an amount that prevents the occurrence of one or more symptoms of a bacterial infection.

A compound or combination of the invention may be administered to a subject to treat one or more symptoms of a bacterial infection. According to this embodiment, the subject typically exhibits symptoms. Such a subject is administered a therapeutically effective amount of the agent or drug. A therapeutically effective amount is an amount effective to alleviate one or more symptoms of the disease.

The subject is administered a therapeutically or prophylactically effective amount of a compound of the invention. The dose may be determined depending on various parameters, in particular depending on the compound used; age, weight and condition of the subject to be treated; route of administration and desired regimen. In addition, the physician will be able to determine the desired route of administration and dosage for any particular patient. A typical daily dose is from about 0.01 to 100 mg/kg, preferably from about 0.1 to 50 mg/kg, for example from about 1 to 10 mg/kg of body weight, depending on the activity of the particular inhibitor, age, body weight. and the condition of the subject being treated, the type and severity of the disease, and the frequency and route of administration. Preferably daily dosage levels are from 5 mg to 2 g.

Other uses

The antibacterial properties of the compounds described herein mean that they can also be used in the treatment of bacterial infection in vitro, i.e. not only for the treatment of people or animals. Thus, this paper also describes a cleaning composition containing an indane derivative of formula (I) or a salt thereof. The cleaning composition may also contain, for example, a detergent, a surfactant (including ionic and non-ionic surfactants), a diluent, a bleach (including hypochlorite such as sodium hypochlorite or calcium hypochlorite, chlorine, chlorine dioxide, hydrogen peroxide or its adduct, sodium perborate and sodium percarbonate), alcohol (such as ethanol or isopropanol), or a disinfectant. Generally, the disinfectant may be selected from benzyl-4-chlorophenol, amylphenol, phenylphenol, glutaraldehyde, alkyldimethylbenzylammonium chloride, alkyldimethylethylbenzylammonium chloride, iodine, peracetic acid, and chlorine dioxide. The detergent can generally be an alkaline detergent such as sodium hydroxide, sodium metasilicate or sodium carbonate, or an acidic detergent such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid or tartaric acid.

In addition, this paper describes the use of an indane derivative of formula (I), as described herein, for the prevention or treatment of bacterial contamination in vitro. Such use may be a method of preventing or treating a bacterial infection in vitro, comprising the step of treating an object with a compound or combination of the invention. Such use is not a therapeutic use and may include, for example, the prevention or treatment of bacterial contamination on a surface, such as the surface of a permanent medical device or object used in a clinical setting. The surface may be the surface of a catheter, nebulizer, ventilator or face mask. Generally, bacterial contamination can be caused by any of the bacteria described herein. Preferably the bacterium is Pseudomonas aeruginosa.

The following examples illustrate the invention. However, they do not limit the present invention in any way. In this regard, it is important to understand that the particular assay used in the Examples section is intended solely to provide insight into biological activity. There are many assay methods for determining biological activity, so a negative result obtained in any particular assay is not definitive.

experimental part

General synthesis procedure

As described below, there are two methods for synthesizing the compounds of the invention.

- 19 041925

Method A. Regiospecific synthesis of a key intermediate (3).

Scheme 1

Deprotonation of a commercially available ethyl ester (1) with a strong base (such as sodium hexamethyldisilazide) followed by alkylation of the anion with t-butyl bromoacetate gives the known diester (2) (Bell, I.M. and Stump, C.A., WO 2006/29153; Robinson, R.P. et al., Bioorganic and Medicinal Chemistry Letters, 1996, 1719). Alkaline hydrolysis of an ethyl ester in the presence of a tert-butyl ester leads to compound (3), where R is tert-butyl. After treatment of the amide formed with the appropriate 2-aminomethylbenzothiazole with TFA to remove the tert-butyl ester, the desired acids are obtained.

This technique can be adapted for substituents on the indane ring.

Scheme 2

For example, the commercially available diol [4,5-difluoro-2-(hydroxymethyl)phenyl]methanol (4) can be converted with HBr (WO 2008/151211) or phosphorus tribromide (US 2006/223830) to the bis-bromomethyl analogue, which can also react with diethylmalonate to form indane (5). Standard hydrolysis of both esters followed by monodecarboxylation leads to the monoacid (WO 2006/125511) which can then be esterified to give compound (6), the difluoro analogue of compound (1). And then, using the same procedure as in the case of the compound (1), receive a key acid (7), difluoro-containing analogue of the intermediate compound (3). Similar chemical transformations can be used to obtain the corresponding dichlorine analogs.

Method B. Synthesis of protected 2-aminomethylbenzothiazoles.

Scheme 3

Equation 1

(8)

There are many ways to form benzothiasoles (for a review, see Seth, S.; A Comprehensive Review on Recent advances in Synthesis & Pharmacotherapeutic potential of Benzothiazoles), Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2015, 14, 98-112). However, most methods result in an alkyl substitution at the C2 position, which requires additional manipulation of functional groups to obtain the desired aminomethyl substituent required in this invention. In the 1980s the pioneering work of Takagi et al. led to a palladium-catalyzed process for the direct preparation of functionalized methyl groups (see Equation 1, Scheme 2; Takagi, K. et al., Chemistry Letters, 1987, 16, 839-840). This chemistry has recently been rediscovered by Mutabilis scientists who have adapted a technique to introduce a protected aminomethyl group into the benzothiazole core (8) (see Equation 2, Scheme 2; Desroy, N., et al., Journal of Medicinal Chemistry, 2013, 56, 1418 -1430). Using this technique allows access to the protected 2-aminomethylbenzothiazoles of the present invention.

- 20 041925

Method C. Transformation of functional groups after the introduction of protection in aminomethylbenzothiazole.

In many cases, a substituent of the desired type can be introduced into the phenyl ring prior to the formation of the benzothiazole using standard functional group transformations. In some cases, it is preferable to perform functional group transformations after the formation of the benzothiazole.

Scheme 4

For example, one of the ways to obtain a phenolic intermediate based on benzothiazole (Scheme 4) is to obtain a bromo derivative (9) of benzothiazole, followed by substitution of the bromide using bis(pinacolato)dibor and Pd(dppf)Cl ₂ CH ₂ Cl ₂ catalyst, obtaining after aqueous treatment of ester (10) of boronic acid (for a related example, see Malinger, A. et al., Journal of Medicinal Chemistry, 2016, 59, 1078-1101). The boronic acid ester can be oxidized to phenol (11) with hydrogen peroxide (see Liu, J. et al., Tetrahedron Letters, 2017, 58, 1470-1473). Further transformation of the phenol group can be carried out by standard alkylation reactions familiar to those skilled in the art.

Method D. Transformation of functional groups after amide coupling of aminomethylbenzothiazole and indanyl moieties.

Scheme 5

For example, using this approach, by alkylating phenol (11) with 1,3-dibromopropane, removing the tert-butoxycarbonyl protecting group, and reacting with acid (3), an intermediate bromopropyloxy derivative (12) can be obtained. When reacted with a tertiary amine such as trimethylamine, the corresponding quaternary ammonium salt (13) is formed, and eventually removal of the tert-butyl ester results in a carboxylic acid forming a zwitterion (14) containing positive and negative charges.

Method E. Synthesis of amide substituents in the benzothiazole ring.

Scheme 6

The ester (15) is subjected to a benzothiazole ring formation procedure during which the ester is also hydrolyzed to give benzothiazolic acid (16). And then get the amides (17) using the standard method of formation of amides by reaction with amines such as ammonia and pyrrolidine.

Method F. Synthesis of sulfonamide substituents on the benzothiazole ring.

Scheme 7

To obtain analogous sulfonamides, a different procedure is required. The reaction of fluoronitrobenzene (18) with sodium sulfite (see Sisodia, S., et al., Can. J. Chem., 1980, 58, 714-715) leads to the formation of the sodium salt of arylsulfonic acid (19). It can be activated with standard activating agents (see Ashfaq, M., Mini-Reviews in Org. Chem., 2013, 10, 160-170) such as thionyl chloride or phosphorus oxychloride to form arylsulfonyl chloride (20). Further interaction with amines leads to the formation of sulfonamides (21). And then the reduction of the nitro derivative to aniline (22) (for an up-to-date review, see Orlandi, M., et al., Organic Process Research and Development, 2018, 22, 430-445) provides a precursor for the formation of benzothiazole (23).

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Method G. Final steps in the synthesis of examples.

Scheme 8

(B) (24) (25) (26)

The final steps in the synthesis typically involve acid-catalyzed removal of the BOC group in compound (8) to give free amines (24) and their subsequent reaction with acids of type (3), usually using the standard HATU peptide bond condensing reagent (for a comprehensive overview of the numerous available condensing reagents for peptide bond formation, see Valeur, E. and Bradley, M, Chem. Soc. Rev., 2008, 28, 606-631). Finally, the tert-butyl ester is removed by subsequent acid treatment with TFA (Trifluoroacetic acid) and the examples of the invention are obtained.

It should be understood that the considered schemes of synthesis are not exclusive; interconversion of functional groups at the stage of the phenyl precursor, at the stage of protection of aminomethylbenzothiazole and at the stage of post-coupling of the amide is possible.

Description of exemplary embodiments of the invention

1H NMR spectra were recorded at 300, 400 or 500 MHz in DMSO-d ₆ solutions (δ in ppm), using DMSO-d ₅ as standard (2.50 ppm), or in CDCl ₃ solutions using chloroform (7.26 ppm) as standard. In the case of multiplet peaks, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), br. s (widened singlet), wide. d (broadened doublet), dd (doublet of doublets), dt (doublet of triplets), sq. (quartet). Coupling constants, if specified, are expressed in hertz (Hz).

Purified by mass directed automated prep HPLC (MDAP) refers to the purification of a compound by a mass directed automated preparative HPLC purification system using an Agilent 1260 Infinity instrument with an XSelect CHS Prep C18 column eluting with 0.1% FA in water/ACN and detection by the Quadrupole LC/MS system.

Abbreviations

ACN Acetonitrile aq. Water

Bpin Bis(pinacolato)diboron

CaCl ₂ Calcium chloride cfu Colony forming unit

Cu(OAc) ₂ Copper (II) acetate

CuO Copper oxide

DXM Dichloromethane

DIPEA Ν,N-Diisopropylethylamine

DMF Ν,N-Dimethyl formamide

DMSO Dimethylsulfoxide dppf 1,1'-Bis(diphenylphosphino)ferrocene

EDCHCI M-(3-Dimethylaminopropyl)-Methylcarbodiimide Hydrochloride

Et ₂ O Diethyl ether

EtOAc Ethyl acetate

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EUN ethanol Et ₃ N Triethylamine Ex Excitation FA Formic acid FCC Purification by flash column chromatography on silica gel h hour (hours) go 1-[Bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate HCI Hydrochloric acid/hydrochloric salt HOBt Hydroxybenzotriazole H2SO4 Sulfuric acid km Michaelis constant MeOH methanol min minute (minutes) MgSO4 Magnesium sulfate NBS N-bromosuccinimide _NaHCO3 Bicarbonate of soda NaHMDS Sodium bis(trimethylsilyl)amide _Na2SO4 Sodium sulfate Pd ₂ (dba) ₃ Tris(dibenzylideneacetone)diallladium(0) PdCI ₂ (dppf) [1,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(Н) RT room temperature SCX-2 strong cation exchange resin (silica gel propyl sulfonic acid) TFA Trifluoroacetic acid THF T tetrahydrofuran T3P Propylphosphine anhydride

Example 1 2-[2-[(4-Carbamoyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid

a) Ethyl 2-amino-3-iodobenzoate

A solution of ethyl 2-aminobenzoate (1.1 g, 3.0 mmol) in toluene (75 ml) was treated with acetic acid (0.34 ml, 3.0 mmol) and N-iodosuccinimide (0.68 g, 3.0 mmol). After 70 h, the mixture was washed with saturated aqueous sodium bicarbonate, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed on silica gel eluting with 0-10% ethyl acetate in toluene to give a red oil which solidified on standing (0.26 g, 29%). M/z 292.5 (M+H)+.

b) 2-({[(tert-Butoxy)carbonyl]amino}methyl)-1,3-benzothiazole-4-carboxylic acid

A solution of ethyl 2-amino-3-iodobenzoate (147 mg, 0.5 mmol) in ACN (2 ml) was treated with tert-butyl-(2-amino-2-thioxoethyl)carbamate (115 mg, 0.61 mmol), calcium oxide (42 mg, 0.76 mmol), tris(dibenzylideneacetone) dipalladium(0) (92 mg, 0.1 mmol) and dppf (224 mg, 0.4 mmol). The flask was evacuated and refilled twice with nitrogen. The mixture was heated at 60°C in a sealed vessel in

- 23 041925 for 1.5 h, then cooled and partitioned between ethyl acetate and 10% aqueous citric acid. The aqueous fraction was further extracted with ethyl acetate, the combined extracts were dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed on silica gel eluting with 0-15% methanol in

DCM to give an oil (151 mg, 97%). M/z 331.4 (M+Na)+.

c) tert-Butyl-N-[(4-carbamoyl-1,3-benzothiazol-2-yl)methyl]carbamate

A solution of the above 2-({[(tert-butoxy)carbonyl]amino}methyl)-1,3-benzothiazole-4-carboxylic acid (170 mg) in DMF (2 mL) was treated with ammonium chloride (54 mg, 1 mmol) , DIPEA (0.35 ml, 2 mmol) and HATU (0.29 g, 2 mmol). After 0.5 h the mixture was partitioned between ethyl acetate and water. The aqueous fraction was further extracted with ethyl acetate, the combined extracts were dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed on silica gel eluting with 30-100% ethyl acetate in hexane to give a brown oil (151 mg, 100%). M/z 330.5 (M+Na)+.

d) 2-(Aminomethyl)-1,3-benzothiazole-4-carboxamide

A solution of tert-butyl-N-[(4-carbamoyl-1,3-benzothiazol-2-yl)methyl]carbamate (76 mg, 0.25 mmol) in DCM (3 ml) was treated with TFA (0.8 ml). After 1.25 h, toluene was added and the mixture was evaporated. The residue was treated with additional toluene and evaporated. The residue was transferred to an SCX cartridge eluting first with methanol then 2M ammonia in methanol to give a light brown solid (18 mg, 33%). M/z 230.5 (M+Na)+.

f) 2,3-Dihydro-1 H-indene-2-carboxylate

To a stirred solution of 2,3-dihydro-1H-indene-2-carboxylic acid (20 g, 123 mmol) in methanol (200 ml) at room temperature was added dropwise concentrated H ₂ SO ₄ (10 ml, 185 mmol) and stirred at a temperature of 80°C for 16 hours the Reaction mass was evaporated to obtain a residue. The residue was dissolved in water (100 ml) and was extracted with EtOAc (2x100 ml). The organic layer was washed with saturated sodium bicarbonate, brine and evaporated to give a light brown liquid (20 g, 92%). M/z 177.1 (M+H)+.

f) Methyl 2-(2-(tert-butoxy)-2-ochoethyl)-2,3-dihydro-1H-indene-2-carboxylate

To a solution of methyl 2,3-dihydro-1H-indene-2-carboxylate (5 g, 28.3 mmol) in THF (100 mL) was added NaHMDS (21 mL, 42.5 mmol, 2M in THF) at - 78° C. under argon atmosphere and stirred at -78° C. for 1 h. 15 min at -78°C and stirred at this temperature for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 ml) at -78°C and left to stir at room temperature for 30 min. The organic layer was separated, the aqueous layer was extracted with EtOAc (2x100 ml) and the combined organic layers were evaporated to give the crude compound. The crude compound was triturated with n-pentane (50 ml) at -78° C. and stirred at this temperature for 15 minutes. The resulting solid was filtered off, dried in vacuo to give an off-white solid (3.7 g, 45%). M/z = 313.0 (M+Na)+.

g) 2-(2-(tert-Butoxy)-2-oxoethyl)-2,3-dihydro-1H-indene-2-carboxylic acid

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To a stirred solution of methyl 2-(2-(tert-butoxy)-2-oxoethyl)-2,3-dihydro-1H-indene-2carboxylate (430 g, 1.48 mol) in THF (2.15 L) and ethanol (2.15 L) at room temperature was added dropwise 0.5 M solution of LiOH-H ₂ O (6.8 L, 2.96 mol) and stirred at this temperature for 2 h. The reaction mass was evaporated to obtain a residue, the residue was diluted with H ₂ O (1 l) and was extracted with diethyl ether. The aqueous layer was acidified with 1N HCl to pH 3-4. The precipitate formed was filtered off, washed with water, n-pentane and dried in vacuo to give a white solid (254.5 g, 62%). M/z 275.2 (M-H) ^- .

¹ H NMR (300 MHz, DMSO-dg), δ: 12.4 (1H, br s), 7.18-7.10 (4H, m), 3.39 (2H, d, J = 16, 2 Hz), 2.92 (2H, d, J = 16.2 Hz), 2.64 (2H, s), 1.37 (9H, s).

h) tert-Butyl-2-[2-[(4-carbamoyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetate

A solution of 2-(aminomethyl)-1,3-benzothiazole-4-carboxamide (18 mg, 0.09 mmol), 2-(2-(tert-butoxy)-2oxoethyl)-2,3-dihydro-1H-inden- 2-carboxylic acid (26 mg, 0.1 mmol) and DIPEA (34 mg, 0.26 mmol) in DMF (0.5 ml) were treated with HATU (50 mg, 0.1 mmol). After 0.33 h the mixture was partitioned between ethyl acetate and 10% aqueous citric acid. The aqueous layer was further extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed on silica gel eluting with 50-100% ethyl acetate in hexane to give a brown oil (36 mg, 90%). M/z 488.2 (M+Na)+.

i) 2-[2-[(4-Carbamoyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid.

