RU2773444C2 - Pharmaceutical compounds - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to benzimidazole derivatives of formula (I) or to a pharmaceutically acceptable salt of the said compound, where: R¹ is -(CH₂)_m-R⁴ or

; R² is halogen; R³ is F; R⁴ is -NH-(CH₂)₂-(NH)_r-R⁵, --NH-(CHR⁵R⁶) or a group of the following formula (A):

(A); -(CH₂)_m-, -CH₂-O-CH₂-, -(CH₂)_r-S(O)₂-CH₂- or -(CH₂)_r-NR⁵-CH₂-, m is an integer from 1 to 3; n is 1; p is 0 and V is N; q is 0 or 1; r is 0 or 1; R⁵ is -SO₂Me, -SO₂Et or - CONH₂; R⁶ is C₁-C₆ alkyl; and R⁷ is -SO₂Me. The invention also relates to a pharmaceutical composition based on a compound of formula (I), the use of a compound of formula (I), a method for treating a subject suffering from or susceptible to RSV infection, and a method for preparing a pharmaceutically acceptable salt of a compound of formula (I).

EFFECT: novel RSV inhibitors useful for treating or preventing RSV infection are obtained.

10 cl, 3 tbl, 45 ex

Description

Technical field

The present invention relates to benzimidazole compounds and their use in the treatment or prevention of respiratory syncytial virus (RSV) infection.

BACKGROUND OF THE INVENTION

RSV is a virus of the paramyxovirus family (Paramyxoviridae) containing a negative-polar single-stranded RNA. RSV is easily transmitted through secretions from an infected person, through surfaces or through direct contact. Unlike the flu, it is not transmitted through the air. After successful inoculation, the incubation period lasts from four to six days, during which time the virus spreads from the nasopharynx to the lower respiratory tract through the fusion of infected cells with uninfected ones and by shedding of necrotic epithelium. Combined with increased mucus secretion and edema in infants, this can lead to mucus blockage, which causes excessive swelling and collapse of the distal lung tissue, indicative of bronchiolitis. In this case, hypoxia is usually observed, and due to respiratory failure, the possibility of feeding is often difficult. In RSV pneumonia, the inflammatory infiltration of the airways consists of uninuclear cells and is more generalized, involving the bronchioles, bronchi, and alveoli. The duration and extent of virus shedding into the environment was found to correlate with clinical signs and disease severity.

RSV is the leading cause of severe respiratory tract infections in infants and young children worldwide. Morbidity and mortality are highest in infants born prematurely and in those with chronic lung or heart disease, although many infants hospitalized with RSV infection do not have other conditions. Severe RSV infection in infancy can lead to recurrent airflow obstruction over several years and is associated with the development of asthma later on.

RSV is also a major cause of morbidity and mortality in the elderly and in immunocompromised children and adults, as well as those suffering from chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF).

The incidence of RSV is seasonal; it can be very accurately predicted and RSV occurs during winter in both hemispheres, from September to May in Europe and North America, with peak incidence in December and January, and in tropical countries RSV can be observed throughout the year. RSV affects > 90% of infants and young children under two years of age, and because natural immunity is fragile, many will become reinfected every year. As with influenza, in the elderly, RSV is responsible for approximately 10% of winter hospital admissions, with an associated mortality rate of 10%.

Current treatments for RSV include the use of an anti-RSV monoclonal antibody called palivizumab. This use of palivizumab is a prophylactic rather than a therapeutic treatment for RSV. Although this antibody is often effective, its use is limited to preterm and high-risk infants. Indeed, the limited applicability of palivizumab means that it is not available for many people who need RSV treatment. Accordingly, there is an urgent need to develop effective alternatives to existing RSV treatments.

In addition, several compounds have been proposed as inhibitors of RSV, including compounds based on benzimidazole. For example, KD Combrink et al., Bioorganic & Medicinal Chemistry Letters, 17 (2007), 4784-4790 describes the compound BMS-433771 and variants thereof. Other benzimidazole-based compounds are described in WO 02/062290, WO 03/053344 and WO 10/103306.

WO 2013/068769 and WO 2016/055780 describe benzimidazole compounds with activity against RSV. However, there is a need to discover additional compounds and in particular compounds having favorable pharmacokinetic profiles.

BRIEF DESCRIPTION OF THE INVENTION

To date, a new group of benzimidazole compounds have been found to be active as RSV inhibitors and have favorable pharmacokinetics. Accordingly, the present invention relates to a compound which is a benzimidazole of formula (I):

(I)

(I)

where:

;R ¹ is -(CH ₂ ) _m -R ⁴ or

;

R ² is halogen, -(CH ₂ ) _m -NH ₂ or -(CH ₂ ) _n -C(=NH)-NH _2;

R ³ is H or F;

R ⁴ is -NH-(CH ₂ ) ₂ -(NH) _r -R ⁵ , -NH-(CHR ⁵ R ⁶ ) or a group of the following formula (A):

(A)

(A)

W is -(CH ₂ ) _m -, -CH ₂ -O-CH ₂ -, -CH ₂ -S-CH ₂ -, -(CH ₂ ) _r -S(O) ₂ -CH ₂ - or -( CH ₂ ) _r -NR ⁵ -CH ₂ -;

m is an integer 1 to 3;

n is 1 or 2;

p is 1 and V is CH; or p is 0 and V is N;

q is 0 or 1;

r is 0 or 1;

R ⁵ is H, -SO ₂ Me, -SO ₂ Et, -SO ₂ CF ₃ , -COMe, -CONMe ₂ , -CONH ₂ or -CH ₂ CH ₂ SO ₂ Me;

R ⁶ is H or C ₁ -C ₆ alkyl; and

R ⁷ is -SO ₂ Me, -SO ₂ Et, -SO ₂ CF ₃ , -COMe, -CONMe ₂ , -CONH ₂ or -CH ₂ CH ₂ SO ₂ Me;

or a pharmaceutically acceptable salt of said compound.

DETAILED DESCRIPTION OF THE INVENTION

When any group, ring, substituent or moiety as defined herein is substituted, it is usually substituted with Q as defined below.

The C _1-6 alkyl group or moiety is straight or branched. The C _1-6 alkyl group is usually a C _1-4 alkyl group or a C _4-6 alkyl group. Examples of C _1-6 alkyl groups and moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl (i.e. 3-methylbut-1-yl), t -pentyl (i.e. 2-methylbut-2-yl), neopentyl (i.e. 2,2-dimethylpropan-1-yl), n-hexyl, isohexyl (i.e. 4-methylpentan-1-yl ), t-hexyl (i.e. 3-methylpentan-3-yl) and neopentyl (i.e. 3,3-dimethylbutan-1-yl). For the avoidance of doubt, if two alkyl moieties are present in a group, the alkyl moieties may be the same or different. The C _1-6 alkyl group is unsubstituted or substituted, usually with one or more Q groups, as defined below. For example, a C _1-6 alkyl group is unsubstituted or substituted with 1, 2 or 3 Q groups as defined below.

Q is halogen, nitro, -CN, OH, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-4 haloalkoxy, -CO ₂ R''', -NR''' ₂ , -SR''', -S(=O)R''', -S(=O) ₂ R''', C ₃ -C ₁₀ cycloalkyl, 5-10 membered heterocyclyl, 5-12 membered aryl or 5-12 membered heteroaryl, where each R''' is independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, 5-12 membered aryl and 5-12 membered heteroaryl.

The C _1-6 alkoxy group is straight or branched. Typically this group is a C _1-4 alkoxy group, for example a methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy or tert-butoxy group. The C _1-6 alkoxy group is unsubstituted or substituted, usually with one or more Q groups, as defined below.

The C _1-6 alkylthio group is straight or branched. Typically this group is a C _1-4 alkylthio group, for example a methylthio, ethylthio, propylthio, isopropylthio, n-propylthio, n-butylthio, sec-butylthio or t-butylthio group. The C _1-6 alkylthio group is unsubstituted or substituted, usually with one or more Q groups, as defined below.

The halogen or halogen group is F, Cl, Br or I. Preferably F or Cl. A C _1-6 alkyl group substituted with halogen may be referred to as "C _1-6 haloalkyl", which means a C _1-6 alkyl group as defined above in which one or more hydrogen atoms are substituted with halogen. Similarly, a C _1-6 alkoxy group substituted with halogen may be referred to as "C _1-6 haloalkoxy", which means a C _1-6 alkoxy group as defined above in which one or more hydrogen atoms are substituted with halogen. Typically C _1-6 haloalkyl or C _1-6 haloalkoxy is substituted with 1, 2 or 3 halogen atoms. Haloalkyl groups and haloalkoxy groups include perhaloalkyl groups and perhaloalkoxy groups such as -CX ₃ and -OCX ₃ where X is halogen, for example -CF ₃ -CCl ₃ -OCF ₃ and -OCCl ₃ .

A C _1-6 hydroxyalkyl group is a C _1-6 alkyl group, as defined above, substituted with one or more OH groups. It is usually substituted with one, two or three OH groups. Preferably it is substituted with one OH group.

A 5-12 membered aryl group is an aromatic carbocyclic group containing 5 to 12 carbon atoms, eg 6 to 10 carbon atoms, eg 6 or 10 carbon atoms. It is a monocyclic or fused bicyclic ring system in which an aromatic ring is fused to another aromatic carbocyclic ring. Examples of the 5-12 membered aryl group include phenyl and naphthyl. When substituted, the aryl group is usually substituted

C _1-4 alkyl or Q group as defined above, eg 1, 2 or 3 groups selected from C _1-4 alkyl group and Q group as defined above.

A C _3-10 cycloalkyl group is a saturated hydrocarbon ring containing 3 to 10 carbon atoms. The C _3-10 cycloalkyl group may be, for example, C ₃ -C ₇ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. It is usually C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ cycloalkyl, for example cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, it is cyclobutyl. The C _3-10 cycloalkyl group is unsubstituted or substituted, usually with one or more Q groups, as defined below.

A 5-12 membered heteroaryl group or fragment is a 5-12 membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N and S. It is monocyclic or bicyclic. It usually contains one N atom and 0, 1, 2 or 3 additional heteroatoms selected from O, S and N. It may be, for example, a 5-7 membered heteroaryl group, such as a 5- or 6-membered N- containing a heteroaryl group. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl and pyrazolyl. Furanyl, thienyl, pyridyl and pyrimidyl are preferred. When substituted, the heteroaryl group is typically substituted with one or more, eg 1, 2 or 3, groups selected from C _1-4 alkyl and a Q group as defined above.

A 5-10 membered heterocyclyl fragment is a monocyclic or bicyclic non-aromatic, saturated or unsaturated C _5-10 carbocyclic ring in which at least one, for example 1, 2 or 3 carbon atoms in the ring are replaced by an atom or group selected from O, S, SO, SO ₂ , CO and N. This is usually a C _5-10 saturated ring in which 1, 2 or 3 carbon atoms in the ring are replaced by an atom or group selected from O, S, SO ₂ , CO and NH. More typically it is a monocyclic ring, preferably a C ₅ -C ₆ monocyclic ring. Examples include piperidyl, piperidine-2,6-dionyl, piperidin-2-onyl, piperazinyl, morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, 1,3-dioxolanyl, pyrrolidinyl, imidazol-2-onyl, pyrrolidin-2-onyl, tetrahydrofuranyl and tetrahydropyranyl fragments.

For the avoidance of doubt, although the above definitions of heteroaryl and heterocyclyl groups refer to the "N" atom that may be present in the ring, as will be apparent to the experienced chemist, the N atom will be protonated (or will carry a substituent as defined above) if attached to each of the neighboring atoms in the ring through a single bond. Such protonated forms are included within the present definition of heteroaryl and heterocyclyl groups.

In one embodiment of the benzimidazoles of formula (I), R ¹ is -(CH ₂ ) _m -R ⁴ where m is 2 or 3 and R ⁴ is -NH-(CH ₂ ) ₂ -(NH) _r - R ⁵ where r is 0 or 1 and R ⁵ is selected from

-SO ₂ Me, -SO ₂ Et and -SO ₂ CF ₃ .

In a further embodiment, R ¹ is -(CH ₂ ) _m -R ⁴ where m is 2 or 3 and R ⁴ is -NH-(CHR ⁵ R ⁶ ) where R ⁵ is -CONH ₂ or -CONMe ₂ and R ⁶ is C ₁ -C ₆ alkyl.

In another embodiment, R ¹ is -(CH ₂ ) _m -R ⁴ where m is 2 or 3 and R ⁴ is -(CH ₂ ) _m -R ⁴ ,

where m is 2 or 3 and R ⁴ is a group of formula (A), where p is 1, q is 0, V is CH and W is -(CH ₂ ) _r -S(O) ₂ -CH ₂ - or -(CH ₂ ) _r -NR ⁵ -CH ₂ -, where r is 0 and R ⁵ is Me or -SO ₂ Et.

