NEW ANTIFUNGAL COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to methods and new compounds for use in the treatment, prophylaxis or prevention of fungal infections, especially Candida infections.

BACKGROUND TO THE INVENTION

Candida albicans is the most common human fungal pathogen, even though it is part of the commensal microflora in the gastrointestinal and urogenital tracts as well as in the oral cavity. Vaginal candidiasis has been described at least once in 75% of all women worldwide (Sobel J. D. Vaginitis. N. Engl. J. Med. 1997, 337, 1896-1903). Although the disease is not invasive, the quality of life of affected individuals is considerably reduced. Bloodstream infections with Candida spp. (candidemia) have been increasing in hospital intensive care units (ICUs) worldwide, with an annual prevalence of 300,000 cases and 30% to 50% mortality (Arendrup M. C. Epidemiology of Invasive Candidiasis. Curr. Opin. Crit. Care. 2010, 16, 445- 452; Zilberberg M. D. et al. Secular Trends in Candidemia-Related Hospitalization in the United States, 2000-2005. Infect. Control Hosp. Epidemiol. 2008, 29, 978-980). Among systemic microbial infections in ICU patients, candidiasis ranks second in Europe and North America, causing more than 50% of the cases. Despite the increase in Candida infections, currently available therapeutic agents remain few in number, and of those, several can lead to severe side effects, such as liver damage.

The most important antifungal drugs can be classified into six categories with confined fungal targets (Stylianou M. et al. Antifungal Application of Nonantifungal Drugs. Antimicrob. Agents Chemother. 2014, 58, 1055-1062). Polyenes bind ergosterol and induce pores in fungal plasma membranes. Azoles and allylamines inhibit the synthesis of ergosterol, rendering the membranes unstable, whereas morpholines and antimetabolites prevent nucleic acid production.

Many currently applied antifungal drugs have severe side effects (Dixon D. M. & Walsh T. J. Antifungal agents. In Medical Microbiology; 4th ed. Baron S. Eds. University of Texas Medical Branch at Galveston: Galveston, TX; 1996). The ergosterol-attacking agents, for instance, can additionally interfere with the human analog cholesterol, resulting in host cell damage. Thus, long-term use of these drugs can cause renal dysfunction, liver toxicity, or bone marrow depression. Finally, echinochadins constitute a new group of antifungal agents. They are inhibitors of glucan synthetase in the cell wall of fungi, which has no counterpart in human hosts, resulting in less severe side effects. However, emergence of echinocandin-resistant strains is a cause of clinical concern. Systemic and superficial candidiasis is strictly associated with the reversible morphotype switching from budding yeasts to the filamentous hyphae (Y-H) (Sudbery P. E. Growth of Candida albicans Hyphae. Nat. Rev. Microbiol. 2011 , 9, 737-748). The yeast is a unicellular morphotype and considered the commensal form of C. albicans. Derogation of innate or adaptive immunity can induce adherence to epithelia and conversion from yeast to hyphal growth. Hyphal growth results in a filamentous morphology initiated by germ tube formation at a yeast mother cell. Apical growth at the tip of the filament continues with occasional branching events. Hyphae have been reported to be essential for invasion and dissemination to noncommensal niches as well as for biofilm formation and escape from host immune cells.

Compounds that inhibit the Y-H transition can be exploited for application as antifungal therapy. Fungal growth should not be altered by these agents but rather redirected into a commensal state that can be controlled by the immune system. According to these

assumptions, the present inventors hypothesize that during treatment with such agents, selection pressure on fungal pathogens is low and, thus, in turn the possibility for resistance development decreased.

DESCRIPTION OF THE INVENTION

A method to screen large chemical compound libraries for Y-H transition inhibitors was developed. The ideal compounds are those that prevent C. albicans morphotype transition without affecting the cellular viability of fungal cells.