Solution of tert-butyl 2-[2-[(4-carbamoyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetate (36 mg, 0.08 mmol) in DCM (2 ml) treated with TFA (0.8 ml). After 1.5 h, toluene was added and the mixture was evaporated. The residue was treated with additional toluene and evaporated. The residue was chromatographed on silica gel eluting with 2-12% methanol in DCM to give the title compound as a white solid (14 mg, 43%). M/z 410.4 (M+H) ⁺ .

1H NMR (400 MHz, d6-DMSO), δ: 12.20 (1H, br s), 9.20 (1H, br s), 9.00 (1H, br s), 8.30 ( 1H, d), 8.15 (1H, d), 7.90 (1H, br s), 7.55 (1H, t), 7.25 (2H, m), 7.15 (2H, m ), 4.75 (2H, d), 3.50 (2H, d), 3.00 (2H, d).

Example 2 2-[2-[[4-(Pyrrolidine-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid

This compound was prepared analogously to Example 1, but with the difference that pyrrolidine was used instead of ammonium chloride, resulting in a white solid (5.0 mg). M/z 464.2 (M+H) ⁺ .

1H NMR (400 MHz, d6-DMSO), δ: 12.20 (1H, br s), 9.00 (1H, br s), 8.10 (1H, d), 7.45 (2H, m), 7.20(2H, m), 7.10(2H, m), 4.70(2H, d), 3.55(2H, m), 3.50(2H, d), 3, 10(2H, m), 3.00(2H, d), 1.90(2H, m), 1.80(2H, m).

Example 3 2-[2-[(4-Pyrrolidin-1-ylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2yl]acetic acid

a) Sodium 3-iodine-2-nitrobenzene-1-sulfonate

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A solution of (commercially available) 1-fluoro-3-iodo-2-nitrobenzene (218 mg, 0.75 mmol) in ethanol (6 ml) was treated with a solution of sodium sulfite (236 mg, 1.9 mmol) in water (5 ml) . The mixture was heated at reflux for 4 hours. The cooled mixture was evaporated to dryness and chromatographed on reverse phase silica gel (C-18 cartridge), eluting first with water then with methanol to give a white solid (144 mg, 55%) . M/z 328.2 (M-Na)'.

b) 1-(3-Iodo-2-nitrobenzenesulfonyl)pyrrolidine

A suspension of 3-iodo-2-nitrobenzene-1-sulfonate sodium (133 mg, 0.38 mmol) in thionyl chloride (1 ml) was treated with DMF (1 drop), the resulting mixture was heated at the boil under reflux for 1.5 h , then diluted with toluene and evaporated. The residue was redissolved three times in toluene and re-evaporated to give 3-iodo-2-nitrobenzene-1-sulfonyl chloride as an oil (124 mg, 94%). Half of this sample (62 mg, 0.18 mmol) was dissolved in toluene (0.5 ml) and added to a solution of pyrrolidine (213 mg, 3 mmol) in THF (2 ml) at 0°C. After the addition, the mixture was stirred at room temperature for 0.5 h, then diluted with toluene and evaporated. The residue was chromatographed on silica gel eluting with 0-5% methanol in DCM to give a colorless solid (65 mg, 96%). M/z 383.3 (M+H)+.

c) 2-Iodine-6-(pyrrolidine-1-sulfonyl)aniline

A solution of 1-(3-iodo-2-nitrobenzenesulfonyl)pyrrolidine (65 mg, 0.17 mmol) in ethanol (2 ml) was treated with iron powder (50 mg, 0.9 mmol) followed by acetic acid (200 mg, 3. 4 mmol). The mixture was heated to 85° C. for 1.5 h, then filtered through Celite, rinsing with isopropanol. The filtrate was evaporated and the residue was chromatographed on silica gel eluting with 0-15% ethyl acetate in toluene to give a colorless oil (46 mg, 73%). M/z 353.3 (M+H)+.

d) tert-Butyl-N-{[4-(pyrrolidin-1-sulfonyl)-1,3-benzothiazol-2-yl]methyl} carbamate

A solution of 2-iodo-6-(pyrrolidine-1-sulfonyl)aniline (46 mg, 0.13 mmol) in ACN (1 ml) was treated with tert-butyl-(2-amino-2-thioxoethyl)carbamate (30 mg, 0 .16 mmol), calcium oxide (11 mg, 0.2 mmol), tris(dibenzylideneacetone) dipalladium(0) (24 mg, 0.03 mmol) and dppf (58 mg, 0.11 mmol). The mixture was heated at 60° C. in a sealed vessel for 2 hours, then cooled, diluted with toluene and filtered through celite. The filtrate was applied directly to a silica gel cartridge (10 g) and chromatographed eluting with 0-50% ethyl acetate in toluene to give an oil (33 mg, 64%). M/z 420.2 (M+Na)+.

f) [4-(Pyrrolidine-1-sulfonyl)-1,3-benzothiazol-2-yl]methanamine

A solution of tert-butyl N-{[4-(pyrrolidin-1-sulfonyl)-1,3-benzothiazol-2-yl]methyl}carbamate (33 mg, 0.08 mmol) in DCM (2 mL) was treated with TFA ( 0.5 ml). After 2 h, toluene was added and the mixture was evaporated. The residue was treated with additional toluene and evaporated. The residue was dissolved in methanol:DCM (1:1), loaded onto an SCX cartridge (10 g) and chromatographed eluting with 1M ammonia/methanol. Fractions containing product were combined and evaporated, the residue was further chromatographed on silica gel eluting with 0-6% 2M ammonia/methanol in DCM to give a brown oil (17 mg, 68%). M/z 298.4 (M+H)+.

f) tert-Butyl-2-[2-[(4-pyrrolidin-1-ylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2yl]acetate

[4-(Pyrrolidine-1-sulfonyl)-1,3-benzothiazol-2-yl]methanamine solution (18 mg, 0.06 mmol), 2-(2(tert-butoxy)-2-oxoethyl)-2, 3-dihydro-1H-indene-2-carboxylic acid (18 mg, 0.07 mmol) and DIPEA (23 mg, 0.03 mmol) in DMF (0.5 ml) were treated with HATU (34 mg, 0.9 mmol ). After 0.5 h, the mixture was partitioned between ethyl acetate and 10% aqueous citric acid. The aqueous layer was further extracted with ethyl acetate, the combined extracts were washed with saturated aqueous sodium chloride, dried (Na ₂ SO ₄ ) and evaporated.

The residue was chromatographed on silica gel eluting with 30-60% ethyl acetate in hexane to give a brown oil (33 mg, 100%). M/z 578.3 (M+Na) ⁺ .

g) 2-[2-[(4-Pyrrolidin-1-ylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid.

Solution of tert-butyl 2-[2-[(4-pyrrolidin-1-ylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetate (33 mg, 0.06 mmol) in DCM (2 ml) was treated with TFA (0.8 ml). After 1.75 hours, toluene was added and the mixture was evaporated. The residue was treated with additional toluene and evaporated. The residue was chromatographed on silica gel eluting with 2-10% methanol in DCM to give the title compound as a white solid (19 mg, 62%). M/z 500.1 (M+H) ⁺ .

1H NMR (400 MHz, d6-DMSO), δ: 12.30 (1H, br s), 9.00 (1H, br s), 8.40 (1H, d), 7.95 (1H, e), 7.58 (1H, t), 7.23 (2H, m), 7.15 (2H, m), 4.70 (2H, d), 3.50 (2H, d), 3, 40(4H, m), 3.00(2H, d), 1.7-1.6(4H, m).

Example 4 2-[2-[(4-Sulfamoyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid

This compound was obtained according to the procedure described in example 3, except that in the stage of formation of sulfonamide with 3-iodo-2-nitrobenzene-1-sulfonyl chloride, ammonium chloride (source of ammonia) was used instead of pyrrolidine. The title compound was isolated as a white solid (15 mg). M/z 446.1 (M+H) ⁺ .

1H NMR (400 MHz, d ₆ -DMSO), δ: 12.00 (1H, br s), 8.30 (1H, d), 7.92 (1H, d), 7.55 (1H, t ), 7.30 (2H, s), 7.20 (2H, m), 7.10 (2H, m), 4.80 (2H, d), 3.45 (2H, d), 3.00 (2H, e).

Example 5 2-[2-[(4-Piperazin-1-ylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2yl]acetic acid

This compound was obtained according to the procedure described in example 3, except that benzylpiperazine-1-carboxylate was used instead of pyrrolidine at the stage of formation of the sulfonamide with 3-iodo-2-nitrobenzene-1-sulfonyl chloride, and it took 55 hours to remove the benzylcarbamate protective group at room temperature in pure TFA. The title compound was isolated after purification as a white solid (9 mg). M/z 515.3 (M+H) ⁺ .

1H NMR (400 MHz, d6-DMSO), δ: 10.00 (1H, br s), 8.40 (1H, d), 7.95 (1H, d), 7.60 (1H, t) , 7.20(2H, m), 7.10(2H, m), 4.75(2H, d), 3.50(4H, m), 3.20(2H, m), 3.00( 2H, d), 2.80 (2H, m), 2.60 (2H, m).

Example 6 2-[2-[[4-(3-Aminopyrrolidin-1-yl)sulfonyl-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid

- 27 041925

This compound was obtained according to the procedure described in example 3, except that in the stage of formation of sulfonamide with 3-iodo-2-nitrobenzene-1-sulfonyl chloride, instead of pyrrolidine, (R,S)-benzyl-N-(pyrrolidine-3- yl)carbamate, and it took 48 hours to remove the benzylcarbamate protecting group at room temperature in pure TFA. The title compound was isolated as a white solid (14 mg). M/z 515.4 (M+H)+.

¹ H NMR (400 MHz, d6-DMSO), δ: 11.00 (1H, br s), 8.40 (1H, d), 8.00 (1H, d), 7.60 (1H, t ), 7.20 (2H, m), 7.15 (2H, m), 4.75 (2H, m), 4.00 (1H, t), 3.60-3.20 (6H, m) , 3.00-2.85(2H, m), 1.95(1H, m), 1.70(1H, m).

Example 7 2-[2-[(4-Methylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid

a) 1-Iodine-3-methanesulfonyl-2-nitrobenzene

A solution of 2-fluoro-3-iodo-2-nitrobenzene (200 mg, 0.75 mmol) in THF (6 ml) was treated in portions with sodium thiomethoxide, then 15-crown-5-(1,4,7,10,13 -pentaoxacycloptadecane) (20 mg). After 7 hours the mixture was diluted with DCM (6 ml) and 3-chloroperbenzoic acid (672 mg, 3 mmol) was added. After 16 hours, the mixture was partitioned between ethyl acetate and 10% aqueous sodium metabisulphite. The aqueous layer was further extracted with ethyl acetate and the combined organic extracts were washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate in toluene to give a white solid (227 mg). The product was further purified by silica gel chromatography eluting with 0-2% methanol in chloroform to give a colorless solid (92 mg, 38%). M/z 246.3 (M+H) ⁺ .

b) 2-[2-[(4-Methylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid.

This compound was prepared from 1-iodo-3-methanesulfonyl-2-nitrobenzene using the same reaction sequence as described in Example (3c) et seq. to give the title compound as a white solid (34 mg). M/z 445.4 (M+H) ⁺ .

¹ H NMR (400 MHz, d ₆ -DMSO), δ: 12.20 (1H, br s), 8.90 (1H, br s), 8.45 (1H, d), 8.00 ( 1H, d), 7.62 (1H, t), 7.22 (2H, m), 7.15 (2H, m), 4.75 (2H, d), 3.52 (3H, s), 3.50 (2H, d), 3.00 (2H, d).

Example 8 2-[2-[[6-Methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl] acetic acid

a) 4-Bromo-5-methoxy-2-nitroaniline

To a stirred solution of 5-methoxy-2-nitroaniline (100 g, 595 mmol) in acetonitrile (2.5 L) was added portionwise NBS (106 g, 595 mmol) at room temperature. The mixture was cooled to a temperature of 0°C, after which TFA (46 ml, 595 mmol) was added dropwise over 30 min and left to stir at room temperature for 16 h. The reaction mass was diluted with water (1 l) and the pH was adjusted to ~ 8 with 1N NaOH solution. The precipitate formed was filtered off, washed with water (500 ml), dried in vacuo to give a yellow solid. (105 g, 72%).

- 28 041925

M/z 247 (M+H)+.

b) 1-Bromo-4-iodine-2-methoxy-5-nitrobenzene

To a stirred solution of 4-bromo-5-methoxy-2-nitroaniline (50 g, 203 mmol) in acetonitrile (750 ml) was added dropwise concentrated H ₂ SO ₄ (24 ml, 457 mmol) at -10°C. Thereafter, a solution of NaNO ₂ (28 g, 406 mmol) in water (175 ml) was added dropwise at -10° C. over 15 min and stirred at this temperature for 30 min. A solution of KI (135 g, 813 mmol) in water (175 ml) was then added dropwise at -10°C over 20 min and stirred at this temperature for 30 min. The reaction mixture was quenched with a solution of sodium metabisulphite (309 g, 1.62 mmol) in water (1.6 L) at -10°C to 0°C for 1 hour. Water (1 L) was then added and the mixture was allowed to stir. at room temperature for 30 min. The precipitate formed was filtered off, washed with water (1 L), dried in vacuo to give a yellow solid. (60 g, 82%). M/z 357.8 (M+H) ⁺ .

c) 5-Bromo-2-iodine-4-methoxyaniline

Fe (49.7 g, 890 mmol) was added to a stirred solution of 1-bromo-4-iodo-2-methoxy-5-nitrobenzene (106 g, 296 mmol) in EtOH:H ₂ O (800 ml: 200 ml) , NH ₄ Cl (80 g, 1.48 mmol) at room temperature and stirred at 90°C for 2 h. Then the reaction mixture was cooled to 60°C, additional Fe (33 g, 593 mmol) was added, NH ₄ Cl (80 g, 1.48 mmol) and stirred at 90° C. for 30 minutes. The reaction mass was filtered through a layer of celite, the layer was washed with methanol (1 l) and the filtrate was concentrated to obtain a residue. The residue was diluted with cold water (1 L) and the pH was adjusted to ~8 with 1N NaOH solution. The precipitate formed was filtered off, dried in vacuo to give a light brown solid (90 g, 92%). M/z 327.8 (M+H) ⁺ .

d) tert-Butyl-N-[(5-bromo-6-methoxy-1,3-benzothiazol-2-yl)methyl]carbamate

To a stirred solution of 5-bromo-2-iodo-4-methoxyaniline (50 g, 152 mmol) in acetonitrile (560 ml) was added tert-butyl-(2-amino-2-thioxoethyl)carbamate (35 g, 183 mmol), CaO (17 g, 305 mmol) and purged with argon for 20 min. Then Pd ₂ (dba) ₃ (14 g, 15.2 mmol), dppf (25.4 g, 15.8 mmol) was added and purged with argon for another 5 min, after which the reaction mass was stirred at a temperature of 80°C in for 4 hours the Reaction mass was filtered through a layer of Celite and the layer was washed with EtOAc (300 ml). The filtrate was washed with water and evaporated to give the crude compound. The crude compound was dissolved in acetonitrile (200 ml) and a solid precipitated on standing for 1 hour. The resulting solid was filtered off, washed with acetonitrile (50 ml), dried in vacuo to give an off-white solid (34 g, 60%). M/z 372.9 (M+H) ⁺ .

f) tert-Butyl-N-[[6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ul)-1,3-benzothiazol-2yl]methyl] carbamate

BPin (6.8 g , 26.8 mmol), KOAc (4.6 g, 47.0 mmol) and purged with argon for 15 min. Pd ₂ Cl ₂ (dppf) DCM (1.1 g, 1.34 mmol) was then added and purged with argon for another 5 minutes. The reaction mixture was heated at 100° C. for 16 hours. The reaction mass was filtered through a pad of celite and the pad was washed with EtOAc (50 ml). The filtrate was washed with water, brine and evaporated to give a white solid (12 g, crude). M/z 339 (M+H) ⁺ .

f) tert-Butyl N-[(5-hydroxy-6-methoxy-1,3-benzothiazol-2-yl)methyl]carbamate

- 29 041925 but

Into a stirred solution of tert-butyl-N-[[6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1,3-benzothiazol-2-yl]methyl ]carbamate (12 g, 35.5 mmol) in THF (180 ml) was added 1N NaOH solution (35 ml, 35.5 mmol), 30% H ₂ O ₂ (6.2 ml, 81.6 mmol) at a temperature 0°C and stirred at this temperature for 30 min. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, washed with water, brine and evaporated to give the crude compound. The crude compound was chromatographed on silica gel eluting with 30% EtOAc in petroleum ether to give an off-white solid. (2.5 g 54%). M/z 311.0 (M+H)+.