In yet another embodiment, R ¹ is -(CH ₂ ) _m -R ⁴ where m is 2 or 3 and R ⁴ is (CH ₂ ) _m -R ⁴ where m is 2 or 3 and R ⁴ is is a group of formula (A) in which p is 0,

V is N, W is -(CH ₂ ) _m - where m is an integer from 1 to 3, q is 1 and R ⁵ is -SO ₂ Me, -SO ₂ Et, -CONH ₂ or - CONMe ₂ .

In another embodiment, R ¹ is -(CH ₂ ) _m -R ⁴ where m is 2 or 3 and R ⁴ is -(CH ₂ ) _m -R ⁴ where m is 2 or 3 and R ⁴ is a group of formula (A), where p is 0,

V is N, q is 0 and W is -CH ₂ -O-CH ₂ -, -CH ₂ -S-CH ₂ -, -(CH ₂ ) _r -S(O) ₂ -CH ₂ - or - (CH ₂ ) _r -NR ⁵ -CH ₂ - where r is 0 or 1 and R ⁵ is -SO ₂ Me, -SO ₂ Et or -COMe.

, где R⁵ представляет собой H, -SO₂Me, -SO₂Et, -COMe, -CONMe₂ или -CH₂CH₂SO₂Me.Alternatively, R ¹ is

where R ⁵ is H, -SO ₂ Me, -SO ₂ Et, -COMe, -CONMe ₂ or -CH ₂ CH ₂ SO ₂ Me.

When in formula (I) R ⁴ is a group of formula (A) and q is 1, the ring substituent R ⁷ may be attached to any available carbon atom in the ring.

When W in formula (A) is -(CH ₂ )r-NR ⁵ -CH ₂ -, q is usually 0.

Examples of the group of formula (A) include the following structures:

The R ² group in formula (I) is usually F, Cl or -CH ₂ NH ₂ .

Specific compounds according to the present description include the following:

1'-({5-chloro-1-[3-(4-methanesulfonylpiperazin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 ''-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-[(5-chloro-1-{2-[(2-methanesulfonylethyl)amino]ethyl}-1H-1,3-benzodiazol-2-yl)methyl]-6'-fluoro-1',2' -dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

N-[2-({2-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl }methyl)-1H-1,3-benzodiazol-1-yl]ethyl}amino)ethyl]1,1,1-trifluoromethanesulfonamide;

3-({2-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl) -1H-1,3-benzodiazol-1-yl]ethyl}amino)-1λ6-thiolane-1,1-dione;

1'-[(5-chloro-1-{2-[(1-methanesulfonylpyrrolidin-3-yl)amino]ethyl}-1H-1,3-benzodiazol-2-yl)methyl]-6'-fluoro-1 ',2'-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1-{2-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl)- 1H-1,3-benzodiazol-1-yl]ethyl}pyrrolidine-2-carboxamide;

1'-({5-chloro-1-[2-(3-methanesulfonylpyrrolidin-1-yl)ethyl]-1H-1,3-benzodiazol-2-yl}methyl)6'-fluoro-1',2' -dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-({5-chloro-1-[2-(4-methanesulfonylpiperidin-1-yl)ethyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-({5-chloro-1-[2-(4-methanesulfonylpiperazin-1-yl)ethyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-[(5-chloro-1-{3-[(2-methanesulfonylethyl)amino]propyl}-1H-1,3-benzodiazol-2-yl)methyl]-6'-fluoro-1',2' -dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-{[5-chloro-1-(3-{[2-(ethanesulfonyl)ethyl]amino}propyl)-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1' ,2'-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

(2S)-2-({3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-1'- yl}methyl)-1H-1,3-benzodiazol-1-yl]propyl}amino)-3-methylbutanamide;

1'-({5-chloro-1-[3-(3-methanesulfonylazetidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-({5-chloro-1-[3-(3-methanesulfonylpyrrolidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

(2S)-1-{3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl }methyl)-1H-1,3-benzodiazol-1-yl]propyl}pyrrolidine-2-carboxamide;

3-({3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl) -1H-1,3-benzodiazol-1-yl]propyl}amino)-1λ6-thiolane-1,1-dione;

1'-[(5-chloro-1-{3-[(1-methanesulfonylpyrrolidin-3-yl)amino]propyl}-1H-1,3-benzodiazol-2-yl)methyl]-6'-fluoro-1 ',2'-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-({5-chloro-1-[3-(morpholin-4-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2'- dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-({5-chloro-1-[3-(thiomorpholin-4-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2'- dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

4-{3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl)- 1H-1,3-benzodiazol-1-yl]propyl}-1λ6-thiomorpholine-1,1-dione;

1'-({5-chloro-1-[3-(4-methanesulfonylpiperidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-({1-[3-(4-acetylpiperazin-1-yl)propyl]-5-chloro-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

6'-fluoro-1'-[(5-fluoro-1-{3-[(2-methanesulfonylethyl)amino]propyl}-1H-1,3-benzodiazol-2-yl)methyl]-1',2' -dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

(2S)-2-({3-[5-fluoro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-1'- yl}methyl)-1H-1,3-benzodiazol-1-yl]propyl}amino)-3-methylbutanamide;

(2S)-1-{3-[5-fluoro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl }methyl)-1H-1,3-benzodiazol-1-yl]propyl}pyrrolidine-2-carboxamide;

6'-fluoro-1'-({5-fluoro-1-[3-(morpholin-4-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-1',2'- dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-({1-[3-(4-acetylpiperazin-1-yl)propyl]-5-fluoro-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

6'-fluoro-1'-({5-fluoro-1-[3-(4-methanesulfonylpiperazin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-{[5-chloro-1-(piperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1',2'-dihydrospiro[cyclopropan-1 ,3'-indole]-2'-he;

1'-{[5-chloro-1-(piperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1',2'-dihydrospiro[cyclobutan-1 ,3'-indole]-2'-he;

1'-{[1-(1-acetylpiperidin-4-yl)-5-chloro-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1',2'-dihydrospiro[cyclopropane -1,3'-indole]-2'-he;

4-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl)-1H-1 ,3-benzodiazol-1-yl]-N,N-dimethylpiperidine-1-carboxamide;

1'-{[5-chloro-1-(1-methanesulfonylpiperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1',2'-dihydrospiro[cyclopropane -1,3'-indole]-2'-he;

1'-{[5-chloro-1-(1-methanesulfonylpiperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1',2'-dihydrospiro[cyclobutane -1,3'-indole]-2'-he;

1'-({5-chloro-1-[1-(ethanesulfonyl)piperidin-4-yl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2'- dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

1'-({5-chloro-1-[1-(2-methanesulfonylethyl)piperidin-4-yl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one;

and pharmaceutically acceptable salts of said compounds.

The compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in various stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present invention. Compounds of formula (I) containing one or more chiral centers may be used in enantiomeric or diastereomeric pure form, or in the form of a mixture of isomers.

The present invention covers all geometric and positional isomers of the compounds of the present invention as defined above. For example, when a compound of the present invention contains a double bond or a fused ring, the cis and trans forms, as well as mixtures thereof, are included within the scope of the invention. Both individual positional isomers and a mixture of positional isomers are also within the scope of the present invention.

The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like, and the present invention covers both solvated and unsolvated forms.

The compounds of the present invention may exist in various tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible across a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include proton migration interconversions such as ketoenol tautomerizations. Valence tautomers involve interconversions by rearranging some of the bonding electrons.

Compounds of the present invention can be obtained by synthetic methods described in the following examples, or by analogy with such methods.

The benzimidazole of formula (I) may be converted to its pharmaceutically acceptable salt and the salt may be converted to the free compound by conventional means. For example, a benzimidazole of formula (I) may be contacted with a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt. A pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.

Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid, and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or p -toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (eg sodium or potassium) and alkaline earth metal (eg calcium or magnesium) hydroxides and organic bases such as alkylamines, aralkylamines and heterocyclic amines.

In biological tests, the compounds of the present invention were found to be respiratory syncytial virus (RSV) inhibitors. Therefore, the compounds are therapeutically useful. Accordingly, the present invention further relates to a compound which is a benzimidazole of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in a method of treating a human or animal body with therapy. The invention also relates to a compound of the present invention, as defined above, for use in a method for treating or preventing RSV infection. In addition, the present invention relates to the use of the compound of the present invention, as defined above, in the preparation of a medicament for the treatment or prevention of RSV infection. Thus, a subject suffering from or susceptible to RSV infection may be treated by a method comprising administering to him a compound of the present invention as defined above. Thus, the condition of the subject can be improved or alleviated.

RSV infection is usually an infection of the respiratory tract. RSV infection can be an infection in a child, for example, a child under ten years of age or a child under two years of age. In one embodiment, the present invention provides a compound as defined above for use in the treatment or prevention of RSV infection in pediatric patients. Alternatively, the infection may be an infection in an adult or elderly adult, for example, an adult over 60 years of age, an adult over 70 years of age, or an adult over 80 years of age. In addition, the present invention relates to a compound for use in the treatment or prevention of RSV infection in geriatric patients.

RSV infection can be an infection in an immunocompromised person or in a person suffering from COPD or CHF. In another embodiment of the present invention, the RSV infection is an infection in an immunocompromised human, eg, a human who is otherwise healthy.

The compound of the present invention can be administered in various dosage forms, for example, orally, for example, in the form of tablets, capsules, sugar-coated or film-coated tablets, liquid solutions or suspensions, or parenterally, for example, intramuscularly, intravenously or subcutaneously. Therefore, the compound can be administered by injection, infusion, or by inhalation or spraying with a nebulizer. The compound is preferably administered orally.

The dosage depends on many factors, including the age, weight and condition of the patient, as well as the route of administration. Daily doses may vary widely and will be adjusted to individual requirements in each case. Typically, the dosage adopted for each route of administration when the compound is administered alone to adult humans is 0.0001 to 650 mg/kg, most commonly in the range of 0.001 to 10 mg/kg body weight, e.g., 0.01 to 1 mg /kg. Such a dosage may be administered, for example, 1 to 5 times per day. For intravenous injection, a suitable daily dose is 0.0001 to 1 mg/kg body weight, preferably 0.0001 to 0.1 mg/kg body weight. The daily dose may be administered as a single dose or according to a divided dose schedule.

A unit dosage form, such as a tablet or capsule, typically contains 1-250 mg of the active ingredient. For example, a compound of formula (I) can be administered to a patient at a dose of 100-250 mg once a day, two or three times a day. For example, a compound of formula (I) can be administered to a patient at a dose of 100-250 mg once a day, two or three times a day.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used alone. Alternatively, they can be administered in the form of a pharmaceutical composition. Therefore, the present invention also relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, in combination with a pharmaceutically acceptable excipient, diluent or carrier. Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

Depending on the route of administration, the pharmaceutical composition will preferably contain from 0.05 to 99 wt. % (mass percent), more preferably from 0.05 to 80 wt. %, even more preferably from 0.10 to 70 wt. %, and even more preferably from 0.10 to 50 wt. % of the active ingredient, with all mass percentages given on the total composition.

The present invention further relates to a process for the preparation of a pharmaceutical composition according to the present invention, comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above with a pharmaceutically acceptable excipient, diluent or carrier.

The compounds of the present invention can be administered in various dosage forms. Thus, they can be administered orally, for example, in the form of tablets, molded lozenges, suckable lozenges, aqueous or oily suspensions, solutions, dispersible powders or granules. The compounds of the present invention can also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intradermally, transdermally, by infusion methods, or by inhalation or spraying with a nebulizer. The compounds may also be administered as suppositories.

Solid forms of a pharmaceutical composition for oral administration according to the present invention may contain, together with the active compound, diluents, for example lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example 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 generally non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical formulations can be prepared in a manner known per se, for example by mixing, granulating, tableting, sugar coating or film coating processes.

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

Suspensions and emulsions may contain as a carrier, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. The suspension or solutions for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier, eg sterile water, olive oil, ethyl oleate, glycols, eg propylene glycol, and, if required, a suitable amount of lidocaine hydrochloride. Other suitable suspension vehicles include sterile water, hydroxypropyl methylcellulose (HPMC), polysorbate 80, polyvinylpyrrolidone (PVP), AOT aerosol (i.e. sodium 1,2-bis(2-ethylhexoxycarbonyl)ethanesulfonate), Pluronic F127, and/or Captisol ( i.e. simple sulfobutyl ether-beta-cyclodextrin).

The compounds of the present invention may, for example, be prepared as aqueous suspensions in a carrier selected from:

(i) 0.5% w/v hydroxypropylmethylcellulose (HPMC)/0.1% w/v polysorbate 80;

(ii) 0.67% w/v polyvinylpyrrolidone (PVP)/0.33% w/v aerosol AOT (sodium 1,2-bis(2-ethylhexoxycarbonyl)ethanesulfonate);

(iii) 1% w/v pluronic F 127; and

(iv) 0.5% w/v polysorbate 80.