Accordingly, the present invention provides a compound according to Formula (I), Formula (II), or Formula (III):

wherein

the bond a is a single bond, a trans double bond (E), or a triple bond;

X and Y are -CH ₂ - or one of X and Y is O and the other is CH ₂ ;

R ₁ is phenyl unsubstituted or substituted with one, two, or three substituents each independently selected from chloro, bromo, trifluoromethyl; R ₂ is or -NH-(CH2) _n -R3 where n is 2 or 3,

R ₃ is -NR ₄ R ₅ , heterocycloalkyl, imidazolyl or triazolyl, where the heterocycloalkyl is

unsubstituted or substituted with -C ₁ -C ₃ alkyl,

R ₄ is -C ₁ -C ₃ alkyl;

R5 is -C1-C3 alkyl;

or a pharmaceutical acceptable salt thereof.

In a representative configuration of compounds of Formula (I), Formula (II) or Formula (III), R ₂ is -NH-(CH ₂ ) _n -R _3.

Preferably, R ₃ is -NR ₄ R ₅ or a heterocycloalkyl selected from morpholino, 1 -piperidyl, or piperazin-1-yl, where the heterocycloalkyl is unsubstituted or substituted with -C ₁ -C ₃ alkyl, R ₄ is -C ₁ -C ₃ alkyl, and R ₅ is -C ₁ -C ₃ alkyl.

Typically, the bond a is a trans double bond (E).

The invention further provides pharmaceutical compositions comprising a compound according to Formula (I), Formula (II) or Formula (III) in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.

The invention further provides a compound according to Formula (I), Formula (II) or Formula (III) for use in medicine.

The invention further provides a compound according to Formula (I), Formula (II) or Formula (III) or a pharmaceutical composition thereof according to the invention for use in treatment, prophylaxis or prevention of fungal infections, preferably Candida infections.

The present invention further provides a method for the prophylaxis, prevention and/or the treatment of fungal infections, preferably Candida infections which comprises the

administration of a therapeutically active amount of a compound according to Formula (I), Formula (II) or Formula (III).

Most preferably, the compound is selected from the group consisting of:

4-[(2,4-dichlorophenoxy)methyl]-N-[2-(dimethylamino)ethyl ]benzamide,

4-[(2,4-dichlorophenyl)methoxy]-N-[2-(dimethylamino)ethyl ]benzamide,

4-[2-(2,4-dichlorophenyl)ethyl]-N-[2-(dimethylamino)ethyl ]benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[2-(dimethylamino)e thyl]benzamide,

N-[2-(dimethylamino)ethyl]-4-(2-phenylethyl)benzamide,

N-[2-(dimethylamino)ethyl]-4-[(E)-styryl]benzamide, 4-[(2,4-dichlorophenoxy)methyl]-N-[3-(4-methylpiperazin-1-yl )ethyl]benzamide,

4-[(2,4-dichlorophenoxy)methyl]-N-[3-(4-methylpiperazin-1 -yl)propyl]benzamide,

N-[2-(dimethylamino)ethyl]-4-[(E)-2-(2,4,6-trichlorophenyl)v inyl]benzamide;methane,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[2-(dimethylamino)ethyl ]benzamide,

4-[(E)-2-(3,5-dibromophenyl)vinyl]-N-[2-(dimethylamino)ethyl ]benzamide,

N-[2-(dimethylamino)ethyl]-4-[(E)-2-[4-(trifluoromethyl)phen yl]vinyl]benzamide,

4-[(E)-2-[2,4-bis(trifluoromethyl)phenyl]vinyl]-N-[2-(dimeth ylamino)ethyl]benzamide,

4-[(E)-2-[3,5-bis(trifluoromethyl)phenyl]vinyl]-N-[2-(dimeth ylamino)ethyl]benzamide,

4-[2-(2,4-dichlorophenyl)butyl]-N-[2-(dimethylamino)ethyl]be nzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[2-(4-methylpiperazin- 1-yl)ethyl]benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[3-(4-methylpiperazin- 1-yl)propyl]benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-(2-morpholinoethyl)ben zamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-(3-morpholinopropyl)be nzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[2-(1-piperidyl)ethyl] benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[3-(1-piperidyl)propyl ]benzamide,

[4-[(E)-2-(2,4-dichlorophenyl)vinyl]phenyl]-(4-morpholino-1- piperidyl)methanone,

[4-[(E)-2-(2,4-dichlorophenyl)vinyl]phenyl]-[4-(4-ethylpiper azin-1-yl)-1-piperidyl]methanone,