¹ H NMR (500 MHz, CDCl ₃ ), δ: 7.50 (1H, s), 7.25 (1H, s), 5.76 (1H, s), 5.30 (1H, s), 4 .68 (2H, d, J = 5.5 Hz), 3.97 (3H, s), 1.54 (9H, s). M/z 311.0 (M+H) ⁺ .

g) tert-Butyl N-({6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2yl}methyl) carbamate

A mixture of tert-butyl-N[(5-hydroxy-6-methoxy-1,3-benzothiazol-2-yl)methyl]carbamate (310 mg, 1 mmol), (commercially available) hydrochloride 1-(2-chloroacetyl)- 4-methylpiperazine (234 mg, 1.1 mmol) and cesium carbonate (980 mg, 3 mmol) in ACN (3 ml) was stirred for 18 h, then partitioned between DCM and saturated aqueous sodium chloride, the organic layer was dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed on silica gel eluting with 2-10% 7M ammonia/methanol in DCM to give a white solid (268 mg, 59%). M/z 451.6 (M+H) ⁺ .

h) 2-{[2-(Aminomethyl)-6-methoxy-1,3-benzothiazol-5-yl]oxy}-1-(4-methylpiperazin-1-yl)ethan-1-one

A solution of tert-butyl N-({6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2yl}methyl) carbamate (265 mg, 0. 6 mmol) in DCM (3 ml) was treated with TFA (1.4 ml). After 1 h, the mixture was applied to an SCX-2 cartridge pre-washed with methanol. The applied mixture was washed with methanol, then eluted with a 7M ammonia/methanol solution. This last fraction was evaporated to give an orange foam (195 mg, 95%). M/z 351.6 (M+H) ⁺ .

i) tert-Butyl-2-[2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2 -yl]acetate

O

2-{[2-(aminomethyl)-6-methoxy-1,3-benzothiazol-5-yl]oxy}-1-(4-methylpiperazin-1-yl)ethan1-one solution (151 mg, 0.55 mmol ), 2-(2-(tert-butoxy)-2-oxoethyl)-2,3-dihydro-1H-indene-2-carboxylic acid (192 mg, 0.55 mmol) and triethylamine (0.23 ml, 166 mg, 0.66 mmol) in DCM (3 ml) was treated with HATU (250 mg, 0.66 mmol). After 2 hours, the mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride. The organic fraction was dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed on silica gel eluting with 2-10% 7M ammonia/methanol in DCM to give an off-white solid (209 mg, 63%). M/z 609.7 (M+H) ⁺ .

j) 2-[2-[[6-Methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl ]acetic acid.

A solution of tert-butyl-2-[2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol2-yl]methylcarbamoyl]indan-2- yl]acetate (206 mg, 0.33 mol) in DCM (3 ml) was treated with water (0.2 ml) then TFA (1.6 ml). After 2 h the mixture was evaporated. Toluene was added and the mixture was re-evaporated. The residue was purified by MDAP followed by freeze drying of the fractions containing the product to give the title compound as a white solid (108 mg, 58%). M/z 553.4 (M+H) ⁺ .

- 30 041925 ¹ H NMR (400 MHz, d ⁶ -DMSO), δ: 8.80 (1H, br s), 7.60 (1H, s), 7.40 (1H, s), 7.20 (2H, m), 7.10 (2H,

m) 4.90 (2H, s), 4.60 (2H, d), 3.80 (3H, s), 3.50 (4H, m), 3.00 (2H, d), 2.70 (2H, m), 2.40 (2H, m), 2.30 (2H, m),

2.20 (3H, s).

Example 9 2-[2-[[6-Methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid

This compound was obtained as a white solid (101 mg) analogously to example 8, with the difference that commercially available 4-(2-chloroethyl)morpholine hydrochloride was used instead of 1-(2-chloroacetyl)-4-methylpiperazine hydrochloride. M/z 526.4 (M+H)+.

¹ H NMR (400 MHz, d ₆ -DMSO), δ: 12.00 (1H, br s), 8.80 (1H, br s), 7.60 (1H, s), 7.50 ( 1H, s), 7.20 (2H, m), 7.10 (2H, m), 4.60 (2H, d), 4.20 (2H, m), 3.80 (3H, s), 3.70(2H, m), 3.50(2H, d), 3.45-3.30(10H, m), 3.00(2H, d).

Example 10 2-[5,6-Difluoro-2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid

a) Dimethyl-4,5-difluorophthalate

To an ice-bath cooled solution of 4,5-difluorophthalic acid (11.9 g, 58.9 mmol) in MeOH (250 ml) was added concentrated H2SO4 (40 ml, 0.75 mol) keeping the temperature below 20°C. The mixture was stirred at 65°C for 4 hours. The cooled reaction mass was concentrated in vacuo, then the residue was carefully added to EtOAc and aqueous NaHCO ₃ . The aqueous layer was extracted with EtOAc, the combined organic extracts were washed with aqueous NaHCO ₃ , then brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a colorless oil (12.98 g, 96%).

¹ H NMR (CDCl ₃ ), δ: 7.56 (2H, t, J=8.7 Hz), 3.91 (6H, s).

b) (4,5-Difluoro-1,2-phenylene)dimethanol

To an ice-bath-cooled solution of lithium aluminum hydride (1M in THF, 226 mL, 0.226 mol) was added a solution of dimethyl 4,5-difluorophthalate (12.98 g, 56.4 mmol) in THF (100 mL) over 30 min, keeping the temperature below 12°C. The mixture was stirred in an ice bath for 30 min, then at room temperature for 1 h. The reaction mixture was cooled to 0° C., then water (8.5 ml), 15% aqueous NaOH solution (8.5 ml ) and water (26 ml), keeping the temperature below 15°C. Celite was added and the mixture was stirred at room temperature for 1 h, then filtered through a pad of celite, washing with more THF. The filtrate was concentrated in vacuo to give the title compound as a white solid (9.52 g, 97%).

¹ H NMR (d6-DMSO), δ: 7.36 (2H, t, J = 10.1 Hz), 5.29 (2H, t, J = 5.5 Hz), 4.47 (4H, d , J = 5.4 Hz).

c) 1,2-Bis(bromomethyl)-4,5-difluorobenzene

A mixture of (4,5-difluoro-1,2-phenylene) dimethanol (9.52 g, 54.7 mmol) and 48% hydrobromic acid (68.5 ml) was stirred at 110° C. for 1 hour. the mass was diluted with water and then extracted with Et ₂ O. The aqueous layer was extracted with Et ₂ O, the combined organic extracts were washed with water then brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to a residue. FCC (1-10% EtOAc in hexane) gave the title compound as a colorless oil (15.2 g, 93%).

¹ H NMR (CDCI3), δ: 7.20 (2H, t, J = 9.1 Hz), 4.55 (4H, s).

d) Diethyl 5,6-difluoro-1,3-dihydro-2H-indene-2,2-dicarboxylate

F F

ΛΑ ______ o o

Sodium hydride (60% in oil, 4.46 g, 112 mmol) was added over 15 min to a mixture of 1,2bis(bromomethyl)-4,5-difluorobenzene (15.2 g, 50.7 mmol) and diethyl malonate (9 .74 g, 60.8 mmol) in THF (200 ml) keeping the temperature below 20°C. The mixture was stirred at room temperature for 4 hours, then saturated ammonium chloride was added. The mixture was concentrated in vacuo and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to a residue. FCC (5-25% EtOAc in hexane) gave the title compound as a colorless oil (9.95 g, 66%).

¹ H NMR (CDCI3), δ: 6.97 (2H, t, J = 8.7 Hz), 4.21 (4H, q, J = 7.1 Hz), 3.52 (4H, s) , 1.26 (6H, t, J = 7.1 Hz).

f) 5,6-Difluoro-2,3-dihydro-1H-indene-2-carboxylic acid

F F

O^O n

Water (130 ml) and concentrated HCl (140 ml). The mixture was heated at the boil under reflux for 23 hours. The cooled reaction mass was diluted with water and extracted with Et ₂ O (x3). The combined organic extracts were washed with water then brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound as a colorless solid (6.6 g, quant.). M/z 197 (M-N) ^- .

f) Methyl 5,6-difluoro-2,3-dihydro-1H-indene-2-carboxylate

F F

ST O I

To an ice-bath cooled solution of 5,6-difluoro-2,3-dihydro-1H-indene-2-carboxylic acid (6.6 g, 33.3 mmol) in MeOH (200 ml) was added concentrated H ₂ SO ₄ ( 40 ml, 0.75 mol), keeping the temperature below 20°C. The mixture was stirred at 65°C for 1 h. The cooled reaction mass was concentrated in vacuo, then the residue was carefully added to EtOAc and aqueous NaHCO ₃ . The aqueous layer was extracted with more EtOAc and the combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to a residue. FCC (5-25% EtOAc in hexane) gave the title compound as a pale yellow solid (5.97 g, 84%).

1H NMR (CDCI3), δ: 6.98 (2H, t, J = 8.8 Hz), 3.73 (3H, s), 3.39 (1H, m), 3.24-3.12 ( 4H, m).

g) Methyl 2-(2-(tert-butoxy)-2-oxoethyl)-5,6-difluoro-2,3-dihydro-1H-indene-2-carboxylate

To a solution of methyl 5,6-difluoro-2,3-dihydro-1H-indene-2-carboxylate (5.97 g, 28.2 mmol) in THF (120 ml) cooled to -78°C was added sodium bis(trimethylsilyl)amide (1M in THF, 42.2 mL, 42.2 mol) for 15 min. The mixture was stirred at -78° C. for 45 minutes, then a solution of tert-butyl bromoacetate (8.24 g, 42.2 mmol) in THF (15 ml) was added over 10 minutes. The reaction mixture was allowed to warm to -10° C. for 1 hour. Saturated ammonium chloride solution was added and the mixture was concentrated under reduced pressure. The residue was extracted twice

- 32 041925

EtOAc, the combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to a residue. FCC (5-20% EtOAc in hexane) gave the title compound as a pale yellow gum (8.78 g, 96%).

1 H NMR (CDCl ₃ ), δ: 6.96 (2H, t, J = 8.9 Hz), 3.72 (3H, s), 3.47 (2H, d, J = 16.2 Hz), 2.90 (2H, d, J = 16.2 Hz), 2.71 (2H, s), 1.42 (9H, s).

h) 2-[(tert-Butoxy)carbonyl]-5,6-difluoro-2,3-dihydro-1H-indene-2-carboxylic acid

To a solution of methyl 2-(2-(tert-butoxy)-2-oxoethyl)-5,6-difluoro-2,3-dihydro-1H-indene-2-carboxylate (0.834 g, 2.56 mmol) in THF (25 ml) and MeOH (10 ml) lithium hydroxide (0.5M in water, 10.2 ml, 5.1 mmol) was added. The mixture was stirred at room temperature for 2.5 hours then concentrated in vacuo. The residual solution was stratified with EtOAc and acidified by adding 6M HCl solution. The aqueous layer was extracted with more EtOAc, the combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to a residue. FCC (2-6% MeOH in DCM) gave the title compound as a cream solid (0.59 g, 74%).

1H NMR (66-DMSO), δ: 12.47 (1H, br s), 7.26 (2H, t, J = 9.2 Hz), 3.33 (2H, d, J = 16.4 Hz), 2.91 (2H, d, J = 16.4 Hz), 2.67 (2H, s), 1.37 (9H, s). m/z 311 (M-N) ^- .

i) 2-[5,6-Difluoro-2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid.

The title product was obtained as a white solid (18 mg) analogously to Example 9, with the difference that instead of 2-[(tert-butoxy)carbonyl]-2,3-dihydro-1H-indene-2carboxylic acid, 2-[(tert-butoxy)carbonyl]-5,6-difluoro-2,3-dihydro-1H-indene-2carboxylic acid. m/z 562.4 (M+H)+.

1H NMR (400 MHz, a ₆ -DMSO), δ: 12.00 (1H, br s), 8.80 (1H, br s), 7.60 (1H, s), 7.50 (1H , s), 7.30 (2H, t), 4.60 (2H, d), 4.20 (2H, t), 3.80 (3H, s), 3.60 (2H, t), 3 .45 (2H, d), 3.30 (4H, m), 3.00 (2H, d), 2.75 (4H, m).

Example 11 2-[5,6-Difluoro-2-[[6-methoxy-5-[(1-methyl-4-piperidyl)methoxy]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl ]acetic acid

This compound was prepared analogously to Example 10, except that (1-methylpiperidin4-yl)methanol hydrochloride was used in the alkylation step instead of 4-(2-chloroethyl)morpholine hydrochloride to give the title compound as a white solid ( 58 mg). M/z 560.4 (M+H)+.

1H NMR (400 MHz, a ₆ -DMSO), δ: 9.00 (1H, br s), 7.60 (1H, s), 7.45 (1H, s), 7.20 (2H, t ), 4.65(2H, d), 3.95(2H, m), 3.85(3H, s), 3.45(2H, d), 2.95(2H, d), 2.80 (2H, m), 2.30 (3H, s), 2.00 (2H, m), 1.80 (3H, m), 1.40 (2H, m).

Example 12 2-[5,6-Difluoro-2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl] indan-2-yl]acetic acid

O

a) tert-Butyl-2-[5,6-difluoro-2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2 -yl]methylcarbamoyl]indan-2-yl]acetate

- 33 041925

2-{[2-(Aminomethyl)-6-methoxy-1,3-benzothiazol-5-yl]oxy}-1-(4-methylpiperazin-1-yl)ethan1-one solution (151 mg, 0.43 mmol ), 2-[(tert-butoxy)carbonyl]-5,6-difluoro-2,3-dihydro-1H-indene-2-carboxylic acid (135 mg, 0.43 mmol) and triethylamine (0.18 ml, 131 mg, 1.3 mmol) in DCM (3 ml) was treated with HATU (197 mg, 0.52 mmol). After 2 hours, the mixture was partitioned between DCM and saturated aqueous sodium chloride. The organic fraction was dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed on silica gel eluting with 1-10% 7M ammonia/methanol in DCM to give an off-white solid (169 mg, 61%). M/z 645.7 (M+H)+.

b) 2-[5,6-Difluoro-2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2yl]methylcarbamoyl]indan -2-yl]acetic acid.

tert-Butyl-2-[5,6-difluoro-2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl] solution methylcarbamoyl]indan-2-yl]acetate (65 mg, 0.1 mol) in DCM (2 ml) was treated with water (0.05 ml) then TFA (0.5 ml). After 2 h the mixture was evaporated. Toluene was added and the mixture was re-evaporated. The residue was purified by MDAP followed by freeze drying of the fractions containing the product to give the title compound as a white solid (11 mg, 19%). M/z 589.6 (M+H)+.

1H NMR (400 MHz, N6-DMSO), δ: 12.20 (1H, br s), 9.80 (1H, br s), 7.60 (1H, s), 7.50 (1H, brs). s), 7.25(2H, t), 4.95(2H, m), 4.65(2H, m), 4.40(1H, m), 4.10(1H, m), 3, 95 (2H, m), 3.80 (3H, s), 3.70-3.50 (3H, m), 3.45 (2H, d), 3.15 (1H, m), 3.00 (2H, d), 2.80 (3H, s).

Example 13 2-[5,6-Difluoro-2-[[6-methoxy-5-[2-(4-methylmorpholin-4-ium-4-yl)ethoxy]-1,3benzothiazol-2-yl]methylcarbamoyl ]indan-2-yl]acetate ^{FF v} ° m lSuy “w o

a) tert-Butyl-2-[5,6-difluoro-2-[[6-methoxy-5-[2-(4-methylmorpholin-4-ium-4-yl)ethoxy]-1,3-benzothiazol-2 iodide -yl]methylcarbamoyl]indan-2-yl]acetate

A solution of tert-butyl-5,6-difluoro-2-[({6-methoxy-5-[2-(morpholin-4-yl)ethoxy]-1,3-benzothiazol-2yl}methyl)carbamoyl]-2, 3-dihydro-1H-indene-2-carboxylate (see example 10) (140 mg, 0.23 mmol) in THF (2 ml) was treated with methyl iodide (161 mg, 0.07 ml, 1.1 mmol) and stirred overnight. Evaporation gave an oil (0.2 g) which was used directly in the next step. M/z 632.6 (M) ⁺ .

b) 2-[5,6-Difluoro-2-[[6-methoxy-5-[2-(4-methylmorpholin-4-ium-4-yl)ethoxy]-1,3-benzothiazol-2yl]methylcarbamoyl] indan-2-yl]acetate.

A solution of the above iodide tert-butyl-2-[5,6-difluoro-2-[[6-methoxy-5-[2-(4-methylmorpholin-4ium-4-yl)ethoxy]-1,3-benzothiazol- 2-yl]methylcarbamoyl]indan-2-yl]acetate (0.2 g, 0.23 mmol) in DCM (2 ml) was treated with water (0.1 ml) then TFA (1 ml). After 2 h the mixture was evaporated. Toluene was added and the mixture was re-evaporated. The residue was purified by MDAP followed by freeze drying of the fractions containing the product to give the title compound as a white solid (54 mg, 41%). M/z 576.4 (M+H) ⁺ .