Carriers can be prepared by standard procedures known to those skilled in the art. For example, each of carriers (i) - (iv) can be prepared by weighing the required amount of excipient into a suitable vessel, adding about 80% of the final volume of water and stirring with a magnetic stirrer until a solution is formed. The carrier is then made up to volume with water. Aqueous suspensions of compounds of formula I can be prepared by weighing the required amount of the compound of formula I into a suitable vessel, adding 100% of the required volume of carrier and stirring with a magnetic stirrer.

Solutions for 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.

The compounds of the present invention may also be administered in combination with other compounds useful in the treatment of viral infections. Thus, the present invention relates to a combination therapy in which a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation containing a compound of the present invention, is administered simultaneously or sequentially or as a combination preparation with another therapeutic agent or agents. , to treat or prevent viral infection, especially RSV infection.

As used herein, the term "combination" should be understood to refer to simultaneous, separate or sequential administration. In one aspect of the present invention, "combination" refers to simultaneous administration. In one aspect of the present invention, "combination" refers to separate administration. In one aspect of the present invention, "combination" refers to sequential administration. Where administration is sequential or separate, the delay in administration of the second component should be such as not to lose the beneficial effect of the combination.

Suitable therapeutic agents for use in combination therapy include

(i) RSV nucleocapsid (N) protein inhibitors;

(ii) other RSV protein inhibitors, such as those that inhibit phosphoprotein (P) and large protein (L);

(iii) anti-RSV monoclonal antibodies such as anti-F protein antibodies;

(iv) immunomodulatory compounds that are toll-like receptors;

(v) other antiviral agents for the treatment of respiratory virus, such as anti-influenza and antirhinovirus compounds; and/or

(vi) anti-inflammatory compounds.

The nucleocapsid (N) protein of RSV plays a key role in viral transcription and replication by mediating the interaction between genomic RNA and the virus-encoded RNA-dependent RNA polymerase. P- and L-proteins are components of the virus-encoded RNA-dependent RNA polymerase RSV.

In a further aspect, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, in combination with one or more of the therapeutic agents listed in (i) to (vi) above, for use in the treatment of RSV.

The following examples illustrate the invention but do not limit it in any way.

Examples

The reagents were obtained from commercial sources and were used without further purification. All temperatures are in °C. Thin layer chromatography (TLC) was performed on aluminum-based silica gel plates with a fluorescence indicator at 254 nM (average pore size 60 Å). Flash column chromatography was performed using a Biotage Isolera One system using KP-Sil, Ultra or KP-NH columns. NMR spectra were recorded on a 400 MHz spectrometer at probe temperature equal to ambient temperature (nominal 295 K). Chemical shifts (δ) are given in ppm and calibrated using the residual solvent peak as an internal standard (CDCl ₃ , δ _H = 7.26 ppm, δ _C = 77.16 ppm; DMSO- d ₆ , δ _H = 2.50 ppm, _δC = 39.52 ppm). Coupling constants are given in hertz (Hz). MSNR was recorded using an Advion Plate Express expression ^L compact mass spectrometer equipped with an APCI or ESI ion source.

Abbreviations

DMF h,-dimethylformamide NN DMSO Dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol h watch) iPrOH Isopropanol m-CPBA meta-chloroperoxybenzoic acid MeCN Acetonitrile MeOH methanol MsCl Methansulfonyl chloride NET ₃ Triethylamine CT Room temperature TFK Trifluoroacetic acid THF Tetrahydrofuran

Preparatory examples

1A:4- chloro-N-(3,3-diethoxypropyl)-2-nitroaniline

To a solution of 4-chloro-1-fluoro-2-nitrobenzene (1.765 mL, 15 mmol) in iPrOH (35 mL) was added N,N-diisopropylethylamine (3.397 mL, 19.5 mmol) followed by 3,3-diethoxypropane- 1-amine (3.154 ml, 19.5 mmol) and heated at 80° C. for 4.5 hours. After cooling to room temperature, the above reaction mixture was diluted with EtOAc (100 ml) and washed successively with H ₂ O (acidified to ~ pH 6 with 0.01 M aqueous HCl, 4 times) and brine (once, 100 ml), dried (MgSO ₄ ) and the solvent was removed under reduced pressure to give the crude product as an orange solid (4.308 g, 97%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.29 (br s, 1H), 8.17 (d, J = 2.6 Hz, 1H), 7.37 (ddd, J = 9.2 , 2.6, 0.6 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 4.65 (t, J = 5.0 Hz, 1H), 3.76 - 3 .65 (m, 2H), 3.59 - 3.49 (m, 2H), 3.44 - 3.37 (m, 2H), 2.07 - 2.01 (m, 2H), 1.24 (t, J = 7.0 Hz, 6H). MSNR (ESI+) m/z 324.9 [M+H] ⁺

The following intermediates were prepared by the same general procedure.

Preparatory Example Name ¹ H NMR δ
(400 MHz, CDCl ₃ ) ISNR TLC _Rf value 1B N-(3,3-diethoxypropyl)-4-fluoro-2-nitroaniline - - 0.66
(EtOAc: petroleum ether 60/40; 1:4) 1C 4-chloro-N-(2,2-diethoxyethyl)-2-nitroaniline 8.19 - 8.11 (m, 2H), 7.38 (ddd, J = 9.2, 2.6, 0.7 Hz, 1H), 6.85 (d, J = 9.2 Hz, 1H), 4.74 (t, J = 5.6 Hz, 1H), 3.81 - 3.72 (m, 2H), 3.65 - 3.55 (m, 2H), 3.43 (t , J = 5.5 Hz, 2H), 1.25 (t, J = 7.0 Hz, 6H) ESI+
311.0 [M+Na] ⁺ - 1D tert-butyl 4-[(4-chloro-2-nitrophenyl)amino]piperidine-1-carboxylate 8.19 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.40 - 7.35 (m, 1H), 6.84 (d , J = 9.3 Hz, 1H), 4.09 - 3.95 (m, 2H), 3.69 - 3.60 (m, 1H), 3.09 - 2.98 (m, 2H), 2.09 - 2.00 (m, 2H), 1.57 - 1.50 (m, 2H), 1.47 (s, 9H) APCI-
353.9 [MH] ^- -

2A: 4-chloro-N ^{one -} (3,3-diethoxypropyl)benzene-1,2-diamine

In a pressurized 250 ml round bottom flask, 4-chloro-N-(3,3-diethoxypropyl)-2-nitroaniline (intermediate 1A) (4.050 g, 13.38 mmol) was dissolved in EtOH (100 ml) and platinum was added on a carbon carrier (load 5 wt.%, 393 mg). The reaction vessel was filled with hydrogen to a pressure of 50 pounds per square inch (~344.73 kPa) and stirred for 3 hours. The reaction mixture was filtered through a glass fiber filter, washed with EtOH and the solvent was removed under reduced pressure. Purification by flash chromatography [SiO ₂ ; CH ₂ Cl ₂ /(CH ₂ Cl ₂ :EtOH:NH ₄ OH 80:20:1); 0-25%] gave the title compound as a dark brown oil (3.440 g, 94%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.74 (dd, J = 8.4, 2.4 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6, 53 (d, J = 8.4 Hz, 1H), 4.65 (t, J = 5.4 Hz, 1H), 3.83 - 3.64 (m, 3H), 3.57 - 3.47 (m, 2H), 3.40 (br s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.02 - 1.96 (m, 2H), 1.23 ( t, J = 7.0 Hz, 6H). MSNR (ESI+) m/z 273.1 [M+H] ⁺

The following intermediates were prepared by the same general procedure.

Preparatory Example Name ¹ H NMR δ
(400 MHz, CDCl ₃ ) MSNR ESI+ TLC _Rf value 2B N ¹ - (3,3-diethoxypropyl) -4-fluorobenzene-1,2-diamine - 279.1 [M+Na] ⁺ 0.35 (EtOAc:heptane; 1:2) 2C 4-chloro-N ¹ - (2,2-diethoxyethyl) benzene-1,2-diamine 6.76 (dd, J = 8.3, 2.3 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H ), 4.75 (t, J = 5.4 Hz, 1H), 3.86 - 3.71 (m, 2H), 3.70 - 3.54 (m, 3H), 3.48 (s, 2H), 3.22 (d, J = 5.4 Hz, 2H), 1.27 (t, J = 7.0 Hz, 6H). - 0.41 (EtOAc:
heptane; 1:1) 2D tert-butyl 4-[(2-amino-4-chlorophenyl)amino]piperidine-1-carboxylate 6.75 - 6.69 (m, 2H), 6.57 (d, J = 8.3 Hz, 1H), 4.03 (br s, 2H), 3.54 - 3.26 (m, 3H), 3.00 - 2.86 (m, 2H), 2.04 - 1.96 (m, 2H), 1.42 (s, 9H), 1.42 - 1.30 (m, 2H) 326.3 [M+H]+ -

3A: 5-chloro-2-(chloromethyl)-1-(3,3-diethoxypropyl)-1H-1,3-benzodiazol

A solution of 4-chloro-N ¹ -(3,3-diethoxypropyl)benzene-1,2-diamine (intermediate 2A) (2.524 g, 9.27 mmol) and 2-chloro-1,1,1-triethoxyethane (2.499 ml) 18.54 mmol) in EtOH (90 ml) was heated at 75°C for 7.5 hours, then stirred at room temperature for 12 hours. Volatiles were removed under reduced pressure and the reaction mixture was purified by flash chromatography (SiO ₂ ; EtOAc/petroleum ether 60/80; 0-60%) to give the product as a brown solid (1.537 g, 50%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.74-7.72 (m, 1H), 7.34-7.26 (m, 2H), 4.87 (s, 2H), 4.48 (t, J = 5.0 Hz, 1H), 4.37 (t, J = 7.1 Hz, 2H), 3.68 - 3.58 (m, 2H), 3.49 - 3.39 ( m, 2H), 2.21 - 2.14 (m, 2H), 1.20 (t, J = 7.1 Hz, 6H). MSNR (APCI+) m/z 331.1 [M+H] ⁺

The following intermediates were prepared by the same general procedure.

Preparatory Example Name ¹ H NMR δ
(400 MHz, CDCl ₃ ) ISNR
AP-CI+ 3B 2-(chloromethyl)-1-(3,3-diethoxypropyl)-5-fluoro-1H-1,3-benzodiazol 7.42 (dd, J = 9.2, 2.4 Hz, 1H), 7.34 - 7.30 (m, 1H), 7.08 (td, J = 9.1, 2.4 Hz, 1H), 4.87 (s, 2H), 4.49 (t, J = 5.0 Hz, 1H), 4.37 (t, J = 7.2 Hz, 2H), 3.68 - 3, 59 (m, 2H), 3.49 - 3.40 (m, 2H), 2.21 - 2.25 (m, 2H), 1.20 (t, J = 7.1 Hz, 6H) 314.9 [M+H]+ 3C 5-chloro-2-(chloromethyl)-1-(2,2-diethoxyethyl)-1Н-
1,3-benzodiazol 7.72 (dd, J = 1.9, 0.6 Hz, 1H), 7.35 (dd, J = 8.7, 0.6 Hz, 1H), 7.28 (dd, J = 8, 6, 1.9 Hz, 1H), 4.93 (s, 2H), 4.71 (t, J = 5.2 Hz, 1H), 4.36 (d, J = 5.2 Hz, 2H) , 3.73 (dq, J = 9.2, 7.0 Hz, 2H), 3.41 (dq, J = 9.2, 7.0 Hz, 2H), 1.12 (t, J = 7 .0 Hz, 6H). 318.1 [M+H]+ 3D tert-butyl 4-[5-chloro-2-(chloromethyl)-1H-1,3-benzodiazol-1-yl]piperidine-1-carboxylate 7.73 (d, J = 1.9 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.24 (dd, J = 8.8, 2.0 Hz, 1H ), 4.85 (s, 2H), 4.52 - 4.27 (m, 3H), 2.98 - 2.81 (m, 2H), 2.46 - 2.31 (m, 2H), 2.03 - 1.93 (m, 2H), 1.52 (s, 9H) 383.9 [M+H]+