N-[2-(4-methylpiperazin-1-yl)ethyl]-4-[(E)-2-(2,4,6-trich lorophenyl)vinyl]benzamide,

N-[3-(4-methylpiperazin-1-yl)propyl]-4-[(E)-2-(2,4,6-trichlo rophenyl)vinyl]benzamide,

N-(2-morpholinoethyl)-4-[(E)-2-(2,4,6-trichlorophenyl)vinyl] benzamide,

N-(3-morpholinopropyl)-4-[(E)-2-(2,4,6-trichlorophenyl)vinyl ]benzamide,

N-[3-(1-piperidyl)propyl]-4-[(E)-2-(2,4,6-trichlorophenyl)vi nyl]benzamide,

(4-morpholino-1-piperidyl)-[4-[(E)-2-(2,4,6-trichlorophenyl) vinyl]phenyl]methanone,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[2-(4-methylpiperazin-1 -yl)ethyl]benzamide,

4-[(E)-2-(3,5-dibromophenyl)vinyl]-N-[3-(4-methylpiperazin-1 -yl)propyl]benzamide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-(2-morpholinoethyl)benz amide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-(3-morpholinopropyl)ben zamide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[2-(1-piperidyl)ethyl]b enzamide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[3-(1-piperidyl)propyl] benzamide,

[4-[(E)-2-(2,4-dibromophenyl)vinyl]phenyl]-(4-morpholino-1-p iperidyl)methanone,

[4-[(E)-2-(2,4-dibromophenyl)vinyl]phenyl]-[4-(4-ethylpipera zin-1-yl)-1-piperidyl]methanone, and

[4-(4-ethylpiperazin-1-yl)-1-piperidyl]-[4-[(E)-2-(2,4,6- trichlorophenyl)vinyl]phenyl]methanone.

In another aspect, the present invention provides a compound according to Formula (I), Formula (II), or Formula (III):

wherein

the bond a is a single bond, a trans double bond (E), or a triple bond;

X and Y are -CH ₂ - or one of X and Y is O and the other is CH ₂ ;

R1 is phenyl unsubstituted or substituted with one, two, or three substituents each independently selected from chloro, bromo, trifluoromethyl;

R ₂ is or -NH-(CH2) _n -R3 where n is 2 or 3,

R ₃ is -NR ₄ R ₅ , heterocycloalkyl, imidazolyl or triazolyl, where the heterocycloalkyl is unsubstituted or substituted with -C ₁ -C ₃ alkyl,

R ₄ is -C ₁ -C ₃ alkyl;

R5 is -C1-C3 alkyl;

or a pharmaceutical acceptable salt thereof,

for use in the treatment, prophylaxis or prevention of fungal infections, preferably Candida infections.

In a representative configuration of compounds of Formula (I), Formula (II) or Formula (III), R ₂ is -NH-(CH ₂ ) _n -R3.

Preferably R ₃ is -NR ₄ R ₅ or a heterocycloalkyl selected from morpholino, 1 -piperidyl, or piperazin-1-yl, where the heterocycloalkyl is unsubstituted or substituted with -C ₁ -C ₃ alkyl, R ₄ is -C ₁ -C ₃ alkyl, and R ₅ is -C ₁ -C ₃ alkyl.

Typically, the bond a is a trans double bond (E).

Most preferably, the compound is selected from the group consisting of:

4-[(2,4-dichlorophenoxy)methyl]-N-[2-(dimethylamino)ethyl ]benzamide,

4-[(2,4-dichlorophenyl)methoxy]-N-[2-(dimethylamino)ethyl ]benzamide,

4-[2-(2,4-dichlorophenyl)ethyl]-N-[2-(dimethylamino)ethyl ]benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[2-(dimethylamino)e thyl]benzamide,

N-[2-(dimethylamino)ethyl]-4-(2-phenylethyl)benzamide, N-[2-(dimethylamino)ethyl]-4-[(E)-styryl]benzamide,

4-[(2,4-dichlorophenoxy)methyl]-N-[3-(4-methylpiperazin-1-yl )ethyl]benzamide,

4-[(2,4-dichlorophenoxy)methyl]-N-[3-(4-methylpiperazin-1-yl )propyl]benzamide,

N-[2-(dimethylamino)ethyl]-4-[(E)-2-(2,4,6-trichlorophenyl)v inyl]benzamide;methane,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[2-(dimethylamino)ethyl ]benzamide,