¹ H NMR (400 MHz, a ₆ -DMSO), δ: 12.90 (1H, br s), 7.65 (1H, s), 7.60 (1H, s), 7.20 (2H, t), 4.65 (2H, m), 4.60 (2H, m), 4.10-3.90 (6H, m), 3.85 (3H, s), 3.70-3.50 (4H, m), 3.40 (2H, d), 3.30 (3H, s), 2.90 (2H, d).

Example 14 2-[2-[[5-[2-(4,4-Dimethylpiperazin-4-ium-1-yl)-2-oxoethoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl] -5,6-difluorindan-2-yl]acetate

- 34 041925

This compound was prepared from tert-butyl-5,6-difluoro-2-[({6-methoxy-5-[2-(4-methylpiperazin-1yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl }methyl)carbamoyl]-2,3-dihydro-1H-indene-2-carboxylate, precursor of Example 12, using methyl iodide quaternization followed by TFA deprotection as described in Example 8, step j, to give the indicated title compound as white solid (48 mg). M/z 603.3 (M+H)+.

Ή NMR (400 MHz, d ₆ -DMSO), δ: 13.10 (1H, br s), 7.68 (1H, s), 7.50 (1H, s), 7.25 (2H, t ), 4.95 (2H, m), 4.60 (2H, m), 4.00-3.90 (4H, m), 3.85 (3H, s), 3.50 (2H, m) , 3.40(2H, m), 3.20(6H, s), 2.90(2H, d), 2.40(2H, d).

Example 15 2-[5,6-Difluoro-2-[[6-methoxy-5-[3-(4-methylmorpholin-4-ium-4-yl)propoxy]-1,3benzothiazol-2-yl]methylcarbamoyl ]indan-2-yl]acetate ^Ν ⁺ / FF

Μ /°H~b Η Η 9

Ο

This compound was prepared from tert-butyl-5,6-difluoro-2-[({6-methoxy-5-[3-(morpholin-4yl)propoxy]-1,3-benzothiazol-2-yl}methyl)carbamoyl] -2,3-dihydro-1H-indene-2-carboxylate, obtained using the same chemical transformations as described in example 10, but with the difference that 4-(2-chloropropyl)morpholine hydrochloride was used in the phenol alkylation step. Quaternization was carried out with tert-butyl-5,6-difluoro-2-[({6-methoxy-5-[3-(morpholin-4-yl)propoxy]-1,3-benzothiazol-2yl}methyl)carbamoyl]-2 ,3-dihydro-1H-indene-2-carboxylate with methyl iodide followed by deprotection with TFA as described in Example 13 to give the title compound as a white solid (80 mg). M/z 590.4 (M+H) ⁺ .

¹ H NMR (400 MHz, d ₆ -DMSO), δ: 11.80 (1H, br s), 7.60 (1H, s), 7.50 (1H, s), 7.25 (2H, t), 4.60(2H, d), 4.20(2H, t), 4.00(2H, m), 3.87(3H, s), 3.70(2H, m), 3, 50 (2H, m), 3.35 (2H, d), 3.20 (3H, s), 3.00 (2H, d), 2.80 (2H, m), 2.50 (2H, m ), 2.25 (2H, m).

Example 16 2-[2-[[6-Methoxy-5-[3-(4-methylmorpholin-4-ium-4-yl)propoxy]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl ] acetate

N ⁺ /

\____ // \\ /°VUK n π ίί o

This compound was prepared from tert-butyl-2-[({6-methoxy-5-[3-(morpholin-4-yl)propoxy]-1,3benzothiazol-2-yl}methyl)carbamoyl]-2,3-dihydro -1H-indene-2-carboxylate, obtained using the same chemical transformations as described in example 8, but with the difference that 4-(2-chloropropyl)morpholine hydrochloride was used in the phenol alkylation step. Quaternization was carried out with tert-butyl-2-[({6-methoxy-5-[3-(morpholin-4-yl)propoxy]-1,3-benzothiazol-2-yl}methyl)carbamoyl]-2,3dihydro-1H -indene-2-carboxylate with methyl iodide followed by deprotection with TFA as described in Example 13 to give the title compound as a white solid. M/z 554.2 (M+H) ⁺ .

1 H NMR (500 MHz, DMSO-d ₆ ), δ: 11.80 (1H, br s), 7.63 (1H, s), 7.54 (1H, s), 7.18-7.16 (2H, m), 7.12-7.10 (2H, m), 4.61 (2H, d, J = 5.5 Hz), 4.14 (2H, t, J = 6.5 Hz) , 3.94-3.92(4H, m), 3.83(3H, s), 3.66-3.63(2H, m), 3.48-3.42(4H, m), 3 .39-3.35 (2H, br s), 3.17 (3H, s), 2.91 (2H, d, J = 16.5 Hz), 2.46 (2H, s), 2.252, 22 (2H, m).

Example 17 2-[2-[[5-[(1,1-Dimethylpiperidin-1-ium-4-yl)methoxy]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl ] acetate

- 35 041925

This compound was prepared from tert-butyl-2-[2-[[6-methoxy-5-[(1-methyl-4-piperidyl)methoxy]-1,3benzothiazol-2-yl]methylcarbamoyl]indan-2-yl] acetate obtained using the same chemical transformations as described in example 8, but with the difference that 4-(chloromethyl)-1-methylpiperidine was used in the phenol alkylation step. Quaternization of tert-butyl-2-[2-[[6-methoxy-5-[(1methyl-4-piperidyl)methoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate was carried out with iodide methyl followed by deprotection with TFA as described in Example 13 to give the title compound as a white solid. M/z 538.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-06), δ: 11.32 (1H, br s), 7.61 (1H, s), 7.50 (1H, s), 7.18-7.16 (2H, m), 7.12-7.10 (2H, m), 4.61 (2H, d, J = 5.5 Hz), 4.02 (2H, d, J = 6.5 Hz) , 3.82 (3H, s), 3.45-3.33 (6H, br s), 3.10 (3H, s), 3.05 (3H, s), 2.91 (2H, d , J = 16 Hz), 2.55-2.45 (2H, br s), 2.07-2.04 (1H, m), 1.94-1.92 (2H, m), 1, 79-1.74 (2H, m).

Example 18 2-[2-[[5-[3-[Diethyl(methyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate

a) tert-Butyl-N-({5-[3 -(diethylamino)propoxy]-6-methoxy-1,3-benzothiazol-2-yl}methyl)carbamate

A solution of tert-butyl N-[(5-hydroxy-6-methoxy-1,3-benzothiazol-2-yl)methyl]carbamate (100 mg, 0.32 mmol), 3-diethylamino-1-propanol (50 mg , 0.38 mmol) and triphenylphosphine (100 mg, 0.38 mmol) in THF (2 ml) were treated with diethyl azodicarboxylate (67 mg, 0.38 mmol). After 2 hours, 3-diethylamino1-propanol (25 mg, 0.19 mmol), triphenylphosphine (50 mg, 0.19 mmol) and diethyl azodicarboxylate (34 mg, 0.19 mmol) were added. After 0.5 h the mixture was diluted with toluene and evaporated. The residue was chromatographed on silica gel eluting with 2-12% 2M ammonia/methanol in DCM to give a pale yellow oil (118 mg, 86%). M/z 424.4 (M+H)+.

Iodide

b) (3-{[2-({[(tert-butoxy)carbonyl]amino}methyl)-6-methoxy-1,3-benzothiazol-5yl]hydroxy}propyl)diethylmethylazania

A solution of tert-butyl 1M-({5-[3-(diethylamino)propoxy]-6-methoxy-1,3-benzothiazol-2-yl}methyl) carbamate (118 mg, 0.28 mmol) in ACN (3 ml) was treated with methyl iodide (200 mg, 0.9 mmol). After 16 hours the mixture was evaporated to dryness and the residue was chromatographed on silica gel eluting with 3-20% 2M ammonia/methanol in DCM to give a colorless oil (95 mg, 61%). M/z 438.5 (M) ⁺ .

c) (3-{[2-(aminomethyl)-6-methoxy-1,3-benzothiazol-5-yl]oxy}propyl)diethylmethylazanium chloride, hydrochloride

- 36 041925

(3-{[2-({[(tert-Butoxy)carbonyl]amino}methyl)-6-methoxy-1,3-benzothiazol-5yl]oxy}propyl)diethylmethylazanium iodide solution (95 mg, 0.17 mmol) in methanol (1 ml) was treated with 4M hydrochloric acid in 1,4-dioxane (3 ml, 12 mmol). After 1.5 hours, toluene was added and the mixture was evaporated to give an oil (100 mg). M/z 338.4 (M) ⁺ .

d) 3-[[2-[[[2-(2-tert-Butoxy-2-oxoethyl)indan-2-carbonyl]amino]methyl]-6-methoxy-1,3benzothiazol-5-yl]oxy] chloride propyldiethylmethylammonium

(3-{[2-(aminomethyl)-6-methoxy-1,3-benzothiazol-5-yl]oxy}propyl)diethylmethylazanium chloride hydrochloride solution (100 mg), 2-(2-(tert-butoxy)-2 -oxoethyl)-2,3-dihydro-1H-indene-2-carboxylic acid (51 mg, 0.18 mmol) and DIPEA (65 mg, 0.5 mmol) in DMF (1.5 ml) were treated with HATU (95 mg, 0.18 mmol). After 20 min the mixture was chromatographed on C18 reverse phase silica gel eluting with 20-50% 0.01 M hydrochloric acid in ACN. Fractions containing product were lyophilized to give a light brown solid (94 mg, 89% over two steps). M/z 596.4 (M) ⁺ .

e) 2-[2-[[5-[3-[Diethyl(methyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate.

3-[[2-[[[2-(2-tert-Butoxy-2-oxoethyl)indan-2-carbonyl]amino]methyl]-6-methoxy1,3-benzothiazol-5-yl]oxy]propyldiethylmethylammonium chloride solution (94 mg, 0.15 mmol) in DCM (3 ml) was treated with TFA (1.5 ml). After 2 h, toluene was added and the mixture was evaporated. The residue was chromatographed on C18 reverse phase silica gel eluting with 10-30% 2M ammonia/methanol in ACN. Fractions containing the product were lyophilized to give the title compound as a white solid (37 mg, 46%). M/z 540.3 (M+H) ⁺ .

¹ H NMR (400 MHz, d6-DMSO), δ: 11.50 (1H, br s), 7.65 (1H, s), 7.52 (1H, s), 7.20 (2H, m ), 7.10 (2H, m), 4.62 (2H, d), 4.15 (2H, t), 3.85 (3H, s), 3.50-3.20 (6H, m) , 3.00 (3H, s), 2.90 (2H, d), 2.40 (2H, m), 2.20 (2H, m), 1.25 (6H, t).

Example 19 2-[5,6-Difluoro-2-[[6-methoxy-5-[3-(1-methylpyrrolidin-1-ium-1-yl)propoxy]-1,3benzothiazol-2-yl]methylcarbamoyl ]indan-2-yl]acetate

This compound was obtained analogously to example 18, but with the difference that instead of 3-diethylamino-1-propanol, 3-(pyrrolidin-1-yl)propan-1-ol was used, and instead of 2-[(tert-butoxy)carbonyl]-2,3- dihydro-1H-indene-2-carboxylic acid 2-[(tert-butoxy)carbonyl]-5,6-difluoro2,3-dihydro-1H-indene-2-carboxylic acid. The title compound was isolated as a white solid (45 mg). M/z 574.4 (M+H) ⁺ .

1H NMR (400 MHz, N6-DMSO), δ: 7.68 (1H, s), 7.55 (1H, s), 7.22 (2H, t), 4.65 (2H, d), 4 .15 (2H, t), 3.85 (3H, s), 3.50 (6H, m), 3.40 (2H, d), 3.05 (3H, s), 2.90 (2H, e), 2.30 (2H, m), 2.10 (4H, m).

Example 20 2-[2-[[5-[3-[2-Hydroxyethyl(dimethyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetate

- 37 041925

A)

Ίret-Butyl-N-{[6-methoxy-5-(3-{methyl-[2-(oxan-2-yloxy)ethyl]amino}propoxy)-1,3-benzothiazol-2-yl]methyl} carbamate

This compound was obtained by the same procedure as described in example (18a), but with the difference that 3-(methyl-(2-((tetrahydro-2H-pyran-2yl)oxy) was used instead of 3-diethylamino-1-propanol )ethyl)amino)propan-1-ol to give a colorless oil (212 mg, 54%). M/z 510.4 (M+H)+.

b) (3-{[2-({[(tert-Butoxy)carbonyl]amino}methyl)-6-methoxy-1,3-benzothiazol-5-yl]oxy}propyl)dimethyl[2-(oxan- 2-yloxy)ethyl]azanium

This compound was prepared from tert-butyl-N-{[6-methoxy-5-(3-{methyl-[2-(oxan-2yloxy)ethyl]amino}propoxy)-1,3-benzothiazol-2-yl]methyl }carbamate using the same procedure as described in example (18b), resulting in a clear oil (201 mg, 74%). M/z 524.4 (M) ⁺ .

c) (3-{[2-(Aminomethyl)-6-methoxy-1,3-benzothiazol-5-yl]oxy}propyl)(2hydroxyethyl)dimethylazanium chloride hydrochloride

This compound was prepared from (3-{[2-({[(tert-butoxy)carbonyl]amino}methyl)-6-methoxy iodide

1,3-benzothiazol-5-yl]oxy}propyl)dimethyl-[2-(oxan-2-yloxy)ethyl]azanium according to the method of example (18c), but with the difference that the reaction time was increased from 1.5 to 2 hours, resulting in an oil in quantitative yield. M/z 340.3 (M) ⁺ .

d) 3-[[2-[[[2-(2-tert-Butoxy-2-oxoethyl)indan-2-carbonyl]amino]methyl]-6-methoxy-1,3benzothiazol-5-yl]oxy] chloride propyl-(2-hydroxyethyl)dimethylammonium

This compound was prepared from (3-{[2-(aminomethyl)-6-methoxy-1,3-benzothiazol-5-yl]oxy}propyl)(2-hydroxyethyl)dimethylazanium chloride hydrochloride by the method of Example (18d) to give a solid white substance (68 mg, 69%). M/z 598.4 (M) ⁺

f) 2-[2-[[5-[3-[2-Hydroxyethyl(dimethyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methyl- 38 041925 carbamoyl]indan-2- yl]acetate.

This compound was prepared from 3-[[2-[[[2-(2-tert-Butoxy-2-oxoethyl)indan-2carbonyl]amino]methyl]-6-methoxy-1,3-benzothiazol-5-yl] chloride hydroxy]propyl-(2-hydroxyethyl)dimethylammonium by the same procedure as in Example (18e) to give the title compound as a white solid (40 mg, 68%). M/z 542.4 (M+H) ⁺ .

1H NMR (400 MHz, d ₆ -DMSO), δ: 13.10 (1H, br s), 7.65 (1H, s), 7.50 (1H, s), 7.15 (2H, m ), 7.05 (2H, m), 5.50 (1H, br s), 4.60 (2H, d), 4.15 (2H, t), 3.90 (2H, m), 3 .85 (3H, s), 3.55 (2H, m), 3.46 (2H, m), 3.35 (2H, d), 3.15 (6H, s), 2.87 (2H, e), 2.40 (2H, m), 2.30 (2H, m).

Example 21 2-[5,6-Difluoro-2-[[5-[3-[2-hydroxyethyl-(dimethyl)ammonio]propoxy]-6-methoxy-1,3benzothiazol-2-yl]methylcarbamoyl]indan- 2-yl]acetate

This compound was obtained analogously to example 20, except that instead of 2-[(tert-butoxy)carbonyl]-2,3-dihydro-1H-indene-2-carboxylic acid, 2-[(tert-butoxy)carbonyl]-5 was used, 6-difluoro-2,3-dihydro-1H-indene-2-carboxylic acid. The title compound was isolated as a white solid (35 mg). M/z 578.3 (M+H) ⁺ .

¹ H NMR (400 MHz, d6-DMSO), δ: 13.00 (1H, br s), 7.65 (1H, s), 7.52 (1H, s), 7.20 (2H, t ), 5.50 (1H, br s), 4.60 (2H, d), 4.15 (2H, t), 3.90 (2H, m), 3.85 (3H, s), 3 .55 (2H, m), 3.45 (2H, m), 3.35 (2H, d), 3.15 (6H, s), 2.90 (2H, d), 2.40 (2H, m), 2.30 (2H, m).

Example 22 2-[2-[[5-[3-[bis(2-Hydroxyethyl)methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetate

This compound was prepared analogously to Example 20, except that 3-(bis(2 -((tetrahydro-2Hpyran-2-yl)oxy)ethyl)amino)propan-1-ol. The title compound was isolated as a white solid (31 mg). M/z 572.4 (M+H) ⁺ .

1H NMR (400 MHz, a ₆ -DMSO), δ: 13.00 (1H, br s), 7.65 (1H, s), 7.50 (1H, s), 7.20 (2H, m ), 7.10 (2H, m), 5.50 (2H, br s), 4.60 (2H, d), 4.20 (2H, t), 3.95 (4H, m), 3 .85 (3H, s), 3.60 (2H, m), 3.50 (4H, m), 3.40 (2H, d), 3.15 (3H, s), 2.90 (2H, e), 2.20 (2H, m).