4A: 6' -fluoro-1 ' , 2'-dihydrospiro [cyclobutan- 1,3'-indole] -2' - one

A dry round bottom flask under N ₂ was charged with 6-fluoro-2-oxindole (3.00 g, 19.9 mmol), anhydrous THF (60 ml) and diisopropylamine (5.7 ml, 40.7 mmol). This mixture was cooled to 0° C. and n -butyllithium (29.4 mL, 79.4 mmol) was added dropwise over 45 minutes. The mixture was stirred for 2 hours at 0° C., then 1,3-dibromopropane (4.03 mL, 39.7 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 1 hour and stirred for 20 hours at room temperature. The reaction was quenched with HCl (1 M aq.) and extracted with EtOAc (3×30 ml). The combined organic extracts were washed with water and brine (30 ml each), dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash chromatography (0-25% EtOAc:heptane) gave the product as an orange solid (1.101 g, 29%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.40 (dd, J = 8.2, 5.3 Hz, 1H), 6.75 (ddd, J = 9, 6, 8.2, 2.3 Hz, 1H), 6.61 (dd, J = 8.8, 2.3 Hz, 1H), 2.78-2.58 (m, 2H), 2.46 -2.30 (m, 3H), 2.29-2.04 (m, 1H). MSNR (APCI+) m/z 191.9 [M+H] ⁺

5A: 1'-{[5-chloro-1-(3,3-diethoxypropyl)-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1',2'-dihydrospiro[cyclopropane -1,3'-indole]-2'-he

Alkyl chloride solution (Intermediate 3A) (938 mg, 2.83 mmol), 6'-fluoro-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-2'-one (502 mg, 2.83 mmol) 83 mmol) and K ₂ CO ₃ (959 mg, 6.94 mmol) in anhydrous MeCN (18 ml) were heated in an inert atmosphere at a temperature of 75°C for 18 hours. After cooling to room temperature, the above reaction mixture was diluted with EtOAc (50 ml) and washed with H ₂ O (2×15 ml). The aqueous layers were extracted with EtOAc (2×25 ml) and the combined organic extracts were washed successively with H ₂ O and brine (50 ml each), dried (MgSO ₄ ) and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO ₂ , EtOAc/petroleum ether 60/80; 8-68%) gave the product as an off-white solid (1.079 g, 81%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.77-7.75 (m, 1H), 7.31-7.21 (m, 3H), 6.75-6.65 (m 2H), 5.28 (s, 2H), 4.45 (t, J = 5.4 Hz, 1H), 4.35 (t, J = 7.3 Hz, 2H), 3.62 - 3.52 (m , 2H), 3.45 - 3.35 (m, 2H), 1.97 - 1.89 (m, 2H), 1.78 (q, J = 4.0 Hz, 2H), 1.54 ( q, J = 4.1 Hz, 1H), 1.16 (t, J = 7.1 Hz, 6H). MSNR (APCI+) m/z 471.9 [M+H] ⁺

The following compounds were obtained by the same General method.

Preparatory
example Name ¹ H NMR δ
(400 MHz, CDCl ₃ ) ISNR
AP-CI+ 5B 1'-{[1-(3,3-diethoxypropyl)-5-fluoro-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1',2'-dihydrospiro[cyclopropan-1 ,3'-indole]-2'-he 7.45 (dd, J = 9.3, 2.4 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.04 (td, J = 9.1, 2.4 Hz, 1H), 6.75 - 6.65 (m, 2H), 5.28 (s, 2H), 4.46 (t, J = 5.5 Hz, 1H), 4.36 (t, J = 7 .3 Hz, 2H), 3.62 - 3.55 (m, 2H), 3.46 - 3.36 (m, 2H), 1.97 - 1.90 (m, 2H), 1.78 ( q, J = 4.1 Hz, 2H), 1.53 (q, J = 4.2 Hz, 2H), 1.16 (t, J = 7.1 Hz, 6H) 455.9 [M+H]+ 5C 1'-{[5-chloro-1-(2,2-diethoxyethyl)-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1',2'-dihydrospiro[cyclopropan-1 ,3'-indole]-2'-he 7.75 (dd, J = 2.0, 0.5 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.29 - 7.21 (m, 2H), 6.76 - 6.65 (m, 2H), 5.30 (s, 2H), 4.61 (t, J = 5.2 Hz, 1H), 4.43 (d, J = 5.2 Hz, 2H), 3.62 (dq, J = 9.3, 7.0 Hz, 2H), 3.35 (dq, J = 9.3, 7.0 Hz, 2H), 1.77 (q, J = 4, 1 Hz, 2H), 1.53 (q, J = 4.1 Hz, 2H), 1.03 (t, J = 7.0 Hz, 6H). 458.1 [M+H]+ 5D tert-butyl 4-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl)- 1H-1,3-benzodiazol-1-yl]piperidine-1-carboxylate 7.79 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.28 - 7.13 (m, 1H), 7.19 (dd , J = 8.7, 2.0 Hz, 1H), 6.74 - 6.65 (m, 2H), 5.30 (s, 2H), 4.85 - 4.75 (m, 1H), 4.35 - 4.26 (m, 2H), 2.94 - 2.76 (m, 2H), 2.33 - 2.20 (m, 2H), 1.77 - 1.73 (m, 2H ), 1.57 - 1.53 (m, 2H), 1.49 (s, 9H) 524.8 [M+H]+ 5E tert-butyl 4-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclobutan-1,3'-indole]-1'-yl}methyl)- 1H-1,3-benzodiazol-1-yl]piperidine-1-carboxylate 7.83 (dd, J = 11.2, 2.0 Hz, 1H), 7.52-7.36 (m, 3H), 7.30-7.27 (m, 1H), 6.77 ( ddd, J = 9.3, 8.2, 2.3 Hz, 1H), 5.37 (s, 2H), 5.05-4.87 (m, 1H), 4.35-4.25 ( m, 2H), 3.03-2.88 (m, 2H), 2.68-2.59 (m, 2H), 2.43-2.23 (m, 6H), 1.70 - 1, 61 (m, 2H), 1.50 (s, 9H). 539.8 [M+H]+

6A: 3-[5-chloro-2-({ 6'-fluoro- 2'-oxo-1 ' , 2'-dihydrospiro [cyclopropan- 1,3'-indole] -1'yl }methyl)-1H- 1,3-benzodiazol-1-yl]propanal

HCl (2 M aqueous solution, 10 ml) was added to a solution of intermediate compound 5A (1.079 g, 2.29 mmol) in THF (15 ml) and stirred at room temperature for 16 hours. The reaction was quenched with saturated aq. NaHCO ₃ (~25 ml) and extracted with EtOAc (4×50 ml). The combined organic extracts were washed successively with H ₂ O and brine (75 ml each), dried (MgSO ₄ ) and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO ₂ , 10-100% EtOAc in heptane) gave the product as an off-white solid (766 mg, 84%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.69 (s, 1H), 7.67-7.55 (m, 2H), 7.30-7.26 (m, 1H), 7.10 - 7.04 (m, 2H), 6.85 - 6.79 (m, 1H), 5.37 (s, 2H), 4.59 (t, J = 6.9 Hz, 2H), 3, 04 (t, J = 6.8 Hz, 2H), 1.72 - 1.69 (m, 2H), 1.60 - 1.54 (m, 2H). MSNR (APCI+) m/z 397.8 [M+H] ⁺

The next intermediate was prepared using the same general procedure.

Preparatory
example Name ¹ H NMR (400 MHz) MSNR AP-CI+ 6B 3-[5-fluoro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl)-1Н-1 ,3-benzodiazol-1-yl]propanol (DMSO-d ₆ ): δ 9.70 (s, 1H), 7.67-7.60 (m, 1H), 7.41 (dd, J = 9.8, 2.4 Hz, 1H), 7.14 - 7.04 (m, 3H), 6.85 - 6.78 (m, 1H), 5.36 (s, 2H), 4.59 (t, J = 6.9 Hz, 2H) , 3.04 (t, J = 6.9 Hz, 2H), 1.71 - 1.67 (m, 2H), 1.59 - 1.54 (m, 2H) 382.0 [M+H]+

7A: 2-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl)-1H -1,3-benzodiazol-1-yl]acetaldehyde

HCl (6 M aqueous solution; 10 ml) was added to a solution of intermediate 5C in anhydrous THF (11 ml) and heated at 60°C for 5.5 hours and then at 40°C for another 16 hours. The reaction was quenched with saturated aqueous NaHCO ₃ (25 ml) and extracted with EtOAc (4×50 ml). The combined organic extracts were washed with water and brine (25 ml each), dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash chromatography (30-70% EtOAc:heptane) gave an orange solid (430 mg, 64%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.58 (s, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.39-7.31 (m, 1H), 7 .30 - 7.25 (m, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.73 (dd, J = 7.7, 1.6 Hz, 2H), 5, 20 (s, 2H), 3.61 (t, J = 6.5 Hz, 2H), 1.77 - 1.71 ( m, 2H), 1.59 - 1.53 (m, 2H). MSNR (APCI+) m/z 384.9 [M+H] ⁺

Examples

Reductive amination

1. 1'-({5-chloro-1-[3-(4-methanesulfonylpiperazin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1' ,2'-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

For reductive amination, the following general procedure was used. 1-methanesulfonylpiperazine (27 mg, 0.166 mmol) was added to a solution of intermediate 6A (60 mg, 0.151 mmol) in 1,2-dichloroethane (2.5 ml) and stirred at room temperature for 7 hours. Then NaBH(OAc) ₃ (45 mg, 0.211 mmol) was added and the reaction mixture was stirred for 18 hours at room temperature. The reaction was quenched with NaOH (1 M aqueous solution, 4 ml), extracted with CH ₂ Cl ₂ (4×10 ml), the combined organic extracts were washed with brine (5 ml), dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO ₂ , 100% EtOAc, then 0-5% MeOH in CH ₂ Cl ₂ ) gave the product as a white solid (64 mg, 78%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.69 (d, J = 1.9 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.28 ( dd, J = 8.6, 2.0 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.86 - 6.79 (m, 1H), 5.34 (s, 2H) , 4.35 (t, J = 6.7 Hz, 2H), 3.09 - 3.02 (m, 4H), 2.85 (s, 3H), 2.40 - 2.33 (m, 4H ), 2.27 (t, J = 6.6 Hz, 1H), 1.90 (p, J = 6.4 Hz, 1H), 1.72 - 1.67 (m, 2H), 1.60 - 1.55 (m, 2H). MSNR (APCI+) m/z 545.7 [M+H] ⁺

The following compounds of the present invention were made with Intermediate 7A following the general reductive amination procedure described for the compound of Example 1.

Table 1 . 5-Chloroaminoethyl analogs obtained by reductive amination

Example Name ^{R1 1} H NMR δ
(400 MHz, CDCl ₃ ) MSNR AP-CI+ 2 1'-[(5-chloro-1-{2-[(2-methanesulfonylethyl)amino]ethyl}-1H-1,3-benzodiazol-2-yl)methyl]-6'-fluoro-1',2' -dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.78 (t, J = 1.2 Hz, 1H), 7.31 (dd, J = 9.0, 2.0 Hz, 1H), 7.26 - 7.23 (m, 2H), 6 .77 - 6.68 (m, 2H), 5.31 (s, 2H), 4.35 (t, J = 6.2 Hz, 2H), 3.08 - 2.96 (m, 4H), 2.93 (t, J = 6.2 Hz, 2H), 2.81 (s, 3H), 1.77 (q, J = 4.0 Hz, 2H), 1.55 (q, J = 4 .0 Hz, 2H). 491.1 [M+H]+ 3 N-[2-({2-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl }methyl)-1H-1,3-benzodiazol-1-yl]ethyl}amino)ethyl]1,1,1-trifluoromethanesulfonamide

7.79 (dd, J = 1.8, 0.7 Hz, 1H), 7.31 - 7.23 (m, 3H), 6.83 - 6.67 (m, 3H), 5.43 ( s, 2H), 4.35 (t, J = 6.1 Hz, 2H), 3.38 - 3.29 (m, 2H), 3.02 (q, J = 5.8 Hz, 2H), 2.91 - 2.77 (m, 2H), 1.81 (q, J = 4.2 Hz, 2H), 1.61 (q, J = 4.2 Hz, 2H). 560.1 [M+H]+ four 3-({2-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl) -1H-1,3-benzodiazol-1-yl]ethyl}amino)-1λ ⁶ -thiolane-1,1-dione

7.80 (q, J = 1.6 Hz, 1H), 7.41 - 7.24 (m, 3H), 6.86 - 6.63 (m, 3H), 5.42 - 5.29 ( m, 2H), 4.37 (t, J = 6.0 Hz, 2H), 3.46 (dt, J = 11.6, 6.5 Hz, 1H), 3.15 (td, J = 13 .7, 7.1 Hz, 2H), 3.09 - 2.87 (m, 4H), 2.72 (dd, J = 13.3, 6.2 Hz, 1H), 2.33 - 2, 16 (m, 1H), 2.02 - 1.79 (m, 2H), 1.58 (dq, J = 8.4, 4.2 Hz, 3H). 503.7 [M+H]+ 5 1'-[(5-chloro-1-{2-[(1-methanesulfonylpyrrolidin-3-yl)amino]ethyl}-1H-1,3-benzodiazol-2-yl)methyl]-6'-fluoro-1 ',2'-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.78 (t, J = 1.2 Hz, 1H), 7.31 (dd, J = 9.0, 2.2 Hz, 1H), 7.26 (d, J = 1.4 Hz, 2H ), 6.78 - 6.65 (m, 2H), 5.35 - 5.27 (m, 2H), 4.34 (t, J = 6.0 Hz, 2H), 3.42 - 3, 18 (m, 4H), 2.89 (dt, J = 7.8, 2.7 Hz, 3H), 2.66 (s, 3H), 2.00 (d, J = 7.2 Hz, 1H ), 1.77 (q, J = 4.0 Hz, 2H), 1.65 - 1.50 (m, 4H) 532.8 [M+H]+ 6 1-{2-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl)- 1Н-1,3-benzodiazol-1-yl]ethyl}pyrrolidine-2-carboxamide

7.78 (dd, J = 1.8, 0.6 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.29 - 7.17 (m, 2H), 6.79 - 6.69 (m, 2H), 6.62 (s, 1H), 5.41 - 5.16 (m, 2H), 4.94 (s, 1H), 4.52 - 4.32 (m, 2H), 3.24 (t, J = 7.9 Hz, 1H), 3.11 - 2.90 (m, 2H), 2.75 (dt, J = 12.4, 5.8 Hz, 1H ), 2.41 - 2.25 (m, 1H), 2.27 - 2.11 (m, 1H), 1.91 - 1.74 (m, 4H), 1.65 - 1.48 (m , 3H). 481.8 [M+H]+ 7 1'-({5-chloro-1-[2-(3-methanesulfonylpyrrolidin-1-yl)ethyl]-1H-1,3-benzodiazol-2-yl}methyl)6'-fluoro-1',2' -dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.78 (t, J = 1.2 Hz, 1H), 7.33 (dd, J = 9.1, 2.1 Hz, 1H), 7.25 (dd, J = 3.2, 1, 6 Hz, 2H), 6.77 - 6.57 (m, 2H), 5.35 - 5.15 (m, 2H), 4.43 - 4.34 (m, 2H), 3.54 - 3 .40 (m, 1H), 3.01 (dd, J = 10.5, 5.5 Hz, 1H), 2.95 - 2.86 (m, 1H), 2.85 - 2.73 (m , 3H), 2.79 (m, 3H), 2.65 (q, J = 8.3, 7.6 Hz, 1H), 2.31 - 2.09 (m, 2H), 1.78 ( q, J = 3.6 Hz, 2H), 1.55 (q, J = 3.6 Hz, 2H) 516.7 [M+H]+ eight 1'-({5-chloro-1-[2-(4-methanesulfonylpiperidin-1-yl)ethyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.81 (dd, J = 1.6, 0.9 Hz, 1H), 7.38 (dd, J = 9.0, 2.1 Hz, 1H), 7.32 - 7.15 (m, 2H), 6.84 - 6.68 (m, 2H), 5.32 (s, 2H), 4.40 (t, J = 6.1 Hz, 2H), 3.06 (d, J = 11 .7 Hz, 2H), 2.84 (s, 3H), 2.84 - 2.79 (m, 1H), 2.64 (t, J = 6.1 Hz, 2H), 2.17 - 2 .08 (m, 4H), 1.93 - 1.77 (m, 4H), 1.55 (q, J = 4.0 Hz, 2H) 531.8 [M+H]+ 9 1'-({5-chloro-1-[2-(4-methanesulfonylpiperazin-1-yl)ethyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.78 (dd, J = 1.7, 0.6 Hz, 1H), 7.33 (dd, J = 8.9, 2.1 Hz, 1H), 7.28 - 7.20 (m, 2H), 6.76 - 6.68 (m, 2H), 5.30 (s, 2H), 4.38 (t, J = 6.2 Hz, 2H), 3.23 - 3.15 (m , 4H), 2.76 (s, 3H), 2.66 (t, J = 6.2 Hz, 2H), 2.62 - 2.56 (m, 4H), 1.77 (q, J = 4.1 Hz, 2H), 1.56 - 1.50 (m, 2H). 532.1 [M+H]+

The following compounds were prepared with Intermediate 6A following the general procedure described above for Example 1.

Table 2 . Examples of 5-chloroaminopropyl obtained by reductive amination

Example Name ^{R1 1} H NMR δ
(400 MHz, DMSO-d ₆ ) ISNR
AP-CI+ ten 1'-[(5-chloro-1-{3-[(2-methanesulfonylethyl)amino]propyl}-1H-1,3-benzodiazol-2-yl)methyl]-6'-fluoro-1',2' -dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.68 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.27 (dd, J = 8.6, 2.0 Hz, 1H ), 7.11 - 7.05 (m, 2H), 6.86 - 6.79 (m, 1H), 5.32 (s, 2H), 4.36 (t, J = 7.1 Hz, 2H), 3.22 (t, J = 6.6 Hz, 2H), 3.00 (s, 3H), 2.89 (t, J = 6.5 Hz, 2H), 2.00 (br, s, 1H), 1.82 (p, J = 6.9 Hz, 2H), 1.72 - 1.67 (m, 5H), 1.60 - 1.55 (m, 2H) 504.8
[M+H] ⁺ eleven 1'-{[5-chloro-1-(3-{[2-(ethanesulfonyl)ethyl]amino}propyl)-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1' ,2'-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.68 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.27 (dd, J = 8.6, 2.0 Hz, 1H ), 7.11 - 7.05 (m, 2H), 6.87 - 6.79 (m, 1H), 5.32 (s, 2H), 4.39 - 4.33 (m, 2H), 3.20 - 3.08 (m, 4H), 2.88 (t, J = 6.7 Hz, 2H), 2.08 (br, s, 1H), 1.81 (p, J = 6, 7 Hz, 2H) 1.72 - 1.67 (m, 2H), 1.59 - 1.55 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). 519.1
[M+H] ⁺ 12 (2S)-2-({3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-1'- yl}methyl)-1H-1,3-benzodiazol-1-yl]propyl}amino)-3-methylbutanamide

7.68 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.34 - 7.30 (m, 1H), 7.26 (dd , J = 8.6, 2.0 Hz, 1H), 7.11 - 7.04 (m, 2H), 6.99 (d, J = 1.9 Hz, 1H), 6.86 - 6, 77 (m, 1H), 5.38 - 5.28 (m, 2H), 4.41 - 4.35 (m, 2H), 2.65 - 2.58 (m, 1H), 2.34 - 2.25 (m, 1H), 1.88 - 1.67 (m, 6H), 1.60 - 1.55 (m, 2H), 0.93 - 0.86 (m, 6H) 497.7 [M+H]+ 13 1'-({5-chloro-1-[3-(3-methanesulfonylazetidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.67 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.27 (dd, J = 8.6, 2.0 Hz, 1H ), 7.11 - 7.05 (m, 2H), 6.86 - 6.79 (m, 1H), 5.34 (s, 2H), 4.32 (t, J = 6.9 Hz, 2H), 4.11 (p, J = 7.1 Hz, 1H), 3.47 (t, J = 8.1 Hz, 2H), 3.33 - 3.28 (m, 2H), 2, 95 (s, 3H), 2.36 - 2.31 (m, 2H), 1.75 - 1.67 (m, 4H), 1.57 - 1.53 (m, 2H) 516.8 [M+H]+ fourteen 1'-({5-chloro-1-[3-(3-methanesulfonylpyrrolidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.68 (d, J = 1.9 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.26 (dd, J = 8.6, 2.0 Hz, 1H ), 7.12 - 7.05 (m, 2H), 6.85 - 6.79 (m, 1H), 5.37 - 5.28 (m, 2H), 4.38 - 4.32 (m , 2H), 3.82 - 3.74 (m, 1H), 2.93 (s, 3H), 2.84 - 2.74 (m, 2H), 2.35 - 2.30 (m, 2H ), 2.12 - 2.05 (m, 2H), 1.93 - 1.85 (m, 2H), 1.71 - 1.67 (m, 2H), 1.60 - 1.55 (m , 2H) 530.8 [M+H]+ fifteen (2S)-1-{3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl }methyl)-1H-1,3-benzodiazol-1-yl]propyl}pyrrolidine-2-carboxamide

7.69 (d, J = 1.9 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.71 - 7.61 (m, 2H), 7.30 - 7 .22 (m, 2H), 7.13 - 7.03 (m, 3H), 6.86 - 6.78 (m, 1H), 5.37 - 5.26 (m, 2H), 4.51 - 4.41 (m, 1H), 4.35 - 4.25 (m, 1H), 3.12 - 3.05 (m, 1H), 2.83 - 2.77 (m, 1H), 2 .64 - 2.55 (m, 1H), 2.41 - 2.32 (m, 1H), 2.23 - 2.15 (m, 1H), 2.05 - 1.96 (m, 1H) , 1.89 - 1.78 (m, 2H), 1.76 - 1.63 (m, 5H), 1.61 - 1.54 (m, 2H) 495.9 [M+H]+ 16 3-({3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl) -1H-1,3-benzodiazol-1-yl]propyl}amino)-1λ ⁶ -thiolane-1,1-dione

7.68 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.28 (dd, J = 8.6, 2.0 Hz, 1H ), 7.12 - 7.05 (m, 2H), 6.86 - 6.79 (m, 1H), 5.32 (s, 2H), 4.36 (t, J = 7.3 Hz, 2H), 3.27 - 3.18 (m, 1H), 3.07 - 2.98 (m, 1H), 2.80 (dd, J = 12.9, 6.6 Hz, 1H), 2 .31 - 2.21 (m, 2H), 1.96 - 1.77 (m, 3H), 1.72 - 1.67 (m, 2H), 1.60 - 1.55 (m, 2H) 517.2
[M+H] ⁺ 17 1'-[(5-chloro-1-{3-[(1-methanesulfonylpyrrolidin-3-yl)amino]propyl}-1H-1,3-benzodiazol-2-yl)methyl]-6'-fluoro-1 ',2'-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.69 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.28 (dd, J = 8.6, 2.0 Hz, 1H ), 7.11 - 7.05 (m, 2H), 6.86 - 6.79 (m, 1H), 5.32 (s, 2H), 4.37 (t, J = 7.3 Hz, 2H), 3.23 - 3.16 (m, 1H), 2.97 (dd, J = 10.2, 4.6 Hz, 1H), 2.86 (s, 3H), 2.00 - 1 .90 (m, 2H), 1.86 - 1.77 (m, 2H), 1.73 - 1.61 (m, 3H), 1.60 - 1.55 (m, 2H) 546.3 [M+H]+ eighteen 1'-({5-chloro-1-[3-(morpholin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2'- dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.68 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.27 (dd, J = 8.6, 2.0 Hz, 1H ), 7.13 - 7.04 (m, 2H), 6.85 - 6.78 (m, 1H), 5.36 (s, 2H), 4.36 (t, J = 6.8 Hz, 2H), 3.57 - 3.50 (m, 4H), 2.29 - 2.22 (m, 4H), 2.19 (t, J = 6.6 Hz, 2H), 1.94 - 1 .84 (m, 2H), 1.71 - 1.66 (m, 2H), 1.59 - 1.55 (m, 2H) 468.9 [M+H]+ 19 1'-({5-chloro-1-[3-(thiomorpholin-4-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2'- dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.69 (d, J = 1.9 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.27 (dd, J = 8.6, 2.0 Hz, 1H ), 7.13 - 7.05 (m, 3H), 6.85 - 6.79 (m, 1H), 5.34 (s, 2H), 4.34 (t, J = 6.8 Hz, 2H), 2.58 - 2.52 (m, 8H), 2.23 (t, J = 6.6 Hz, 2H), 1.88 (p, J = 6.7 Hz, 2H), 1, 72 - 1.67 (m, 2H), 1.60 - 1.55 (m, 2H) 484.8 [M+H]+ twenty 1'-({5-chloro-1-[3-(4-methanesulfonylpiperidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.69 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.27 (dd, J = 8.7, 2.0 Hz, 1H ), 7.13 - 7.05 (m, 2H), 6.85 - 6.80 (m, 1H), 5.34 (s, 2H), 4.35 (t, J = 6.9 Hz, 2H), 3.05 - 2.96 (m, 1H), 2.94 - 2.87 (m, 5H), 2.21 (t, J = 6.6 Hz, 2H), 1.97 - 1 .79 (m, 6H), 1.72 - 1.67 (m, 2H), 1.65 - 1.53 (m, 4H) 544.8 [M+H]+ 21 1'-({1-[3-(4-acetylpiperazin-1-yl)propyl]-5-chloro-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.69 (d, J = 1.9 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.27 (dd, J = 8.6, 2.0 Hz, 1H ), 7.13 - 7.05 (m, 3H), 6.86 - 6.79 (m, 1H), 5.36 (s, 2H), 4.37 (t, J = 6.7 Hz, 2H), 3.41 - 3.35 (m, 4H), 2.29 - 2.19 (m, 6H), 1.96 (s, 3H), 1.94 - 1.86 (m, 2H) , 1.72 - 1.66 (m, 2H), 1.60 - 1.55 (m, 2H) 509.9 [M+H]+

The following compounds were made with Intermediate 6B following the general reductive amination procedure described in Example 1.