Example 23 2-[2-[[5-[3-[bis(2-Hydroxyethyl)methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]-5,6-difluorindan-2- yl] acetate

This compound was obtained analogously to example 22, except that instead of 2-[(tert-butoxy)carbonyl]-2,3-dihydro-1H-indene-2-carboxylic acid, 2-[(tert-butoxy)carbonyl]-5 was used, 6-difluoro-2,3-dihydro-1H-indene-2-carboxylic acid. The title compound was isolated as a white solid (10 mg). M/z 608.4 (M+H)+.

1H NMR (400 MHz, d ₆ -DMSO), δ: 13.00 (1H, br s), 7.65 (1H, s), 7.50 (1H, s), 7.20 (2H, t ), 5.40 (2H, br s), 4.60 (2H, d), 4.10 (2H, t), 3.95 (4H, m), 3.85 (3H, s), 3 .60 (2H, m), 3.50 (4H, m), 3.40 (2H, d), 3.15 (3H, s), 2.90 (2H, d), 2.20 (2H, m).

Example 24 2-[2-[[5-[2-(4-Methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid

- 39 041925

a) 2-Hidroxy-1 - (4-methylpiperazin-1 -yl) ethan-1 -one

Ethyl 2-hydroxyacetate (520 mg, 4.99 mmol) was added to a stirred solution of 1-methylpiperazine (500 mg, 4.99 mmol) in dioxane (5 mL) at room temperature. The reaction mixture was heated at 120° C. for 12 h, after distilling off the solvent, a pale yellow thick mass was obtained (200 mg, crude product). M/z 159.1 (M+H)+.

b) tert-Butyl N-[(5-bromo-1,3-benzothiazol-2-yl)methyl]carbamate

Br

S n

To a stirred solution of 5-bromo-2-iodaniline (2.5 g, 8.30 mmol) and tert-butyl-N-(2-amino-2-thioxoethyl)carbamate (2 g, 10.9 mmol) in DMF (15 ml ) CuO (1 g, 12.6 mmol) was added at room temperature and the reaction mixture was purged with argon for 15 min. Then dppf (929 mg, 1.60 mmol) and Pd ₂ (dba) ₃ (768 mg, 0.8 mmol) were added to the reaction mixture and purged with argon for another 5 min. The reaction mixture was stirred in a sealed tube at 70°C for 4 h and filtered through a pad of celite, which was washed with EtOAc (50 ml). The filtrate was washed with water (2x30 ml) and concentrated under reduced pressure. The crude compound was purified by flash chromatography eluting with 20% EtOAc in petroleum ether to give an off-white solid (2 g, 71%). M/z 343.0 (M+H) ⁺ .

c) (5-Bromo-1,3-benzothiazol-2-yl)methanamine hydrochloride

Vg

A 4N solution of HCl in dioxane (30 ml). The reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The crude compound was triturated with n-pentane (20 ml) and Et ₂ O (20 ml) to give a pale yellow solid (2.2 g, 90%). M/z 243.0 (M) ⁺ .

d) tert-Butyl-2-[2-[(5-bromo-1, 3-benzothiazol-2-yl)methylcarbamoyl] indan-2-yl] acetate

O

Et ₃ N (1.5 ml, 10 8 mmol) and the reaction mixture was stirred for 15 min. Then 2-(2-tert-butoxy-2-oxoethyl)indan-2carboxylic acid (1 g, 3.6 mmol), EDCHCI (833 mg, 4.3 mmol) and HOBt (684 mg, 5.0 mmol) were added . The reaction mixture was stirred at room temperature for 16 h, diluted with ice water (100 ml) and extracted with EtOAc (2x50 ml).

The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude compound was purified by flash chromatography eluting with 25% EtOAc in petroleum ether to give an off-white solid (1 g, 56%). M/z 501.1 (M+H) ⁺ .

f) tert-Butyl-2-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]methylcarbamoyl ]indan-2-yl]acetate

- 40 041925

To a solution of tert-butyl 2-[2-[(5-bromo-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetate (1.5 g, 3.0 mmol) in dioxane ( 20 mL) potassium acetate (588 mg, 6.0 mmol) and Bpin (838 mg, 3.3 mmol) were added at room temperature and the reaction mixture was purged with argon for 15 min. PdCl ₂ (dppf)·DCM (171 mg, 0.21 mmol) was then added to the reaction mixture and the mixture was purged with argon for another 5 minutes. The reaction mixture was stirred in a sealed tube at 90°C for 4 hours. The reaction mass was filtered through a layer of Celite, the layer was washed with EtOAc (50 ml). The organic extracts were washed with water (2x50 ml) and brine, then dried over sodium sulfate, filtered to give the crude product (1.6 g, crude) as a brown paste after removal of the solvent. Mixture of boronic acid M/z 467.2 (M+H) ⁺ and boronate ester M/z 549.2 (M+H) ⁺ .

f) [2-[[[2-(2-tert-Butoxy-2-oxoethyl)indan-2-carbonyl]amino]methyl]-1,3-benzothiazol-5-yl]boronic acid

Into a solution of tert-butyl-2-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2yl]methylcarbamoyl]indan -2-yl]acetate (1.6 g, 2.9 mmol) in THF:H ₂ O (4:1, 20 mL) sodium periodate (1.9 g, 8.7 mmol) was added at room temperature and stirred within 30 min. Then 1N HCl (2 ml, 2.0 mmol) was added to the reaction mixture at room temperature and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic extracts were washed with water and brine, then dried over sodium sulfate, filtered and the solvent was removed. The crude compound was purified by column chromatography (silica gel 100-200, 10% MeOH/DCM gradient) to give the product (900 mg, 66%) as a yellow solid. m/z 467.2 (M+H)+.

g) tert-Butyl-2-(2-(((5-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)benzo[d]thiazol-2-yl)methyl)carbamoyl)-2, 3-dihydro-1 H-inden-2-yl)acetate

To a solution of [2-[[[2-(2-tert-butoxy-2-oxoethyl)indan-2-carbonyl]amino]methyl]-1,3-benzothiazol-5yl]boronic acid (300 mg, 0.64 mmol ) in DCM (10 ml) at room temperature were added Cu(OAc) ₂ (175 mg, 0.96 mmol), triethylamine (0.2 ml, 1.28 mmol) and molecular sieves (0.5 g). The reaction mixture was stirred for 10 min, then 2-hydroxy-1-(4-methylpiperazin-1-yl)ethan1-one (153 mg, 0.96 mmol) was added and stirred at room temperature in air for 16 h. the mass was filtered through a pad of celite, the pad was washed with dichloromethane, the filtrate was evaporated to give the crude compound. The crude product was chromatographed on silica gel eluting with 3% MeOH in DCM to give tert-butyl-2-(2-(((5-(2-(4-methylpiperazin-1-yl)-2oxoethoxy)benzo[c1]thiazol- 2-yl)methyl)carbamoyl)-2,3-dihydro-1H-inden-2-yl)acetate as a pale brown solid (60 mg, 16%). m/z 579.3 (M+H) ⁺ .

h) 2-[2-[[5-[2-(4-Methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan2-yl]acetic acid.

Solution of tert-butyl-2-(2-(((5-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)benzo[d]thiazol-2-yl)methyl)carbamoyl)-2.3 -dihydro-1H-inden-2-yl)acetate (50 mg, 0.086 mmol) in DCM (4 ml) was treated with TFA (0.5 ml) at room temperature for 2 h. The mixture was evaporated and the residue was triturated with diethyl ether ( 6 ml). The crude compound was purified by preparative HPLC [SYMMETRY-C8 (3000*19), 7 μm, mobile phase: A: 0.1% formic acid in H ₂ O, B: MeCN], lyophilized to give an off-white solid (15 mg, 34%). m/z 523.2 (M+H) ⁺ .

¹ H NMR (500 MHz, MeOD), δ: 7.79 (1H, d, J = 9 Hz), 7.44 (1H, s), 7.23-7.21 (2H, m), 7, 16-7.15 (2H, m), 7.13 (1H, d, J = 9 Hz), 4.94 (2H, s), 4.75 (2H, s), 3.85-3.75 (4H, br s), 3.52 (2H, d, J = 16.5 Hz), 3.16-3.07 (4H, br s), 3.09 (2H, d, J = 16 .5 Hz), 2.82 (2H, s), 2.78 (3H, s).

- 41 041925

Example 25 2-[2-[[5-[2-(4-Methylpiperazin-1-yl)ethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid

This compound was prepared analogously to example 24 using 2-(4-methylpiperazin1-yl)ethanol in step d. The title compound was isolated as a white solid. m/z 509.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ), δ: 12.16 (1H, br s), 8.72 (1H, t, J = 6 Hz), 7.88 (1H, d, J = 9 Hz), 7.48 (1H, s), 7.22-7.21 (2H, m), 7.17-7.14 (2H, m), 7.04 (1H, d, J = 9 Hz), 4.62 (2H, d, J = 6 Hz), 4.19 (2H, br s), 3.55-3.30 (4H, br s), 3.22-3.10 (4H, m), 3.10-3.00 (2H, m), 2.99 (2H, d, J = 16.5 Hz), 2.98-2.85 (2H, m), 2, 80-2.70 (2H, m), 2.74 (3H, m).

Example 26 2-[2-[[6-[3-(Dimethylamino)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid

a) Methyl 2-[(tert-butoxycarbonylamino)methyl]-1,3-benzothiazole-6-carboxylate

To a stirred solution of methyl 4-amino-3-iodobenzoate (6 g, 21.6 mmol) in acetonitrile (60 ml) at room temperature was added tert-butyl-(2-amino-2-thioxoethyl) carbamate (4.9 g , 25.9 mmol) and CuO (2.6 g, 32.4 mmol). The reaction mixture was purged with argon for 15 min, after which dppf (2.4 g, 4.33 mmol) and Pd ₂ (dba) ₃ (2 g, 2.16 mmol) were added thereto. The reaction mixture was purged with argon for another 5 min and heated in a sealed tube at 80° C. for 16 h. The reaction mass was filtered through a pad of celite, the pad was washed with DCM (60 ml) and the filtrate was evaporated. The crude product was chromatographed on silica gel eluting with 20-30% EtOAc in petroleum ether to give a yellow solid (4 g, 57%). m/z 323.1 (M+H) ⁺ .

b) 2-[(tert-Butoxycarbonylamino)methyl]-1,3-benzothiazole-6-carboxylic acid

To a solution of methyl 2-(((tert-butoxycarbonyl)amino)methyl)benzo[d]thiazole-6-carboxylate (2.5 g, 7.76 mmol) in THF/water (1:1, 100 mL) LiOH-H ₂ O (652 mg, 15.5 mmol) was added at room temperature and stirred for 6 hours. The reaction mass was evaporated, the resulting residue was diluted with water (10 ml) and the pH was adjusted to ~7 with saturated citric acid solution . The product was extracted with 10% MeOH in DCM (2x50 ml) and evaporated to give a yellow solid (2 g, 83%). m/z 307.0 (M-H) ⁺ .

c) tert-Butyl N-[[6-[3-(dimethylamino)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methyl]carbamate

N,N-dimethylazetidine hydrochloride 3 -amine (281 mg, 1.62 mmol) and Et ₃ N (0.7 ml, 4.87 mmol) and stirred for 10 minutes. Then T3P (750 mg, 2.43 mmol) was added and stirred for 12 h. The reaction mixture was diluted with cold water (10 ml), extracted with EtOAc (2x25 ml), the organic layer was evaporated to give a pale yellow solid (525 mg , crude product). m/z 391.2 (M+H)+.

d) (2-(Aminomethyl)benzo[d]thiazol-6-yl)(3-(dimethylamino)azetidin-1-yl)methanone hydrochloride

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To a solution of tert-butyl-((6-(3-(dimethylamino)azetidine-1-carbonyl)benzo[d]thiazol-2-yl)methyl)carbamate (520 mg, 1.33 mmol) in dioxane (5 ml) 4M HCl in dioxane (4 ml) was added at room temperature and stirred for 3 hours. The reaction mass was evaporated, the resulting residue was triturated with diethyl ether (15 ml) to give a yellow solid (500 mg, crude product). m/z 291.0 (M+H)+.

e) tert-Butyl-2-[2-[[6-[3-(dimethylamino)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate /

O

Et ₃ N (0.5 ml, 3.37 mmol) and stirred for 10 min. Then 2-(2-(tert-butoxy)-2-oxoethyl)-2,3dihydro-1H-indene-2-carboxylic acid (208 mg, 0.74 mmol) and T3P (660 mg, 1.03 mmol) were added and stirred for 12 hours. The reaction mass was diluted with cold water (10 ml), was extracted with EtOAc (2x30 ml), the organic layer was evaporated and received the crude product. The crude product was chromatographed on silica gel eluting with 2% MeOH in DCM to give a brown solid (120 mg, 33%). m/z 549.3 (M+H) ⁺ .

f) 2-[2-[[6-[3-(Dimethylamino)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid.

A solution of tert-butyl-2-(2-(((6-(3-(dimethylamino)azetidine-1-carbonyl)benzo[d]thiazol-2-yl)methyl)carbamoyl)-2,3-dihydro-1H- inden-2-yl)acetate (110 mg, 0.20 mmol) in DCM (5 ml) was treated with TFA (2 ml) at room temperature for 4 h. The mixture was evaporated, the residue was triturated with diethyl ether (10 ml). The crude compound was purified by preparative HPLC [YMC-TRIART-C18 (150*25), 10 µm, mobile phase: A: 0.1% formic acid in H ₂ O, B: MeCN], lyophilized to give the title product as an off-white solid (53 mg, 54%). m/z 493.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ), δ: 12.16 (1H, br s), 8.79 (1H, t, J = 6 Hz), 8.35 (1H, d, J = 1.5 Hz), 8.00 (1H, d, J = 8.5 Hz), 7.75 (1H, dd, J = 8.5 Hz, J = 1.5 Hz), 7.23-7 .21 (2H, m), 7.16-7.14 (2H, m), 4.69 (2H, d, J = 6 Hz), 4.62-4.58 (1H, m), 4, 48-4.42 (1H, m), 4.31-4.19 (2H, m), 4.15-4.05 (1H, m), 3.46 (2H, d, J = 16.5 Hz), 3.01 (2H, d, J = 16.5 Hz), 2.85-2.65 (8H, br s).

Example 27 2-[2-[[5-(4-Methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan2-yl]acetic acid

O

This compound was prepared analogously to Example 26 starting from methyl 3-amino-4-iodobenzoate in step a and using 1-methylpiperazine in step c. The title compound was isolated as a white solid. m/z 493.2 (M+H) ⁺ .

^1H NMR (500 MHz, DMSO-d ₆ ), δ: 12.15 (1H, br s), 9.80 (1H, br s), 8.79 (1H, t, J = 5.5 Hz), 8.13 (1H, d, J = 8.5 Hz), 8.00 (1H, s), 7.46 (1H, d, J = 8.5 Hz), 7.23-7, 21 (2H, m), 7.15-7.13 (2H, m), 4.67 (2H, d, J = 5.5 Hz), 3.47 (2H, d, J = 16 Hz), 3.18-3.01 (8H, m), 2.99 (2H, d, J = 16 Hz), 2.79 (2H, s), 2.75 (3H, s).

Example 28 2-[2-[[5-[2-(Dimethylamino)ethylcarbamoyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid

- 43 041925

This compound was prepared analogously to Example 26 starting from methyl 3-amino-4-iodobenzoate in step a and using N',N'-dimethyl αn-1,2-diα amine in step c. The title compound was isolated as a white solid. m/z 481.2 (M+H)+.

¹ H NMR (500 MHz, DMSOCH), δ: 11.42 (1H, br s), 8.79 (1H, t, J = 5.5 Hz), 8.68 (1H, t, J = 5 Hz), 8.40 (1H, s), 8.11 (1H, d, J = 8.5 Hz), 7.88 (1H, dd, J = 8.5 Hz, J = 1.5 Hz) , 7.23-7.21 (2H, m), 7.15-7.13 (2H, m), 4.68 (2H, d, J = 6.0 Hz), 3.51-3.48 (2H, m), 3.46 (2H, d, J = 16.5 Hz), 3.00 (2H, d, J = 16.5 Hz), 2.88-2.82 (2H, br. s), 2.75 (2H, s), 2.55-2.50 (6H, br s).

Example 29 2-[2-[[6-(4-Methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan2-yl]acetic acid

This compound was prepared analogously to Example 26 starting from methyl 4-amino-3-iodobenzoate in step a and using 1-methylpiperazine in step c. The title compound was isolated as a white solid. m/z 493.2 (M+H) ⁺ .

¹ H NMR (500 MHz, MeOD), δ: 8.07 (1H, d, J = 1.0 Hz), 7.99 (1H, d, J = 8.5 Hz), 7.57 (1H, dd, J = 8.5 Hz, J = 1 Hz), 7.23-7.21 (2H, m), 7.16-7.15 (2H, m), 4.79 (2H, s), 3.88-3.75 (4H, m), 3.54 (2H, d, J = 16 Hz), 3.203.15 (4H, m), 3.10 (2H, d, J = 16 Hz), 2.83 (2H, s), 2.81 (3H, s).