Table 3 . 5-fluoroaminopropyl analogs obtained by reductive amination

Example Name ^{R1 1} H NMR δ
(400 MHz, DMSO-d ₆ ) MSNR AP-CI+ 22 6'-fluoro-1'-[(5-fluoro-1-{3-[(2-methanesulfonylethyl)amino]propyl}-1H-1,3-
benzodiazol-2-yl)methyl]-1',2'-dihydrospiro[cyclopropan-1,3'-indol]-2'-one

7.60 (dd, J = 8.9, 4.8 Hz, 1H), 7.43 (dd, J = 9.8, 2.4 Hz, 1H), 7.15 - 7.04 (m, 3H), 6.86 - 6.79 (m, 1H), 5.31 (s, 2H), 4.36 (t, J = 7.2 Hz, 2H), 3.22 (t, J = 6 .7 Hz, 2H), 3.01 (s, 3H), 2.89 (t, J = 6.7 Hz, 2H), 2.08 - 1.98 (m, 1H), 2.02 (br s, 1H), 1.82 (p, J = 6.9 Hz, 2H), 1.72 - 1.67 (m, 5H), 1.60 - 1.55 (m, 2H) 488.8 [M+H]+ 23 (2S)-2-({3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-1'- yl}methyl)-1H-1,3-benzodiazol-1-yl]propyl}amino)-3-methylbutanamide

7.60 (dd, J = 8.9, 4.8 Hz, 1H), 7.42 (dd, J = 9.8, 2.4 Hz, 1H), 7.32 (d, J = 2, 2 Hz, 1H), 7.14 - 7.04 (m, 3H), 6.99 (d, J = 2.0 Hz, 1H), 6.85 - 6.79 (m, 1H), 5, 37 - 5.26 (m, 2H), 4.42 - 4.33 (m, 2H), 2.66 - 2.59 (m, 1H), 2.34 - 2.26 (m, 1H), 1.91 - 1.66 (m, 6H), 1.60 - 1.55 (m, 2H), 0.93 - 0.86 (m, 6H) 481.9 [M+H]+ 24 (2S)-1-{3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl }methyl)-1H-1,3-benzodiazol-1-yl]propyl}pyrrolidine-2-carboxamide

7.62 (dd, J = 8.9, 4.7 Hz, 1H), 7.43 (dd, J = 9.8, 2.4 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.15 - 7.02 (m, 4H), 6.86 - 6.78 (m, 1H), 5.35 - 5.21 (m, 2H), 4.50 - 4.40 ( m, 1H), 4.34 - 4.24 (m, 1H), 3.12 - 3.05 (m, 1H), 2.83 - 2.78 (m, 1H), 2.64 - 2, 55 (m, 1H), 2.41 - 2.35 (m, 1H), 2.19 (q, J = 8.2 Hz, 1H), 2.05 - 1.96 (m, 1H), 1 .89 - 1.77 (m, 2H), 1.74 - 1.67 (m, 5H), 1.61 - 1.55 (m, 2H) 479.8 [M+H]+ 25 6'-fluoro-1'-({5-fluoro-1-[3-(morpholin-4-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-1',2'- dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.63 - 7.55 (m, 1H), 7.46 - 7.40 (m, 1H), 7.15 - 7.04 (m, 3H), 6.86 - 6.77 (m, 1H ), 5.33 (s, 2H), 4.36 (t, J = 6.8 Hz, 2H), 3.57 - 3.37 (m, 4H), 2.34 - 2.15 (m, 6H), 1.93 - 1.83 (m, 2H), 1.71 - 1.66 (m, 2H), 1.59 - 1.55 (m, 2H) 453.3 [M+H]+ 26 1'-({1-[3-(4-acetylpiperazin-1-yl)propyl]-5-fluoro-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.61 (dd, J = 8.9, 4.7 Hz, 1H), 7.43 (dd, J = 9.8, 2.4 Hz, 1H), 7.15 - 7.05 (m, 3H), 6.86 - 6.79 (m, 1H), 5.35 (s, 2H), 4.37 (t, J = 6.8 Hz, 2H), 3.42 - 3.39 (m , 4H), 2.30 - 2.18 (m, 6H), 1.96 (s, 3H), 1.94 - 1.86 (m, 2H), 1.72 - 1.67 (m, 2H ), 1.60 - 1.55 (m, 2H) 493.9 [M+H]+ 27 6'-fluoro-1'-({5-fluoro-1-[3-(4-methanesulfonylpiperazin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one

7.61 (dd, J = 8.9, 4.7 Hz, 1H), 7.43 (dd, J = 9.8, 2.4 Hz, 1H), 7.16 - 7.05 (m, 3H), 6.86 - 6.79 (m, 1H), 5.33 (s, 2H), 4.35 (t, J = 6.9 Hz, 2H), 3.09 - 3.04 (m , 4H), 2.85 (s, 3H), 2.41 - 2.35 (m, 4H), 2.30 - 2.25 (m, 2H), 1.90 (p, J = 6.7 Hz, 1H), 1.72 - 1.66 (m, 2H), 1.60 - 1.55 (m, 2H) 530.0 [M+H]+

28: 4-{3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl )-1H-1,3-benzodiazol-1-yl]propyl}-1λ6-thiomorpholine-1,1-dione

m -CPBA (purity ~ 77%, 155 mg, 0.691 mmol) was added to a chilled (0°C) solution of compound 19 (112 mg, 0.231 mmol) in CH ₂ Cl ₂ (5 ml) and stirred at room temperature for 5 ,5 o'clock. The reaction mixture was diluted with CH ₂ Cl ₂ (10 ml) and washed with saturated aqueous NaHCO ₃ (3×15 ml). The combined aqueous washes were extracted with CH ₂ Cl ₂ (2×10 ml). The combined organic extracts were washed with saturated aqueous NaHCO ₃ (3×15 ml), dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure. Purification by flash chromatography (SiO ₂ , 0-20% MeOH in CH ₂ Cl ₂ with 1% NH ₄ OH) gave a white solid (43 mg, 36%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.71-7.69 (m, 2H), 7.28 (dd, J = 8.6, 2.1 Hz, 1H), 7.13 (dd, J = 9.6, 2.4 Hz, 1H), 7.08 (dd, J = 8.2, 5.4 Hz, 1H), 6.85 - 6.79 (m, 1H), 5.37 (s, 2H), 4.54 (t, J = 7.3 Hz, 2H), 3.96 - 3.86 (m, 2H), 3.83 - 3.74 (m, 2H) , 3.41 - 3.35 (m, 4H), 3.23 - 3.15 (m, 2H). 2.25 (p, J = 7.0 Hz, 2H), 1.72 - 1.67 (m, 2H), 1.60 - 1.55 (m, 2H). MSNR (APCI+) m/z 534.2 [M+NH ₄ ] ⁺

29: 1 ' -{[5-chloro-1-(piperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl} -6'-fluoro-1 ' , 2'-dihydrospiro [cyclopropane -1,3' - indole]-2' -one

A solution of intermediate 5D (725 mg, 1.38 mmol) in trifluoroacetic acid (TFA; 2.59 ml) and CH ₂ Cl ₂ (8 ml) was stirred at room temperature for 5 hours. The volatiles were removed under reduced pressure, the residue was partitioned between saturated aqueous NaHCO ₃ (20 ml) and CH ₂ Cl ₂ (20 ml) and separated. The aqueous layer was extracted with CH ₂ Cl ₂ (3×20 ml), the combined organic extracts were washed with brine (10 ml), dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure. Purification by flash chromatography [0-100% EtOH:CH ₂ Cl ₂ :NH ₄ OH (50:8:1) in CH ₂ Cl ₂ ] gave a pale brown solid (584 mg, 99%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.79 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.26 ( dd, J = 8.8, 2.1 Hz, 1H), 7.11 - 7.04 (m, 2H), 6.84 - 6.78 (m, 1H), 5.36 (s, 2H) , 4.67 - 4.57 (m, 1H), 4.36 (br s, 1H), 3.16 - 3.09 (m, 2H), 2.65 - 2.56 (m, 2H) , 2.30 - 2.17 (m, 2H), 1.72 - 1.64 (m, 4H), 1.58 - 1.55 (m, 2H). MSNR (APCI+) m/z 424.8 [M+H] ⁺

30: 1 ' -{[5-chloro-1-(piperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl} -6'-fluoro-1 ' , 2'-dihydrospiro [cyclobutane -1,3' - indole]-2' -one

Obtained by a method similar to that described for compound 29 using intermediate compound 5E. MSNR (APCI+) m/z 439.9 [M+H] ⁺ . R _f 0.02 EtOH:CH ₂ Cl ₂ :NH ₄ OH (100:8:1).

31: 1 ' -{[1-(1-acetylpiperidin-4-yl)-5-chloro-1H-1,3-benzodiazol-2-yl]methyl} -6' -fluoro-1 ' , 2'-dihydrospiro [cyclopropane-1,3'- indole]-2' -one

Acetyl chloride (20.1 µl, 0.280 mmol) was added to a chilled (0°C) solution of compound 29 (60 mg, 0.140 mmol) and NEt ₃ (43.3 µl, 0.310 mmol) in anhydrous CH ₂ Cl ₂ (2.5 ml) under N ₂ and stirred at room temperature for 17 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (20 ml), washed with water and brine (10 ml each), dried (MgSO ₄ ) and the solvent was removed under reduced pressure. Purification by flash chromatography (0-5% EtOH in CH ₂ Cl ₂ ) gave a pale brown solid (36 mg, 54%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.75 - 7.70 (m, 2H), 7.20 (dd, J = 8.7, 2.1 Hz, 1H), 7.12 - 7.05 (m, 2H), 6.85 - 6.79 (m, 1H), 5.40 (s, 2H), 4.83 - 4.74 (m, 1H), 4.65 - 4 .58 (m, 1H), 4.06 - 3.98 (m, 1H), 3.19 - 3.10 (m, 1H), 2.65 - 2.54 (m, 1H), 2.39 - 2.27 (m, 1H), 2.16 - 2.03 (m, 4H), 1.86 - 1.75 (m, 2H), 1.72 - 1.68 (m, 2H), 1 .60 - 1.55 (m, 2H). MSNR (APCI+) m/z 466.8 [M+H] ⁺

32: 4-[5-chloro-2-({ 6'-fluoro- 2'-oxo-1 ' , 2'-dihydrospiro [cyclopropan- 1,3'-indole] -1' - yl}methyl)-1H -1,3-benzodiazol-1-yl]-N,N-dimethylpiperidine-1-carboxamide

N,N- dimethylcarbamoyl chloride (19.5 µl, 0.210 mmol) was added to a chilled (0°C) solution of compound 29 (60 mg, 0.140 mmol) and NEt ₃ (30.5 µl, 0.219 mmol) in anhydrous CH ₂ Cl ₂ (2.5 ml) under N ₂ and stirred at room temperature for 17 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (10 ml) and was extracted with CH ₂ Cl ₂ (10 ml). The organic extracts were washed with water and brine (10 ml each), dried (MgSO ₄ ) and the solvent was removed under reduced pressure. Purification by flash chromatography (0-10% EtOH in CH ₂ Cl ₂ ) gave a pale brown solid (70 mg, 69%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.73 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 ( dd, J = 8.7, 2.1 Hz, 1H), 7.12 - 7.05 (m, 2H), 6.85 - 6.79 (m, 1H), 5.39 (s, 2H) , 4.75 - 4.67 (m, 1H), 3.73 - 3.66 (m, 2H), 2.86 - 2.76 (m, 8H), 2.31 - 2.21 (m, 2H), 1.80 - 1.72 (m, 2H), 1.73 - 1.68 (m, 2H), 1.59 - 1.55 (m, 2H). MSNR (APCI+) m/z 495.8 [M+H] ⁺

33: 1 ' -{[5-chloro-1-(1-methanesulfonylpiperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl} -6' -fluoro-1 ' , 2'-dihydrospiro [cyclopropane-1,3'- indole]-2' -one