Example 30 2-[2-[[6-[2-(Dimethylamino)ethylcarbamoyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid

This compound was prepared analogously to Example 26 starting from methyl 4-amino-3-iodobenzoate in step a and using N',N'-dimethylethane-1,2-diamine in step c. The title compound was isolated as a white solid. m/z 481.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-06), δ: 12.15 (1H, br s), 8.77 (2H, t, J = 5.5 Hz), 8.51 (1H, s), 8.02 (1H, d, J = 8.5 Hz), 7.96 (1H, dd, J = 8.5 Hz, J = 1.5 Hz), 7.23-7.21 (2H, m ), 7.15-7.13 (2H, m), 4.68 (2H, d, J = 6.0 Hz), 3.63-3.60 (2H, m), 3.48 (2H, d, J = 16.5 Hz), 3.26-3.20 (2H, m), 3.00 (2H, d, J = 16.5 Hz), 2.83 (6H, s), 2, 76 (2H, s).

Example 31 2-[2-[[5-[4-[3-(Dimethylamino)propyl]piperazine-1-carbonyl]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetic acid

This compound was prepared analogously to Example 26 starting from methyl 3-amino-4-iodobenzoate in step a and using N,N-dimethyl-3-n-piperazin-1-yl-p-propan-1-amine in step c. The title compound was isolated as a white solid. m/z 564.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-06), δ: 9.07 (1H, br s), 8.10 (1H, d, J = 8.5 Hz), 7.89 (1H, s), 7.39 (1H, d, J = 8.5 Hz), 7.22-7.20 (2H, m), 7.14-7.13 (2H, m), 4.67 (2H, d, J = 5.5 Hz), 3.64-3.62 (2H, m), 3.46 (2H, d, J = 16 Hz), 3.25-3.15 (2H, br s), 3.01 (2H, d, J = 16 Hz), 2.72 (2H, s), 2.48-2.25 (8H, br s) 2.18 (6H, s), 1.581.55 ( 2H, m).

Example 32 2-[2-[[5-[3-(Dimethylamino)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid

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This compound was prepared analogously to Example 26 starting from methyl 3-amino-4-iodobenzoate in step a. The title compound was isolated as a white solid. m/z 493.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-66), δ: 12.05 (1H, br s), 8.94 (1H, br s), 8.11 (1H, s), 8.10 (1H , d, J = 8.0 Hz), 7.65 (1H, dd, J = 8 Hz, J = 1 Hz), 7.22-7.20 (2H, m), 7.14-7.13 (2H, m), 4.67 (2H, d, J = 5.5 Hz), 4.344.31 (1H, m), 4.13-4.06 (2H, m), 3.86-3, 83 (1H, m), 3.46 (2H, d, J = 16 Hz), 3.10-3.05 (1H, m), 2.99 (2H, d, J = 16 Hz), 2, 73 (2H, s), 2.08 (6H, s).

Example 33 2-[2-[[6-Methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid

a) Methyl-4-iodine-2-methoxy-5-nitrobenzoate

A solution of commercially available methyl 4-iodo-2-methoxybenzoate (1.05 g, 3.6 mmol) in concentrated sulfuric acid (1.6 ml) was treated at 0°C with a mixture of concentrated nitric acid/concentrated sulfuric acid (0. 6 ml/1 ml). The reaction mass was stirred at room temperature for 5 h, then poured into ice water and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride. The organic layer was dried (MgSO ₄ ) and evaporated to give a yellow solid (1.03 g, 85%) which was used without purification. m/z 338.4 (M+H) ⁺ .

b) Methyl 5-amino-4-iodo-2-methoxybenzoate

A mixture of methyl 4-iodo-2-methoxy-5-nitrobenzoate (600 mg, 1.8 mmol), iron powder (840 mg, 15 mmol) and methanol (9 ml) was treated with aqueous hydrochloric acid (0.2 M; 9 ml, 1.8 mmol) and heated at the boil under reflux for 3 h. The mixture was left to cool to room temperature, then filtered through celite and evaporated. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate, dried (MgSO ₄ ) and evaporated to give a yellow solid. The resulting material was triturated with methanol and filtered to give unreacted starting material (183 mg). The filtrate was evaporated and the residue was purified by SCX cartridge chromatography eluting with 2M ammonia in methanol to give a yellow oil (132 mg, 24%). m/z 308.0 (M+H)+.

c) Methyl 2-({[(tert-butoxy)carbonyl]amino}methyl)-6-methoxy-1,3-benzothiazole-5-carboxylate

A solution of methyl 5-amino-4-iodo-2-methoxybenzoate (132 mg, 0.43 mmol) in ACN (3 mL) was treated with tert-butyl-(2-amino-2-thioxoethyl)carbamate (100 mg, 0. 52 mmol), calcium oxide (50 mg, 0.52 mmol), tris(dibenzylideneacetone) dipalladium(0) (38 mg, 0.41 mmol) and dppf (90 mg, 0.16 mmol), then degassed and purged with argon . The mixture was heated at 65° C. in a sealed vessel for 5 hours, then cooled, diluted with ethyl acetate and washed first with 10% aqueous citric acid solution, then with saturated aqueous sodium chloride solution. Organic extract dried

- 45 041925 (MgSO ₄ ) and evaporated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate in hexane to give an oil (97 mg, 64%). m/z 353.3 (M+H)+.

d) 2-({[(tert-Butoxy)carbonyl]amino}methyl)-6-methoxy-1,3-benzothiazole-5-carboxylic acid

A solution of methyl 2-({[(tert-butoxy)carbonyl]amino}methyl)-6-methoxy-1,3-benzothiazole-5-carboxylate (96 mg, 0.27 mmol) in THF (3 ml) was treated with an aqueous solution lithium hydroxide (1M; 0.5 ml, 0.5 mmol). After 16 hours, the mixture was reduced in volume by evaporation and acidified to pH 4 with aqueous hydrochloric acid (1M), then extracted with DCM. The DCM extract was washed with water, brine, dried (MgSO ₄ ), evaporated to give a brown foam (55 mg, 60%). m/z 283.3 (M - t-Bu) ⁺ .

f) tert-Butyl-N-{[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methyl}carbamate

Solution of 2-({[(tert-butoxy)carbonyl]amino}methyl)-6-methoxy-1,3-benzothiazole-5-carboxylic acid (55 mg, 0.16 mmol), 1-methylpiperazine (20 mg, 0 .2 mmol), DIPEA (63 mg, 0.5 mmol) in DCM (4 ml) was treated with HATU (74 mg, 0.2 mmol). After 4 hours the mixture was diluted with DCM and washed with water then saturated aqueous sodium chloride, dried (MgSO4), evaporated to give a brown foam (135 mg). The foam was chromatographed on silica gel eluting with 0-10% methanol in DCM to give an oil (41 mg, 60%). m/z 421.2 (M+H) ⁺ .

f) [6-Methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methanamine

A solution of tert-butyl N-{[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2yl]methyl}carbamate (41 mg, 0.01 mmol) in DCM (1 ml ) was treated with TFA (0.5 ml). After 3 hours the mixture was evaporated and the residue was purified by SCX cartridge chromatography eluting with 2M ammonia in methanol to give a yellow oil (21 mg, 66%). m/z 321.2 (M+H) ⁺ .

g) tert-Butyl-2-[2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate

ABOUT

Solution of [6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methanamine (21 mg, 0.07 mmol), 2-(2-(tert-butoxy)- 2-oxoethyl)-2,3-dihydro-1H-indene-2-carboxylic acid (22 mg, 0.08 mmol), DIPEA (26 mg, 0.2 mmol) in DCM (3 mL) was treated with HATU (26 mg , 0.07 mmol). After 16 h the mixture was diluted with DCM and washed with water then saturated aqueous sodium chloride, dried (MgSO4), evaporated to give a yellow oil. The oil was chromatographed on silica gel eluting with 0-10% methanol in DCM to give an oil (32 mg, 84%). m/z 579.4 (M+H) ⁺ .

h) 2-[2-[[6-Methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid.

tert-Butyl 2-[2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetate solution (32 mg, 0 .05 mmol) in DCM (2 ml) was treated with TFA (0.25 ml). After 2 h the mixture was evaporated. The residue was purified by MDAP, product containing fractions were lyophilized to give the title compound as a white solid (20 mg, 69%). m/z 523.1 (M+H)+.

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1H NMR (400 MHz, d ₆ -DMSO), δ: 12.20 (1H, br s), 8.80 (1H, br s), 7.95 (1H, s), 7.75 (1H , With),

7.22(1H, m), 7.15(2H, m), 5.40(2H, br s), 4.60(2H, m), 3.85(3H, s), 3.50 (2H, d), 3.45-3.20 (8H, m), 3.15 (3H, s), 2.90 (2H, d).

Example 34 2-[5,6-Difluoro-2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetic acid

This compound was obtained analogously to example

33, except that 2-[(tert-butoxy)carbonyl]-5,6-difluoro-2 ,3-dihydro-1H-indene-2-carboxylic acid. The title compound was isolated as a white solid (35 mg). m/z 573.2 (M+H) ⁺ .

1H NMR (400 MHz, d ₆ -DMSO), δ: 12.50 (1H, br s), 8.80 (1H, br s), 7.75 (1H, s), 7.70 (1H , s), 7.25 (2H, t), 4.60 (2H, m), 3.85 (3H, s), 3.45 (2H, d), 3.15 (3H, s), 3 .00 (2H, d).

Example 35 2-[2-[[5-(4,4-Dimethylpiperazin-4-ium-1-carbonyl)-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]-5,6-difluorindan-2 -yl]acetate

a) tert-Butyl-2-[2-[[5-(4,4-dimethylpiperazin-4-ium-1-carbonyl)-6-methoxy-1,3-benzothiazol2-yl]methylcarbamoyl]-5.6 iodide -difluorindan-2-yl] acetate

A solution of tert-butyl-5,6-difluoro-2-({[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2yl]methyl}carbamoyl)-2,3-dihydro -1H-indene-2-carboxylate, the final intermediate of Example 34 (140 mg, 0.23 mmol), in THF (5 mL) was treated with methyl iodide (365 mg, 2.6 mmol). After 2 hours the mixture was evaporated to give a white solid (170 mg, 98%). m/z 629.3 (M) ⁺ .

b) 2-[2-[[5-(4,4-Dimethylpiperazin-4-ium-1-carbonyl)-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan- 2-yl]acetate.

A solution of tert-butyl-2-[2-[[5-(4,4-dimethylpiperazin-4-ium-1-carbonyl)-6-methoxy-1,3benzothiazol-2-yl]methylcarbamoyl]-5,6- difluorindan-2-yl]acetate (170 mg, 0.27 mmol) in DCM (4 ml) was treated with TFA (0.5 ml). After 2 h the mixture was evaporated. The residue was purified by MDAP, product containing fractions were lyophilized to give the title compound as a white solid (20 mg, 69%). m/z 574.2 (M+H) ⁺ .

¹ H NMR (400 MHz, d ₆ -DMSO), δ: 9.80 (1H, br s), 7.80 (2H, m), 7.25 (2H, t), 4.60 (2H, m), 4.10 (1H, m), 3.85 (3H, s), 3.80 (1H, m), 3.60-3.30 (12H, m), 3.20 (2H, d ), 3.00 (2H, d).

Example 36 2-[2-[[5-[3-(Dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetic acid

This compound was prepared using the procedures described in Example 33, with the difference that 3-dimethylaminoazetidine was used instead of 1-methylpiperazine, resulting in the title compounds as a white solid (62 mg). m/z 523.2 (M+H)+.

1 H NMR (400 MHz, d ₆ -DMSO), δ: 12.30 (1H, br s), 8.80 (1H, s), 7.78 (1H, s), 7.72 (1H, s ), 7.50 (1H, s), 7.20 (1H, m), 7.10 (1H, m), 5.40 (2H, br s), 4.62 (2H, m), 3 .90 (3H, s), 4.20-3.80 (5H, m), 3.50 (2H, d), 3.30 (6H, s), 2.90 (2H, d).

Example 37 2-[2-[[5-[3-(Dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]-5,6-difluoroindan-2-yl] acetic acid

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This compound was prepared using the procedures described in Example 36, with the difference that instead of 2-[(tert-butoxy)carbonyl]-2,3-dihydro-1H-indene-2-carboxylic acid, 2-[(tert-butoxy )carbonyl]-5,6-difluoro-2,3-dihydro-1H-indene-2-carboxylic acid to give the title compounds as a white solid (48 mg). m/z 559.2 (M+H) ⁺ .

1H NMR (400 MHz, d ₆ -DMSO), δ: 12.30 (1H, br s), 8.85 (1H, br s), 7.78 (1H, s), 7.72 (1H , s), 7.50 (1H, s), 7.25 (2H, t), 4.60 (2H, d), 3.85 (3H, s), 4.10-3.70 (5H, m), 3.50 (4H, m), 3.30 (6H, s), 2.95 (2H, d).

Example 38 2-[2-[[5-[4-(Dimethylamino)piperidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetic acid

This compound was prepared using the procedures described in Example 34, with the difference that 3-dimethylaminoazetidine was used instead of 1-methylpiperazine, resulting in the title compounds as a white solid (75 mg). m/z 551.7 (M+H)+.

1H NMR (400 MHz, d6-DMSO), δ: 9.00 (1H, br s), 7.80 (2H, m), 7.25 (2H, m), 7.15 (2H, m) , 4.65 (2H, m), 4.50 (1H, m), 3.85 (3H, s), 3.50 (2H, d), 3.00-2.60 (5H, m), 2.40(1H, m), 2.20(6H, s), 1.80(1H, m), 1.60(1H, m), 1.50(2H, m).

Example 39 2-[2-[[6-Methoxy-5-[4-(trimethylammonio)piperidine-1-carbonyl]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetate

This compound was prepared from tert-butyl-2-[({5-[4-(dimethylamino)piperidine-1-carbonyl]-6methoxy-1,3-benzothiazol-2-yl}methyl)carbamoyl]-2,3-dihydro -1H-indene-2-carboxylate, the final intermediate of Example 38, was quaternized and then deprotected with TFA as described in Example 35 to give the compound as a white solid (83 mg). m/z 565.7 (M+H) ⁺ .

¹ H NMR (400 MHz, d ₆ -DMSO), δ: 9.00 (1H, br s), 7.80 (2H, s), 7.20 (4H, m), 7.10 (2H, m), 4.70(2H, m), 3.85(3H, m), 3.60(2H, m), 3.45(2H, d), 3.05(9H, s), 2, 90 (3H, m), 2.20 (2H, m), 2.00 (2H, m), 1.50 (2H, m).

Example 40 2-[2-[[5-[2-[(Dimethylamino)methyl]morpholine-4-carbonyl]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetic acid

This compound was prepared using the procedures described in Example 33, with the difference that dimethyl-[(morpholin-2-yl)methyl]amine was used instead of 1-methylpiperazine, resulting in the title compounds as a white solid (70 mg). m/z 567.7 (M+H) ⁺ .

1H NMR (400 MHz, d ₆ -DMSO), δ: 9.00 (1H, br s), 7.80 (1H, s), 7.70 (1H, s), 7.20 (2H, m ), 7.10(2H, m), 4.65(2H, m), 4.20-4.00(2H, m), 3.95(2H, m), 3.85(3H, s) , 3.80-3.50(3H, m), 3.45(2H, d), 3.10(6H, m), 3.05(2H, d), 2.90(2H, m).

Example 41 2-[2-[[6-Methoxy-5-[2-[(trimethylammonio)methyl]morpholine-4-carbonyl]-1,3benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate

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This compound was prepared from tert-butyl-2-{[(5-{2-[(dimethylamino)methyl]morpholine-4carbonyl}-6-methoxy-1,3-benzothiazol-2-yl)methyl]carbamoyl}-2, 3-dihydro-III-indene-2-carboxylate, the final intermediate of Example 40, was quaternized and then deprotected with TFA as described in Example 35 to give the compound as a white solid (77 mg). m/z 581.6 (M+H)+.

1H NMR (400 MHz, d6-DMSO), δ: 13.30 (1H, br s), 7.80 (1H, s), 7.70 (1H, s), 7.20 (2H, m) , 7.10(2H, m), 4.65(2H, m), 4.20-4.00(2H, m), 3.95(2H, m), 3.85(3H, s), 3.80-3.50(3H, m), 3.45(2H, d), 3.15(9H, s), 3.05(2H, d), 2.80(2H, m).

Example 42 2-[2-[[6-Methoxy-5-[3-(trimethylammonio)azetidine-1-carbonyl]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetate

This compound was prepared from tert-butyl-2-[({5-[3-(dimethylamino)azetidine-1-carbonyl]-6methoxy-1,3-benzothiazol-2-yl}methyl)carbamoyl]-2,3-dihydro -1 H-indene-2-carboxylate, the final intermediate of Example 36, was quaternized and then deprotected with TFA as described in Example 35 to give the compound as a white solid (68 mg). m/z 537.6 (M+H) ⁺ .

1H NMR (400 MHz, d6-DMSO), δ: 13.40 (1H, br s), 7.80 (2H, m), 7.20 (2H, m), 7.10 (2H, m) , 4.65(2H, d), 4.40(2H, m), 4.30(2H, m), 4.15(1H, m), 3.90(2H, m), 3.85( 3H, s), 3.55(2H, m), 3.35(2H, d), 3.15(9H, s), 2.90(2H, d).

Example 43 2-[5,6-Difluoro-2-[[6-methoxy-5-[3-(trimethylammonio)azetidine-1-carbonyl]-1,3benzothiazol-2-yl]methylcarbamoyl]indan-2-yl ]acetate

This compound was prepared from tert-butyl-2-[({5-[3-(dimethylamino)azetidine-1-carbonyl]-6methoxy-1,3-benzothiazol-2-yl}methyl)carbamoyl]-5,6-difluoro -2,3-dihydro-1H-indene-2-carboxylate, the final intermediate of Example 37, was quaternized and then deprotected with TFA as described in Example 35 to give the compound as a white solid (75 mg). m/z 573.6 (M+H) ⁺ .

1H NMR (400 MHz, d6-DMSO), δ: 13.30 (1H, br s), 7.80 (2H, m), 7.20 (2H, t), 4.65 (2H, d) , 4.40(2H, m), 4.30(2H, m), 4.15(1H, m), 3.90(2H, m), 3.85(3H, s), 3.55( 2H, m), 3.35(2H, d), 3.15(9H, s), 2.90(2H, d).

Example 44 2-[2-[[5-[(1,1-Dimethylpiperidin-1-ium-4-yl)methoxy]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]-5,6- difluorindan-2-yl]acetate

This compound was prepared from tert-butyl-5,6-difluoro-2-[({6-methoxy-5-[(1-methylpiperidin-4yl)methoxy]-1,3-benzothiazol-2-yl}methyl)carbamoyl] -2,3-dihydro-1H-indene-2-carboxylate, the final intermediate in the synthesis of Example 10, was quaternized and then deprotected with TFA as described in Example 35 to give the compound as a white solid (56 mg). m/z 574.4 (M+H) ⁺ .

1H NMR (400 MHz, d6-DMSO), δ: 13.10 (1H, br s), 7.60 (1H, s), 7.45 (1H, s), 7.20 (2H, t) , 4.65 (2H,

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e), 4.05 (2H, m), 3.85 (3H, s), 3.50 (2H, m), 3.45 (2H, d), 3.40 (2H, m), 3, 10(3H, s), 3.05(3H, s), 2.90(2H, d),

2.30 (2H, s), 2.05 (1H, m), 1.90 (2H, m), 1.80 (2H, m).

Example 45 2-[2-[[6-Methoxy-5-(4-methylpiperazin-1-yl)sulfonyl-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid

a) tert-Butyl-N-{[5-(benzylsulfanyl)-6-methoxy-1,3-benzothiazol-2-yl]methyl}carbamate

Mixture of tert-butyl N-[(5-bromo-6-methoxy-1,3-benzothiazol-2-yl)methyl]carbamate (200 mg, 0.54 mmol), benzyl mercaptan (100 mg, 0.8 mmol) , xantphos (eng. Xantphos) (31 mg, 0.05 mmol), tris (dibenzylideneacetone) dipalladium (0) (25 mg, 0.027 mmol) and DIPEA (277 mg, 2.1 mmol) in 1,4dioxane (5 ml ) was heated at 115°C in a sealed tube for 1.25 h, then evaporated. The residue was treated with toluene and re-evaporated. The evaporation residue was chromatographed on silica gel eluting with 5-25% ethyl acetate in toluene to give a pale yellow solid (220 mg, 99%). m/z 317.8 (M+H) ⁺ with the loss of the BOS group.

b) tert-Butyl N-{[5-(chlorosulfonyl)-6-methoxy-1,3-benzothiazol-2-yl]methyl}carbamate

Solution of tert-butyl N-{[5-(benzylsulfanyl)-6-methoxy-1,3-benzothiazol-2-yl]methyl}carbamate (220 mg, 0.54 mmol) in acetic acid (3 ml) and water (0.4 ml) was treated with N-chlorosuccinimide (215 mg, 1.6 mmol). After 0.5 h the mixture was diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried (Na ₂ SO ₄ ) and evaporated. The residue was dissolved in toluene and re-evaporated to give a yellow oil which was used directly in the next step (210 mg, 100%). m / z 373.8 (M-H) ^- with the loss of a proton from the corresponding sulfonic acid.

c) tert-Butyl-N-({6-methoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]-1,3-benzothiazol-2yl}methyl)carbamate

A solution of tert-butyl N-{[5-(chlorosulfonyl)-6-methoxy-1,3-benzothiazol-2-yl]methyl}carbamate (210 mg, 0.54 mmol) in DCM (5 ml) was treated at 0°C with triethylamine (81 mg, 0.8 mmol) followed by 1-methylpiperazine (64 mg, 0.64 mmol). After 0.5 h, the mixture was diluted with DCM and washed with dilute aqueous sodium bicarbonate, water, then dried (Na ₂ SO ₄ ) and evaporated. The residue was chromatographed on silica gel eluting with 2-8% 2M ammonia/methanol in DCM to give a colorless oil (195 mg, 79%). m/z 457.6 (M+H)+.

d) {6-Methoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]-1,3-benzothiazol-2-yl}methanamine

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A solution of tert-butyl Na({6-methoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]-1,3-benzothiazol-2yl}methyl)carbamate (195 mg, 0.43 mmol) in DCM ( 3 ml) was treated with TFA (1 ml). After 1 h, toluene was added and the mixture was evaporated. Toluene was added again and the mixture was evaporated again. The residue was chromatographed on silica gel eluting with 2-12% 2M ammonia/methanol in DCM to give a colorless oil (133 mg, 87%). m/z 357.4 (M+H)+.

f) tert-Butyl-2-[2-[[6-methoxy-5-(4-methylpiperazin-1-yl)sulfonyl-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate

A solution of {6-methoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]-1,3-benzothiazol-2-yl}methanamine (133 mg, 0.37 mmol), 2-(2-(tert- butoxy)-2-oxoethyl)-2,3-dihydro-1H-indene-2-carboxylic acid (103 mg, 0.37 mmol) and DIPEA (145 mg, 1.1 mmol) in DMF (2 ml) were treated with HATU (213 mg, 0.56 mmol). After 0.33 h the mixture was partitioned between ethyl acetate and dilute aqueous sodium bicarbonate, then washed with water, dried (Na ₂ SO ₄ ) and evaporated.

The residue was chromatographed on silica gel eluting with 2-10% 2M ammonia/methanol in DCM to give a light brown foam (233 mg, 95%). m/z 615.4 (M+H) ⁺ .

f 2-[2-[[6-Methoxy-5-(4-methylpiperazin-1-yl)sulfonyl-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid.

tert-Butyl-2-[2-[[6-methoxy-5-(4-methylpiperazin-1-yl)sulfonyl-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetate solution (92 mg , 0.15 mmol) in DCM (3 ml) was treated with TFA (1.5 ml). After 3 h the mixture was diluted with toluene and evaporated. Toluene was added and the mixture was evaporated again. The residue was purified by reverse phase chromatography (C18 cartridge) eluting with 5-20% ACN in 2M ammonia/methanol to give the title compound as a white solid (66 mg, 79%). m/z 559.2 (M+H) ⁺ .

¹ H NMR (400 MHz, d ₆ -DMSO), δ: 9.00 (1H, br s), 8.20 (1H, s), 7.95 (1H, s), 7.22 (1H, m), 7.15(1H, m), 4.65(2H, m), 3.95(3H, s), 3.50(2H, d), 3.15(4H, m), 2, 90 (2H, d), 2.30 (4H, m), 2.20 (3H, s).

Example 46 2-[2-[[5-[[4-(Dimethylamino)-1-piperidyl]sulfonyl]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetic acid

This compound was prepared according to the procedure described in Example 45, except that N,N-dimethylpiperidine-4-amine was used instead of 1-methylpiperazine to give the title compound as a white solid (69 mg). m/z 587.2 (M+H) ⁺ .

1 H NMR (400 MHz, d ₆ -DMSO), δ: 9.00 (1H, br s), 8.20 (1H, s), 7.90 (1H, s), 7.20 (2H, m ), 7.10(2H, m), 4.65(2H, d), 3.90(3H, s), 3.70(2H, m), 3.40(2H, d), 2.90 (2H, d), 2.60 (1H, t), 2.30 (2H, m), 2.20 (6H, s), 1.80 (2H, m), 1.40 (2H, m) .

Example 47 2-[2-[[6-Methoxy-5-[[4-(trimethylammonio)-1-piperidyl]sulfonyl]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetate

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This compound was prepared from tert-butyl-2-{[(5-{[4-(dimethylamino)piperidin-1-yl]sulfonyl}6-methoxy-1,3-benzothiazol-2-yl)methyl]carbamoyl}-2 ,3-dihydro-1H-indene-2-carboxylate, the final intermediate in the synthesis of Example 46, was quaternized and then deprotected with TFA as described in Example 35 to give the compound as a white solid (91 mg). m/z 601.3 (M+H)+.

¹ H NMR (400 MHz, d ₆ -DMSO), δ: 8.20 (1H, s), 8.00 (1H, s), 7.15 (2H, m), 7.10 (2H, m) , 4.65(2H, d), 3.95(3H, s), 3.90(2H, m), 3.40(2H, d), 3.00(9H, s), 2.90( 2H, d), 2.60(1H, m), 2.30(1H, m), 2.10(2H, m), 1.60(2H, m).

Example 48 2-[2-[(6-Cyano-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid

a) tert-Butyl-2-[2-[(6-bromo-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetate

This compound was prepared as described in Example 24 from step b to step d starting from 4-bromo-2-iodaniline to give the title compound as a white solid. m/z 501.1 (M+H) ⁺ .

b) tert-Butyl-2-[2-[(6-cyano-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetate

To a stirred solution of tert-butyl 2-[2-[(6-bromo-1,3-benzothiazol-2-yl)methylcarbamoyl]indan2-yl]acetate (300 mg, 0.59 mmol) in DMF (6 mL) Zn(CN) ₂ (140 mg, 1.19 mmol) was added and purged with argon for 10 minutes. Pd ₂ (dba) ₃ (55 mg, 0.05 mmol) and xanthos (70 mg, 0.11 mmol) were then added, purged with argon for another 5 min. The reaction mixture was heated in a sealed tube at a temperature of 90°C for 4 h and then filtered through a layer of Celite, the layer was washed with EtOAc (50 ml), the filtrate was evaporated. The crude product was purified by silica gel chromatography eluting with 20-30% EtOAc in petroleum ether to give an off-white solid (180 mg, 68%). m/z 448.2 (M+H) ⁺ .

c) 2-[2-[(6-Cyano-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid.

Solution of tert-butyl 2-[2-[(6-cyano-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetate (160 mg, 0.35 mmol) in DCM (5 ml) treated with TFA (2.5 ml) at room temperature for 4 h. The mixture was evaporated, the residue was triturated with diethyl ether (10 ml). The crude compound was purified by preparative HPLC [X-BRIDGE-C18 (150*30), 5 µm, mobile phase: A: 0.1% formic acid in H ₂ O, B: MeCN] to give the title product in as a white solid (26 mg, 19%). m/z 392.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ), δ: 9.31 (1H, br s), 8.65 (1H, s), 8.09 (1H, d, J = 8.5 Hz) , 7.90 (1H, dd, J = 8.5 Hz, J = 1.5 Hz), 7.22-7.20 (2H, m), 7.14-7.13 (2H, m), 4.71 (2H, d, J = 5.5 Hz), 3.45 (2H, d, J = 16.5 Hz), 2.99 (2H, d, J = 16.5 Hz), 2, 70 (2H, s).

Example 49 2-[2-[(5-Cyano-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid

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This compound was prepared from t-butyl 2-[2-[(5-bromo-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetate using the conditions described in Example 48 to give compound as a white solid. m/z 392.1 (M+H)+.

¹ H NMR (500 MHz, DMSO-d6), δ: 10.7 (1H, br s), 8.46 (1H, s), 8.28 (1H, d, J = 8.5 Hz), 7.79 (1H, d, J = 8.5 Hz), 7.19-7.18 (2H, m), 7.13-7.11 (2H, m), 4.70 (2H, d, J = 5 Hz), 3.42 (2H, d, J = 16 Hz), 2.95 (2H, d, J = 16 Hz), 2.57 (2H, s).

Example 50 LasB inhibitory activity measurements.

The significance of LasB elastase in PA infection has been demonstrated using experiments to measure lung load in a rat model of chronic lung infection following infection with wild type PA WT (expressing LasB) and a PA mutant (A/asS PA) in which LasB not expressed. This could be clearly seen by the fact that after infection, the LasB deficient strain could not survive for more than 5 days, while the wild type strain could survive for at least 14 days. The importance of LasB for the development of RA biofilms has also been shown. Biofilms formed 3 days later by both PA26 wt and PA26 lasB deletion strains were examined by confocal imaging and subsequent analysis (using Comstat software). This study showed that biofilms formed by the LAsB deletion strain of PA26 were significantly reduced in thickness and biomass compared to the wild-type strain, demonstrating a significant role for LasB elastase in the development of PA biofilms.

The significance of LasB for Pseudomonas aeruginosa (PA) infection is illustrated in FIG. 1, which shows the incidence of deaths versus survival and chronic colonization versus bacterial clearance in a mouse model of lung infection. The chronicity of infection is defined by the RA load in the lungs exceeding 10 ^-3 CFU seven days after infection. In this model of infection, both the wild-type strain (expressing LasB; wt RP45 (wit-type RP45)) and the isogenic lasB-deleted strain (not expressing LasB; mutant RP45) result in similar mortality (in about 40% of infected mice); however, the frequency of chronic colonization was significantly lower with the mutant strain compared to its wild-type counterpart (87% for wild-type versus 43% for the lasB-deleted strain; Fisher's exact test p < 0.01). This discovery demonstrates the role of LasB in establishing chronic colonization.

With this in mind, experiments were carried out to (1) measure the effectiveness of the compounds of the invention in inhibiting the purified Pseudomonas aeruginosa LasB enzyme and (2) measure the ability of the compounds of the invention to inhibit LasB-catalyzed degradation of elastin. In the first assay, commercially available fluorescent synthetic peptide and purified LasB enzyme were used. To measure the kinetics of LasB hydrolysis, the IC ₅₀ and Ki of the inhibitors were determined; the second assay is more physiological and uses dialyzed Pseudomonas aeruginosa supernatant as the enzyme source plus its natural substrate elastin. This assay is an endpoint assay that determines the percent inhibition of LasB by each compound at any given time point and at any given concentration of inhibitor. Technical details are described below.

Fluorimetric analysis to determine Ki.

This assay uses a commercially available substrate (Abz-Ala-Gly-Leu-Ala-p-NitroBenzyl-Amide (Ex (excitation wavelength): 340 nm; Em (emission wavelength): 415 nm) from Peptide International) and purified LasB protein from P. aeruginosa (provided by Merck or Charles River Laboratories). The experiment was carried out to determine the activity of LasB elastase and evaluate the inhibitory ability of the compounds in the format of a 96-well plate.

All compounds of formula (I) were evaluated using the methodology described below.

Method: 10 to 140 ng/ml purified LasB was incubated with 250 μM Abz-Ala-Gly-Leu-Ala-pNitro-Benzyl-Amide in 50 mM Tris-HCl, pH 7.4, 2.5 mM CaCl ₂ .0 01% Triton X100 at 37°C. LasB activity (corresponding to fluorescence emission induced by substrate hydrolysis) was measured for 30 min at 37° C. using a fluorescent plate reader such as Perkin Elmer Envision or equivalent. To determine the IC ₅₀ usually evaluated different ranges of inhibitor concentrations depending on the effectiveness of the inhibitor from 0.0016 to 200 μm (series of 2-fold dilutions).

The equation for calculating Ki from IC ₅₀ is Ki = IC ₅₀ /(1+([S]/Km)), where [S] = 250 µM and Km = 214 µM.

Elastin analysis to determine % inhibition.

When analyzing elastin, P. aeruginosa PAO1 dialyzed supernatant is used as the enzyme source, and Congo red elastin is used as the substrate. The natural substrate of LasB, elastin, forms a complex with the dye Congo red (Elastin Congo-Red, ECR). The action of elastolysis in the culture supernatant will result in the breakdown of elastin and the release of the Congo red dye into the supernatant. This red dye release can be measured with a spectrophotometer.

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All compounds of formula (I) were evaluated using the methodology described below.

Method: to determine the activity of LasB elastase and evaluate the inhibitory ability of the compounds, an overnight culture of PAO1 strain P. aeruginosa was diluted in LB medium (Luria-Bertani). After reaching an OD600 _nm of 0.6, this culture was diluted and incubated for an additional 18-24 hours in an incubator shaker. Culture supernatants were collected by centrifugation and filtered through a 0.22 μM filter. The resulting supernatants were dialyzed (filterable molecules less than 20 kDa) into a solution containing 50 mM Tris-HCl, pH 7.4, 2.5 mM CaCl ₂ , at 4° C. with stirring for 24 h. The dialyzed supernatant was then mixed by volume. with ECR suspension (eng. Elastin Congo-Red complex elastin-congo red) (20 mg/ml ECR in 100 mm Tris-HCl, pH 7.4, buffer with the addition of 1 mm CaCl ₂ ) with the addition of Triton X100 (final concentration 0 .01%) in the presence of DMSO (positive control) and/or various concentrations of the compound (typically 50 to 1.56 μM). As a negative control, the dialyzed supernatant was replaced with a Tris-HCl solution (50 mM Tris-HCl, pH 7.4, 2.5 mM CaCl ₂ ). Then the mixed reaction mass was incubated overnight at a temperature of 37°C in a shaker-incubator. The reaction supernatant was separated by centrifugation, and the release of Congo red was measured by its absorption at a wavelength of 495 nm (OD ₄₉₅ nm).