Methanesulfonyl chloride (MsCl, 13.1 μl, 0.170 mmol) was added to a chilled (0°C) solution of compound 29 (60 mg, 0.140 mmol) and NEt ₃ (24.6 μl, 0.180 mmol) in anhydrous CH ₂ Cl ₂ (2 .5 ml) under N ₂ and stirred at room temperature for 17 hours. Additional MsCl (8.7 μl, 0.113 mmol) and NEt ₃ (15.8 μl, 0.113 mmol) were added and the reaction mixture was stirred for an additional 4.5 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (20 ml), washed with water and brine (10 ml each), dried (MgSO ₄ ) and the solvent was removed under reduced pressure. Purification by flash chromatography [50-100% EtOAc in heptane, then 0-10% EtOH:CH ₂ Cl ₂ :NH ₄ OH (50:8:1) in CH ₂ Cl ₂ ] gave a white solid (49 mg, 69 %). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.72 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.23 ( dd, J = 8.7, 2.1 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.85 - 6.79 (m, 1H), 5.39 (s, 2H) , 4.78 - 4.68 (m, 1H), 3.83 - 3.76 (m, 2H), 3.00 (s, 3H), 2.92 - 2.84 (m, 2H), 2 .40 - 2.34 (m, 2H), 1.95 - 1.89 (m, 2H), 1.73 - 1.68 (m, 2H), 1.61 - 1.56 (m, 2H) . MSNR (APCI+) m/z 502.8 [M+H] ⁺

34: 1 ' -{[5-chloro-1-(1-methanesulfonylpiperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl} -6' -fluoro-1 ' , 2'-dihydrospiro [cyclobutane-1,3'- indole]-2' -one

Prepared by a procedure similar to that described for compound 33 using intermediate 30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.74 - 7.59 (m, 3H), 7.23 (dd, J = 8 .8, 2.1 Hz, 1H), 7.06 (dd, J = 9.6, 2.4 Hz, 1H), 6.88 (ddd, J = 10.4, 8.2, 2.4 Hz, 1H), 5.28 (s, 2H), 4.75 (t, J = 12.4 Hz, 1H), 3.81 (d, J = 11.8 Hz, 2H), 3.02 ( s, 3H), 2.89 (s, 2H), 2.41 - 2.31 (m, 4H), 2.25 (q, J = 7.4 Hz, 2H), 1.91 (d, J = 12.3 Hz, 2H). MSNR (APCI+) m/z 517.9 [M+H] ⁺

35: 1 ' -({5-chloro-1-[1-(ethanesulfonyl)piperidin-4-yl]-1H-1,3-benzodiazol-2-yl}methyl) -6'-fluoro-1 ' ,2 ' -dihydrospiro[cyclopropan-1,3'- indole]-2' -one

Ethansulfonyl chloride (23.4 µl, 0.247 mmol) was added to a chilled (0°C) solution of compound 29 (60 mg, 0.140 mmol) and NEt ₃ (34.5 µl, 0.248 mmol) in anhydrous CH ₂ Cl ₂ (2.5 ml) under N ₂ and stirred at room temperature for 19 hours. This reaction mixture was diluted with CH ₂ Cl ₂ (20 ml), washed with saturated aqueous NH ₄ Cl, water (twice) and brine (10 ml each), dried (MgSO ₄ ) and the solvent was removed under reduced pressure. Purification by flash chromatography (30-100% EtOAc in heptane) gave an off-white solid (73 mg, 79%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.79 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.34 - 7, 30 (m, 1H), 7.23 (dd, J = 8.7, 2.0 Hz, 1H), 6.74 - 6.67 (m, 2H), 5.28 (s, 2H), 4 .94 - 4.85 (m, 1H), 4.02 - 3.95 (m, 2H), 3.06 - 2.93 (m, 4H), 2.55 - 2.44 (m, 2H) , 1.74 - 1.67 (m, 4H), 1.57 - 1.53 (m, 2H), 1.41 (t, J = 7.4 Hz, 3H). MSNR (APCI+) m/z 516.8 [M+H] ⁺

36: 1 ' -({5-chloro-1-[1-(2-methanesulfonylethyl)piperidin-4-yl]-1H-1,3-benzodiazol-2-yl}methyl) -6'-fluoro-1 ' , 2'-dihydrospiro[cyclopropan-1,3'- indole]-2' -one

Methyl vinyl sulfone (21.2 µl, 0.240 mmol) was added to a chilled (0°C) solution of compound 29 (76 mg, 0.179 mmol) in anhydrous THF (2.5 ml) under N ₂ and stirred at room temperature for 22 hours . Added additional amount of methyl vinyl sulfone (7.8 μl, 0.89 mmol) and the specified reaction mixture was stirred for another 1.5 hours. The volatiles were evaporated under reduced pressure and the crude residue was purified directly by flash chromatography (30-100% EtOAc in heptane) to give the product as a pale brown solid (54 mg, 57%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.73 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.24 ( dd, J = 8.8, 2.1 Hz, 1H), 7.11 - 7.04 (m, 2H), 6.84 - 6.81 (m, 1H), 5.36 (s, 2H) , 4.58 - 4.48 (m, 1H), 3.10 - 3.02 (m, 5H), 2.78 (t, J = 6.8 Hz, 2H), 2.35 - 2.24 (m, 3H), 2.17-2.08 (m, 2H), 1.77-1.67 (m, 4H), 1.60-1.55 (m, 2H). MSNR (APCI+) m/z 531.1 [M+H] ⁺

Example 37: Efficiency in vitro

Compounds were subjected to an RSV fusion assay and a plaque suppression assay according to the following protocols.

RSV merger analysis

HEK 293T cells ((ECACC 12022001) were cultured in T75 culture flasks in Dulbecco's Medium (DMEM) containing 10% fetal bovine serum (FBS), 50 units per ml penicillin and 50 μg/ml streptomycin and heated to 37°C before Cells were passaged with a first short wash with 5 ml of phosphate buffered saline (PBS), then 2 ml of trypsin-ethylenediaminetetraacetic acid (EDTA) was added to separate the cells.After the cells were separated from the flask, 8 ml of medium was added and the cells were dispersed with a pipette at the bottom of the flask .

Cells were counted and diluted to 3×10 ⁵ cells/ml in fresh medium. 15.6 ml of diluted cells were seeded in each of two T75 flasks, cells were also subcultured at a ratio of 1:2 to 1:10 to maintain the original culture. Then the flasks were incubated for 24 hours at 37°C and 5% CO ₂ .

Plasmid DNA (for pFR-Luc and pcDNA3.l_Gal4/NFKB) for transfection into HEK 293T cells was first prepared in serum-free medium (Opti-MEM, Invitrogen) containing FuGENE® 6 transfection reagent (Promega). The serum-free medium was placed in a 1.5 ml Eppendorf tube, then FuGENE 6 was added to the medium. The tube was shaken with a vortex mixer for 1 second, then incubated at room temperature for 5 minutes. 7.79 ng of pFR_luc and pCDNA3.1_A2_F plasmid DNA were added to tube 1, and 7.79 ng of pCDNA3.1_GAL4-NF-κB plasmid was added to tube 2. The tubes were shaken with a vortex mixer for 1 second and then incubated at room temperature for 15 minutes. Each transfection mixture was then added to the medium of one of the T75 flasks with 293T cells. Cells were cultured for 24 hours at 37°C, 5% CO ₂ in a humidified incubator.

Compounds were diluted (in a 96 round bottom well polypropylene plate) 1:3 in a twelve point dilution curve to give an upper [final] 25 µl, 3 µl, 1 µl, or 500 nM. A control compound was included in each assay at a maximum concentration of 3 μM. Transfected cells were counted and diluted to 4×10 ⁵ cells/ml in fresh medium. 50 μl of transfected population 1 was added to all wells of white opaque 96 well flat bottom assay plates. 100 µl of diluted compound (2 rows per compound), control compound (one row) and controls (DMSO (0% inhibition, four wells), 3 µl of positive control (100% inhibition, four wells) and medium (only transfected population 1, four wells) were added to the appropriate wells.After that, 50 µl of diluted (4×10 ⁵ cells/ml) population 2 cells were added to all wells except four wells with transfected population 1, where an additional 50 µl of this cell population was injected.

Then the tablets were incubated for 24 hours at a temperature of 37°C and 5% CO ₂ . At the end of this time, 100 µl was removed from all wells and 60 µl of ONE-Glo™ reagent (Promega) previously brought to room temperature was added. The plates were then incubated for 3 minutes at room temperature, after which the luminescence was read using the ONE-Glo protocol on a GloMax Explorer System (Promega) multimode reader. The analysis was carried out using the Dotmatics program. Before calculating the IC ₅₀ all raw data were subtracted from the background (subtraction of the average value of the positive control 3 μm).

Plaque suppression reaction

HEp-2 cells (ATCC, CCL23) were passaged in flasks and seeded in 96-well plates in DMEM containing antibiotics supplemented with 10% FBS. During inoculation and subsequent incubation, cells were cultured in DMEM containing 3% FBS. 100 plaque forming units (PFU)/well RSV (RSV A2 VR-1540) were mixed with ten serial dilutions of the compound. Then, 100 μl of virus/compound mixtures were added to confluent monolayers of HEp-2 cells. Cells and virus/compound mixtures were incubated at 35° C. in a humidified 5% CO ₂ incubator for 1 day.

Cells were washed twice with PBS before adding 50% v/v. EtOH/MeOH and then stored at -20°C. On the day of staining, the fixative was first removed from the plates. The plates were washed 3 times with PBS. The pre-titrated amount of primary antibody was added to 60 μl PBS/2% milk powder and the plates were incubated for 1 hour at room temperature. The plates were washed 3 times with PBS/0.05% Tween 20 before adding horseradish peroxidase-conjugated goat anti-mouse immunoglobulin G in 60 μl PBS/2% milk powder and incubated for 1 hour at room temperature. After three washes with PBS/0.05% Tween 20, 60 µl ready-to-use TrueBlue was added and the plates were incubated at room temperature for 10-15 minutes before adding MilliQ water. The plates were washed once with water, incubated for 30–60 min, and, after removal of water, dried in air in the dark.

Plates were scanned and analyzed using an Immunospot S6 UV analyzer equipped with BioSpot analysis software for counting immunostained plaques (virospots). The number of plaques was used to calculate the % infection relative to the mean number of spots (SC) in the RSV virus control wells. IC ₅₀ /IC ₉₀ values were calculated as signal reductions of 50% or 90%, respectively, by interpolation of inhibition curves in a four-parameter non-linear regression with variable slope in GraphPad 5.0 (Prism).

results

Compound RSV merger analysis
(n ≥ 2) RSV Plaque Suppression Assay
Strain A2 (n = 1) IC ₅₀ (nM) ^* IC ₅₀ (nM) IC ₉₀ (nM) fourteen eighteen 3.5 34 twenty 12 5.9 7.5 33 3.3 0.49 4.4 35 5.0 0.87 5.2 13 ten 4.5 41 eleven 24 5 41 9 fifteen 4.2 28 ten 12 2.5 31 one 19 5.9 fifty eighteen 70 7.6 66 12 71 29 200 28 115 9.5 48

^* The reported IC ₅₀ value is the average of at least 2 independent experiments.

Example 38: Pharmacokinetics in vitro

Compounds were studied using the following assays to study stability in liver microsomes and permeability.

Microsomal Incubation: Experimental Procedure

Pooled liver microsomes were purchased from a reputable commercial supplier and stored at -80°C prior to use.

Microsomes (final protein concentration 0.5 mg/mL), 0.1 M phosphate buffer pH 7.4 and test compound (final substrate concentration 3 μM; final concentration DMSO 0.25%) were preincubated at 37°C before adding NADPH (final concentration 1 mM) to initiate the reaction. The final incubation volume was 50 μl. A control incubation is included for each test compound, where 0.1 M phosphate buffer pH 7.4 (minus NADPH) is added instead of NADPH. Two control compounds are included for each species. All incubations were performed separately for each test compound.

Each compound was incubated for 0, 5, 15, 30 and 45 minutes. The control (minus NADPH) was incubated for 45 minutes only. Reactions were stopped by transferring 20 μl of the incubate in 60 μl of MeOH at the appropriate time points. The terminal plates were centrifuged at 2500 rpm for 20 min at 4°C to precipitate the protein.

After protein precipitation, sample supernatants were combined into cassettes containing up to 4 compounds, an internal standard was added, and the samples were analyzed by LC-MS/MS. From a plot of In peak area (compound peak area/internal standard peak area) versus time, the gradient of the line was determined. Then the half-life and intrinsic clearance were calculated.

MDR1-MDCK Permeability: Experimental Procedure

MDR1-MDCK cells obtained from NIH (National Institutes of Health) (Rockville, MD, USA) were used for passages 6-30. Cells were seeded onto Millipore Multiscreen Transwell dishes at 3.4×10 ⁵ cells/cm ² . Cells were cultured in DMEM and the medium was changed on the third day. On the fourth day, a permeability study was performed. Cell culture incubation and analysis was carried out at 37°C in an atmosphere of 5% CO ₂ with a relative humidity of 95%. On the day of analysis, monolayers were prepared by washing both the basolateral and apical surfaces twice with Hanks' Balanced Salt Solution (HBSS) at the desired pH at 37°C. Cells were then incubated with HBSS at the desired pH in both the apical and basolateral compartments for 40 minutes to stabilize physiological parameters.

Dosing solutions were prepared by diluting test compound with assay buffer to give a final concentration of test compound of 10 μl (final concentration of DMSO 1% v/v). Lucifer yellow fluorescent integrity marker was also included in the injection solution. Analytical standards were prepared from dilutions of the test compound in DMSO and transferred into buffer, maintaining the concentration of DMSO at 1% v/v.

To assess A-B permeability, HBSS was removed from the apical compartment and replaced with dosing solution of the test compound. The apical compartment insert was then placed in a paired plate containing fresh buffer (containing 1% v/v DMSO). To evaluate B-A permeability, HBSS was removed from the paired plate and replaced with test compound dosing solution. Fresh buffer (containing 1% v/v DMSO) was added to the apical compartment insert, which was then placed in a paired plate. After 60 minutes, the apical compartment inserts and paired plates were separated and the apical and basolateral samples were diluted for analysis. The permeability of the test compound was evaluated in duplicate. As controls, compounds with known permeability characteristics were tested on each plate.

Test and control compounds were quantified by LC-MS/MS cassette analysis using an 8-point calibration at appropriate sample dilutions. Initial concentration (C ₀ ) was determined from the administration solution and the experimental yield calculated from C ₀ and both concentrations in the apical and basolateral compartments. The integrity of the monolayers throughout the experiment was checked by monitoring the penetration of lucifer yellow using fluorimetric analysis. Lucifer yellow penetration is high if the monolayer has been damaged.

results

Pharmacokinetic property Meaning Stability in liver microsomes
[t _½ (min); rat/dog/human] Compound 33: 14.8/186/486 Compound 35: 5.5 / 166 / 34.6 Permeability MDR1-MDCK
P _app (10 ^-6 sms ^-1 ) AB / BA Compound 14: 4.8/68 Compound 20: 1.6 / 61.3 Compound 33: 12.4/35.5 Compound 35: 12.7/22.8

Example 39 Cytochrome P450 Inhibition

The compounds of the invention were tested for inhibition of cytochrome P450 enzymes.

Test compound (0.1, 0.25, 1, 2.5, 10, 25 µM in DMSO; final DMSO concentration 0.3%) was incubated with human liver microsomes (0.25 mg/mL) and NAPPH (1 mM ) in the presence of a marker substrate specific for cytochrome P450 isoform. Metabolites were monitored by LC-MS/MS and the reduction in metabolite formation was compared to a vehicle control used to calculate the IC ₅₀ value (concentration of test compound that causes 50% inhibition). A cytochrome P450 isoform-specific selective inhibitor was co-analysed with test compounds as a positive control.

Results for Compound 33:

Isoform (substrate) Cytochrome P450 inhibition IC ₅₀ (μM) Compound 33 CYP1A2 >25 CYP2B6 >25 CYP2C8 >25 CYP2C9 >25 CYP2C19 >25 CYP2D6 >25 CYP3A4 ^* 0.674 CYP3A4 ^† 3.94

Note: *substrate = midazolam. †substrate = testosterone.

Example 40: Pharmacokinetics in vivo

The pharmacokinetics of the compounds of the invention were studied in vivo in dogs at doses of 3 mg/kg (PO).

Ways

Beagle dogs (n = 3) received experimental compounds orally (3 mg/kg). Oral administration was carried out using a gastric tube at a dose of 3 mg/kg at a concentration of 0.6 mg/ml in a solution of % dimethylacetamide, 30% PEG 400 and 65% (2-hydroxypropyl)-β-cyclodextrin (20% aq. wt./ about.). Serial blood samples were taken at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after compound dosing. Animals were observed for any overt clinical signs or symptoms. Serial plasma samples were taken at certain time points and stored immediately under conditions at -80°C.

After precipitation of the protein with acetonitrile, the samples were analyzed by liquid chromatography with tandem mass spectrometry using electrospray ionization. An internal standard curve was used and PK parameters were calculated.

results

Compound 33:

Pharmacokinetic property Meaning t _1/2 (h) 7.24 T _max (h) 0.67 _Cmax (ng/ml) 535.40 AUC _last (h * ng / ml) 3874.91 AUC _all (h * ng / ml) 3874.91 AUC _inf (h * ng / ml) 4282.46

Example 41: Water composition

The compound from example 1 was prepared as a solution in 30% wt./about. captisol (i.e., sulfobutyl ether beta-cyclodextrin) at pH 4 according to the following procedure.

Media representing 30% wt./about. captisol (i.e., sulfobutyl ether-beta-cyclodextrin) was prepared by weighing the required amount of captisol into a suitable vessel, adding about 80% of the final volume of water and stirring with a magnetic stirrer until a solution was formed. The carrier was then made up to volume with water.

An aqueous solution of the compound of Example 1 was prepared by weighing 175 mg of said compound into a suitable vessel and adding approximately 80% of the required volume of carrier. The pH was adjusted to pH 2 with an aqueous solution of hydrochloric acid, and the resulting mixture was stirred with a magnetic stirrer until a solution was formed. The formulation was then brought up to volume with carrier and the pH adjusted to pH 4 using aqueous sodium hydroxide solution.

Example 42 Tablet Composition

Tablets each weighing 0.15 g and containing 25 mg of the compound of the present invention were made as follows:

Composition for 10,000 tablets

Compound according to the present invention (250 g)

Lactose (800 g)

Corn starch (415 g)

Talc powder (30 g)

Magnesium stearate (5 g)

Mixed the compound according to the present invention, lactose and half of the cornstarch. The mixture was then forced through a 0.5 mm sieve. Suspended corn starch (10 g) in warm water (90 ml). The resulting paste was used to granulate the powder. The granulate was dried and broken into small fragments on a sieve with a hole size of 1.4 mm. The remaining amount of starch, talc and magnesium was added, thoroughly mixed and processed into tablets.

Example 43 Composition for injection

Compound according to the present invention 250 mg 0.1M hydrochloric acid solution or 0.1M sodium hydroxide solution in an amount sufficient to reach pH 4.0 to 7.0 Sterile water in an amount sufficient to achieve 10 ml

The compound according to the present invention was dissolved in most of the water (35-40°C) and, if necessary, the pH was adjusted to 4.0-7.0 with hydrochloric acid or sodium hydroxide. The batch was then made up to volume with water and filtered through a sterile microporous filter into a sterile 10 ml amber glass vial (type 1) and sealed with sterile stoppers and additional caps.

Example 44 Intramuscular Injection

Compound according to the present invention 250 mg benzyl alcohol 0.10 g Glycofurol 75 1.45 g Water for injection in an amount sufficient to achieve 3.00 ml

The compound according to the present invention was dissolved in glycofurol. Then benzyl alcohol was added and dissolved and water was added to 3 ml. The mixture was then filtered through a sterile microporous filter and sealed in sterile 3 ml glass vials (type 1).

Example 45 Syrup Composition

Compound according to the present invention 250 mg Sorbitol solution 1.50 g Glycerol 2.00 g sodium benzoate 0.005 g flavoring 0.0125 ml Purified water in an amount sufficient to achieve 5.00 ml

The compound according to the present invention was dissolved in a mixture of glycerol and most of the purified water. An aqueous solution of sodium benzoate was then added to the solution, followed by the addition of a solution of sorbitol and finally flavoring. Purified water was brought to volume and mixed well.

Claims (46)

1. A compound which is a benzimidazole derivative of formula (I):

(I) where: R ¹ is -(CH ₂ ) _m -R ⁴ or

; R ² is halo _; R ³ is F; R ⁴ is -NH-(CH ₂ ) ₂ -(NH) _r -R ⁵ , -NH-(CHR ⁵ R ⁶ ) or a group of the following formula (A):

(A) W is -(CH ₂ ) _m -, -CH ₂ -O-CH ₂ -, -(CH ₂ ) _r -S(O) ₂ -CH ₂ - or -(CH ₂ ) _r -NR ⁵ -CH ₂ -; m is an integer from 1 to 3; n is 1; p is 0 and V is N; q is 0 or 1; r is 0 or 1; R ⁵ is -SO ₂ Me, -SO ₂ Et or -CONH ₂ ; R ⁶ is C ₁ -C ₆ alkyl; and R ⁷ is -SO ₂ Me; or a pharmaceutically acceptable salt of said compound. 2. The compound according to claim 1, characterized in that R ¹ is -(CH ₂ ) _m -R ⁴ , where m is 2 or 3 and R ⁴ is selected from: (i) -NH-(CH ₂ ) ₂ -(NH) _r -R ⁵ , where r is 0 or 1 and R ⁵ is selected from -SO ₂ Me and -SO ₂ Et; (ii) -NH-(CHR ⁵ R ⁶ ), where R ⁵ is -CONH ₂ and R ⁶ is C ₁ -C ₆ alkyl; (iii) a group of formula (A) in which p is 0, V is N, W is -(CH ₂ ) _m -, where m is an integer from 1 to 3, q is 1 and R ⁷ is -SO ₂ Me; and (iv) a group of formula (A) in which p is 0, V is N, q is 0 and W is -CH ₂ -O-CH ₂ -, -(CH ₂ ) _r -S(O) ₂ - CH ₂ - or -(CH ₂ ) _r -NR ⁵ -CH ₂ -, where r is 0 or 1 and R ⁵ is -SO ₂ Me or -SO ₂ Et. 3. Connection according to claim 1, characterized in that R ¹ is

where R ⁵ represents -SO ₂ Me or -SO ₂ Et. 4. The connection according to any one of paragraphs. 1-3, characterized in that R ² is F or Cl. 5. The compound according to claim 1, characterized in that the group of formula (A) is selected from the following structures:

6. Compound according to claim 1, selected from: 1'-({5-chloro-1-[3-(4-methanesulfonylpiperazin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 ''-dihydrospiro[cyclopropan-1,3'-indole]-2'-one; 1'-({5-chloro-1-[2-(4-methanesulfonylpiperazin-1-yl)ethyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one; 1'-[(5-chloro-1-{3-[(2-methanesulfonylethyl)amino]propyl}-1H-1,3-benzodiazol-2-yl)methyl]-6'-fluoro-1',2' -dihydrospiro[cyclopropan-1,3'-indole]-2'-one; 1'-{[5-chloro-1-(3-{[2-(ethanesulfonyl)ethyl]amino}propyl)-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1' ,2'-dihydrospiro[cyclopropan-1,3'-indole]-2'-one; (2S)-2-({3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-1'- yl}methyl)-1H-1,3-benzodiazol-1-yl]propyl}amino)-3-methylbutanamide; 1'-({5-chloro-1-[3-(3-methanesulfonylazetidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one; 1'-({5-chloro-1-[3-(3-methanesulfonylpyrrolidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one; 1'-({5-chloro-1-[3-(morpholin-4-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2'- dihydrospiro[cyclopropan-1,3'-indole]-2'-one; 4-{3-[5-chloro-2-({6'-fluoro-2'-oxo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-1'-yl}methyl)- 1H-1,3-benzodiazol-1-yl]propyl}-1λ6-thiomorpholine-1,1-dione; 1'-({5-chloro-1-[3-(4-methanesulfonylpiperidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2 '-dihydrospiro[cyclopropan-1,3'-indole]-2'-one; 1'-{[5-chloro-1-(1-methanesulfonylpiperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1',2'-dihydrospiro[cyclopropane -1,3'-indole]-2'-one; 1'-({5-chloro-1-[1-(ethanesulfonyl)piperidin-4-yl]-1H-1,3-benzodiazol-2-yl}methyl)-6'-fluoro-1',2'- dihydrospiro[cyclopropan-1,3'-indole]-2'-one; and its pharmaceutically acceptable salts. 7. Pharmaceutical composition for the treatment or prevention of respiratory syncytial virus (RSV) infection, containing an effective amount of the compound according to any one of paragraphs. 1-6 and a pharmaceutically acceptable carrier or diluent. 8. The use of a compound according to any one of paragraphs. 1-6 for the preparation of a medicament for the treatment or prevention of RSV infection. 9. A method of treating a subject suffering from or susceptible to RSV infection, comprising administering to said subject an effective amount of a compound according to any one of paragraphs. 1-6. 10. A process for preparing a pharmaceutically acceptable salt according to claim 1, comprising treating the benzimidazole derivative of formula (I) according to claim 1 with a suitable acid in a suitable solvent, wherein said acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid , aspartic acid and glutamic acid.