Percent inhibition was determined using the following equation:

((OD _{495 nm} value of positive control - OD value of _{495 nm} of negative control) - (OD value of _{495 nm} of treated supernatant - OD value of _{495 nm} of negative control))/(OD value of _{495 nm} of positive control - OD value of _{495 nm} of negative control)x 100.

The results of both analyzes are presented in the table below and divided into categories A, B and C. Ki values are classified as A (Ki = 0.00 to 0.05 µM), B (Ki = 0.05 to 0.2 µM) and C (Ki = 0.2 to 10.00 μM). Similarly, in the elastase hydrolysis assay, values are classified as A (>80% inhibition), B (60 to 80% inhibition), and C (10 to 60% inhibition), all measured at 25 μM inhibitor concentration (n/o - undefined).

Example Ki (µM) Inhibition of elastin hydrolysis, % at an inhibitor concentration of 25 µM 1 WITH WITH 2 WITH But 3 IN IN 4 WITH But 5 WITH But 6 IN IN 7 WITH But 8 IN IN 9 A A 10 A A

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eleven A A 12 IN IN 13 IN IN 14 IN IN 15 IN IN 16 A IN 17 IN IN 18 A IN 19 A A 20 A IN 21 A A 22 A IN 23 A A 24 WITH IN 25 WITH IN 26 WITH But 27 IN IN 28 WITH But 29 WITH But thirty WITH But 31 WITH But 32 IN V 33 A IN 34 A A 35 IN IN 36 A A 37 A A 38 IN IN 39 WITH But 40 IN IN 41 IN IN 42 WITH IN 43 IN IN 44 A A 45 IN IN 46 IN IN 47 IN IN 48 IN IN 49 IN IN

Example 51 Inhibition of LasB mediated IL-Ιβ activation.

The activity of the compounds of the invention in inhibiting the LasB-mediated hydrolysis of pro-IL-1β to IL-13 was demonstrated by an in vitro enzymatic assay using purified LasB and a reporter substrate (FRET peptide (Fluorescence Resonance Energy Transfer). fluorescence energy) mimicking the LasB cleavage site of IL-1e). Hydrolysis of this FRET peptide was continuously monitored using a Victor multi-mode plate reader (Perkin Elmer) at 355 nm excitation and 450 nm emission wavelength in the presence of various concentrations of the compounds of the invention. Inhibition constants (Ki) were determined for some compounds of the invention (at least 2 independent repeats) using a competitive inhibitor model. The results are presented in the table below.

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Claims (49)

Example Ki (LasB mediated hydrolysis of pro-IL-1 β to IL-1P)/mkM 9 0.16 eleven 0.22 19 0.27 20 0.34 22 0.40 23 0.50 44 0.30 Example 52 In vivo efficacy of the compounds of the invention. Experiments were carried out to demonstrate the efficacy of the compounds of the invention in the treatment of a mouse model of Pseudomonas aeruginosa lung infection. Mice were intranasally inoculated with PA (PAO1) and sacrificed 24 hours later. The extent of lung infection was quantified by bacterial load (determination of CFU, colony forming units) and levels of pro-inflammatory !Ρ-1β. Analysis of statistical data for both indicators was performed using ANOVA (Analysis of Variation - analysis of variants, analysis of variance) with Dunnett's posterior test. Compounds were administered intravenously in a two-dose regimen (1 h and 2 h after infection) at two different doses (10 and 30 mg/kg). As shown in FIG. 2, Example 23 inhibited IL-1e production and activation in mice infected with wild-type RA (PA01) at the same level as a lasB deletion mutant strain (AlasB) unable to produce LasB. As shown in FIG. 3, the compound of Example 23 reduced lung infection to that of the LasB deletion mutant strain (AlasB) as determined by CFU levels. CLAIM 1. An indane compound of formula (I) or a pharmaceutically acceptable salt thereof where R ¹ represents OH, or in the case where the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O', so that the connection forms a zwitterion; R ² is H; each of the R ³ groups is independently halogen; n is an integer from 0 to 2; R ⁴ is H; L represents -CH ₂ -; p is 0 or 1; R ⁵ is selected from -OMe and -OH; each R ⁶ is independently selected from - R ^6a RA, -OR ^6a RA, -NR ²⁰ -R ^6a R ^A , -R ^6b R ^B , -OR ^6b R ^B and -NR ²⁰ -R ^6b R ^B ; -R ^x R ^r , -OR ^x R ^r , -OR ^x -C(O)-R ^r , -R ^x -C(O)-R ^r , -NR ²⁰ -R ^x R ^r and -NR ²⁰ -R ^x -C(O)-R ^r ; And - CN; -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^x R ^b ; -C(O)NR ⁴⁰ R ⁴¹ ; -SO2R ²⁰ ; -SO2NR ²⁰ R ²¹ and -SO ₂ NR ⁴⁰ R ⁴¹ ; where each R ^X is independently R ^6a ; each R ^6a is independently C1-C4 alkylene; each R ^6b is independently [C1-C3 alkylene]-C(R ^z )2, where two R ^z groups are bonded together and together with the atom to which they are attached form a 5- or 6-membered heterocyclic group; RA is selected from -NR ²⁰ R ³⁰ ; -N ⁺ R ²⁰ R ²¹ R ³⁰ ; -NR ²⁰ NR ²¹ R ²² ; -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ; R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² ; -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ; R ⁴⁰ and R ⁴¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group wherein any nitrogen atom in the ring is independently selected from secondary, tertiary and quaternary nitrogen atoms; each RR is independently a 4-10 membered heteroaryl or heterocyclic group containing at least one nitrogen atom, said nitrogen atom(s) being independently selected from secondary, tertiary and quaternary nitrogen atoms; where each RR and each ring formed by -NR ⁴⁰ R ⁴¹ are independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ , -R ⁷ -OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ - N ⁺ R ²⁰ R ²¹ R ²² ; each R ⁷ is independently selected from a bond and an unsubstituted C ₁ -C ₃ alkylene; R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are each independently selected from H and C ₁ -C ₃ alkyl, unsubstituted or substituted with one -OH or -OMe group; each R ³⁰ is independently selected from C ₂ -C ₃ alkyl, unsubstituted or substituted with one -OH or -OMe group. 2. The compound according to claim 1 where R ⁵ -OMe. 3. The compound according to claim 1, where p is equal to 0. 4. A compound according to any one of claims 1 to 3, where n is 0. 5. A compound according to any one of claims 1 to 3, wherein n is 2 and each R ³ group is fluorine. 6. A compound according to any one of claims 1 to 5, wherein each R ⁶ is independently selected from -R ^6a R ^A , -OR ^6a R ^A , -NR ²⁰ R ^6a R ^A , -R ^6b R ^B , -OR ^6b R ^B , -NR ²⁰ -R ^6b R ^B , -R ^x R ^r , -OR ^x R ^r , -OR ^x -C(O)-R ^r and -R ^x -C(O)-R ^r , where R ^{a is} selected from -NR ²⁰ R ³⁰ ; -N ⁺ R ²⁰ R ²¹ R ³⁰ ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ; R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ; each RR is independently a 5-6 membered heteroaryl or 4-6 membered heterocyclic group containing at least one nitrogen atom, said nitrogen atom(s) being independently selected from secondary, tertiary and quaternary nitrogen atoms; where each RR is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ , -R ⁷ -OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² . 7. The compound according to any one of claims 1-6, where each R ⁶ is independently selected from -OR ^6a R ^A , -OR ^x R ^r and -OR ^x -C(O) -R ^r , where R ^a is selected from -NR ²⁰ R ³⁰ and -N ⁺ R ²⁰ R ²¹ R ³⁰ ; each RR is independently a 5-6 membered heteroaryl or 4-6 membered heterocyclic group containing at least one nitrogen atom, said nitrogen atom(s) being independently selected from secondary, tertiary and quaternary nitrogen atoms; where each RR is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² . 8. Connection according to any one of paragraphs.1-5, where each R ⁶ is independently selected from -CN; -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^x R ^b ; -C(O)NR ⁴⁰ R ⁴¹ ; -SO2R ²⁰ ; -SO2NR ²⁰ R ²¹ and -SO ₂ NR ⁴⁰ R ⁴¹ ; where R ^B is selected from -NR ²⁰ R ²¹ ; -N ⁺ R ²⁰ R ²¹ R ²² ; -NR ²⁰ NR ²¹ R ²² and -NR ²⁰ N ⁺ R ²¹ R ²² R ²³ ; each R ⁴⁰ and R ⁴¹ together with the nitrogen atom to which they are attached independently form a 4-6 membered heterocyclic group, wherein any nitrogen atom in the ring is independently selected from secondary, tertiary and quaternary nitrogen atoms; where each ring formed by -NR ⁴⁰ R ⁴¹ is independently unsubstituted or substituted with one or two or three groups independently selected from -R ²⁰ , -R7-OR ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ - n + r ² ° r ²ⁱ r ²² . 9. The compound according to any one of claims 1 to 5, where each R ⁶ is independently selected from -CN; -C(O)NR ²⁰ R ²¹ ; -C(O)NR ²¹ -R ^x R ^b ; -C(O)NR ⁴⁰ R ⁴¹ ; -SO2R ²⁰ ; -SO2NR ²⁰ R ²¹ and -SO ₂ NR ⁴⁰ R ⁴¹ ; where R ^B is selected from -NR ²⁰ R ²¹ and -N ⁺ R ²⁰ R ²¹ R ²² ; each R ⁴⁰ and R ⁴¹ together with the nitrogen atom to which they are attached independently form a 4-6 membered heterocyclic group, wherein any nitrogen atom in the ring is independently selected from secondary, tertiary and quaternary nitrogen atoms; where each ring formed by NR40R ⁴¹ is independently unsubstituted or substituted with one or two groups independently selected from -R ²⁰ ; -R ⁷ -NR ²⁰ R ²¹ and -R ⁷ -N ⁺ R ²⁰ R ²¹ R ²² . 10. A compound according to any one of claims 1 to 9, wherein each RR or each ring formed by -NR40R ⁴¹ , if present, is independently selected from azetidine, morpholine, piperazine, piperidine, pyrrolidine and triazole. 11. Connection according to claim 1, where R ¹ is OH or, if the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O, so that the compound forms a zwitterion; R ² is H; each R ³ group is independently fluorine; n is an integer from 0 to 2; R ⁴ is H; L represents -CH ₂ -; - 57 041925 p is equal to 1; R ⁵ is -OMe; each R ⁶ is independently -OR ^6a R ^A ; where each R ^6a is independently C ₁ -C ₄ alkylene; R ^a is selected from -NR ²⁰ R ³⁰ and -N ⁺ R ²⁰ R ²¹ R ³⁰ ; each of R ²⁰ and R ²¹ is independently selected from H and C ₁ -C ₃ alkyl which is unsubstituted or substituted with one —OH group; each R ³⁰ is independently selected from C ₂ -C ₃ alkyl which is unsubstituted or substituted with one —OH group. 12. Connection according to claim 1, where R ¹ is OH or, if the compound of formula (I) contains a positively charged nitrogen atom, R ¹ may be O ^- so that the compound forms a zwitterion; R ² is H; each R ³ group is independently fluorine; n is 0 or n is 2; R ⁴ is H; L represents -CH ₂ -; p is 1; R ⁵ is -OMe; each R ⁶ is independently -OR ^6a R ^A ; where each R ^6a is independently C ₁ -C ₄ alkylene; R ^a is -N ⁺ R ²⁰ R ²¹ R ³⁰ ; each of R ²⁰ and R ²¹ is independently C ₁ -C ₂ alkyl which is unsubstituted or substituted with one —OH group; each R ³⁰ is independently selected from C2-C3 alkyl which is unsubstituted or substituted with one —OH group. 13. The compound according to claim 1, wherein the compound is selected from 1) 2-[2-[(4-carbamoyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid; 2) 2-[2-[[4-(pyrrolidin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid; 3) 2-[2-[(4-pyrrolidin-1-ylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid; 4) 2-[2-[(4-sulfamoyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid; 5) 2-[2-[(4-piperazin-1-ylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid; 6) 2-[2-[[4-(3-Aminopyrrolidin-1-yl)sulfonyl-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid; 7) 2-[2-[(4-methylsulfonyl-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid; 8) 2-[2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2 -yl]acetic acid; 9) 2-[2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid; 10) 2-[5,6-difluoro-2-[[6-methoxy-5-(2-morpholinoethoxy)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid; 11) 2-[5,6-difluoro-2-[[6-methoxy-5-[(1-methyl-4-piperidyl)methoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2- yl]acetic acid; 12) 2-[5,6-difluoro-2-[[6-methoxy-5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2yl]methylcarbamoyl]indan -2-yl]acetic acid; 13) 2-[5,6-difluoro-2-[[6-methoxy-5-[2-(4-methylmorpholin-4-ium-4-yl)ethoxy]-1,3-benzothiazol-2-yl] methylcarbamoyl]indan-2-yl]acetate; 14) 2-[2-[[5-[2-(4,4-dimethylpiperazin-4-ium-1-yl)-2-oxoethoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl ]-5,6-difluoroindan-2-yl]acetate; 15) 2-[5,6-difluoro-2-[[6-methoxy-5-[3-(4-methylmorpholin-4-ium-4-yl)propoxy]-1,3-benzothiazol-2yl]methylcarbamoyl] indan-2-yl]acetate; 16) 2-[2-[[6-methoxy-5-[3-(4-methylmorpholin-4-ium-4-yl)propoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2- yl]acetate; 17) 2-[2-[[5-[(1,1-dimethylpiperidin-1-ium-4-yl)methoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan- 2-yl]acetate; 18) 2-[2-[[5-[3-[diethyl(methyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate; 19) 2-[5,6-difluoro-2-[[6-methoxy-5-[3-(1-methylpyrrolidin-1-ium-1-yl)propoxy]-1,3-benzothiazol-2yl]methylcarbamoyl] indan-2-yl]acetate; - 58 041925 20) 2-[2-[[5-[3-[2-hydroxyethyl(dimethyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetate; 21) 2-[5,6-difluoro-2-[[5-[3-[2-hydroxyethyl(dimethyl)ammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan- 2-yl]acetate; 22) 2-[2-[[5-[3-[bis(2-hydroxyethyl)methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl]acetate; 23) 2-[2-[[5-[3-[bis(2-hydroxyethyl)methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan-2 -yl]acetate; 24) 2-[2-[[5-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid; 25) 2-[2-[[5-[2-(4-methylpiperazin-1-yl)ethoxy]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid; 26) 2-[2-[[6-[3-(dimethylamino)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan2-yl]acetic acid; 27) 2-[2-[[5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid; 28) 2-[2-[[5-[2-(dimethylamino)ethylcarbamoyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid; 29) 2-[2-[[6-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid; 30) 2-[2-[[6-[2-(dimethylamino)ethylcarbamoyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2yl]acetic acid; 31) 2-[2-[[5-[4-[3-(dimethylamino)propyl]piperazin-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid; 32) 2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan2-yl]acetic acid; 33) 2-[2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid; 34) 2-[5,6-difluoro-2-[[6-methoxy-5-(4-methylpiperazin-1-carbonyl)-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acids; 35) 2-[2-[[5-(4,4-dimethylpiperazin-4-ium-1-carbonyl)-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan- 2-yl]acetate; 36) 2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid ; 37) 2-[2-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-difluorindan-2 -yl]acetic acid; 38) 2-[2-[[5-[4-(dimethylamino)piperidine-1-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid; 39) 2-[2-[[6-methoxy-5-[4-(trimethylammonio)piperidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate; 40) 2-[2-[[5-[2-[(dimethylamino)methyl]morpholine-4-carbonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acids; 41) 2-[2-[[6-methoxy-5-[2-[(trimethylammonio)methyl]morpholine-4-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate ; 42) 2-[2-[[6-methoxy-5-[3-(trimethylammonio)azetidine-1-carbonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate; 43) 2-[5,6-difluoro-2-[[6-methoxy-5-[3-(trimethylammonio)azetidine-1-carbonyl]-1,3-benzothiazol-2yl]methylcarbamoyl]indan-2-yl] acetate; 44) 2-[2-[[5-[(1,1-dimethylpiperidin-1-ium-4-yl)methoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5 ,6-difluorindan-2-yl]acetate; 45) 2-[2-[[6-methoxy-5-(4-methylpiperazin-1-yl)sulfonyl-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid; 46) 2-[2-[[5-[[4-(dimethylamino)-1-piperidyl]sulfonyl]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetic acid ; 47) 2-[2-[[6-methoxy-5-[[4-(trimethylammonio)-1-piperidyl]sulfonyl]-1,3-benzothiazol-2-yl]methylcarbamoyl]indan-2-yl]acetate; 48) 2-[2-[(6-cyano-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid; 49) 2-[2-[(5-cyano-1,3-benzothiazol-2-yl)methylcarbamoyl]indan-2-yl]acetic acid; or a pharmaceutically acceptable salt thereof. 14. The compound according to claim 1, which is 2-[2-[[5-[3-[bis(2-hydroxyethyl)methylammonio]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl] -5,6-difluorindan-2-yl]acetate or a pharmaceutically acceptable salt thereof. -