4-[(E)-2-(3,5-dibromophenyl)vinyl]-N-[2-(dimethylamino)ethyl ]benzamide,

N-[2-(dimethylamino)ethyl]-4-[(E)-2-[4-(trifluoromethyl)phen yl]vinyl]benzamide,

4-[(E)-2-[2,4-bis(trifluoromethyl)phenyl]vinyl]-N-[2-(dimeth ylamino)ethyl]benzamide,

4-[(E)-2-[3,5-bis(trifluoromethyl)phenyl]vinyl]-N-[2-(dimeth ylamino)ethyl]benzamide,

4-[2-(2,4-dichlorophenyl)butyl]-N-[2-(dimethylamino)ethyl]be nzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[2-(4-methylpiperazin- 1-yl)ethyl]benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[3-(4-methylpiperazin- 1-yl)propyl]benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-(2-morpholinoethyl)ben zamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-(3-morpholinopropyl)be nzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[2-(1-piperidyl)ethyl] benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[3-(1-piperidyl)propyl ]benzamide,

[4-[(E)-2-(2,4-dichlorophenyl)vinyl]phenyl]-(4-morpholino-1- piperidyl)methanone,

[4-[(E)-2-(2,4-dichlorophenyl)vinyl]phenyl]-[4-(4-ethylpiper azin-1-yl)-1-piperidyl]methanone,

N-[2-(4-methylpiperazin-1-yl)ethyl]-4-[(E)-2-(2,4,6-trich lorophenyl)vinyl]benzamide,

N-[3-(4-methylpiperazin-1-yl)propyl]-4-[(E)-2-(2,4,6-trichlo rophenyl)vinyl]benzamide,

N-(2-morpholinoethyl)-4-[(E)-2-(2,4,6-trichlorophenyl)vinyl] benzamide,

N-(3-morpholinopropyl)-4-[(E)-2-(2,4,6-trichlorophenyl)vinyl ]benzamide,

N-[3-(1-piperidyl)propyl]-4-[(E)-2-(2,4,6-trichlorophenyl)vi nyl]benzamide,

(4-morpholino-1-piperidyl)-[4-[(E)-2-(2,4,6-trichlorophenyl) vinyl]phenyl]methanone,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[2-(4-methylpiperazin-1 -yl)ethyl]benzamide,

4-[(E)-2-(3,5-dibromophenyl)vinyl]-N-[3-(4-methylpiperazin-1 -yl)propyl]benzamide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-(2-morpholinoethyl)benz amide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-(3-morpholinopropyl)ben zamide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[2-(1-piperidyl)ethyl]b enzamide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[3-(1-piperidyl)propyl] benzamide,

[4-[(E)-2-(2,4-dibromophenyl)vinyl]phenyl]-(4-morpholino-1-p iperidyl)methanone,

[4-[(E)-2-(2,4-dibromophenyl)vinyl]phenyl]-[4-(4-ethylpipera zin-1-yl)-1-piperidyl]methanone, and

[4-(4-ethylpiperazin-1-yl)-1-piperidyl]-[4-[(E)-2-(2,4,6- trichlorophenyl)vinyl]phenyl]methanone.

The invention further relates to the use of a compound according to Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment, prophylaxis or prevention of fungal infections, preferably Candida infections. The present invention further provides a method for the prophylaxis, prevention and/or the treatment of fungal infections, preferably Candida infections which comprises the administration of a therapeutically active amount of a compound according to Formula (I), Formula (II), or Formula (III).

The present invention further provides compounds according to Formula (IV) and Formula (V)

wherein

the bond a is a single bond, a trans double bond (E), or a triple bond;

Ri is phenyl substituted with one, two, or three substituents each independently selected from chloro, bromo, trifluoromethyl;

R ₂ is or -NH-(CH ₂ ) _n -R3 where n is 2 or 3,

R ₃ is -NR ₄ R ₅ , heterocycloalkyl, imidazolyl or triazolyl, where the heterocycloalkyl is unsubstituted or substituted with -C ₁ -C ₃ alkyl,

R ₄ is -C1-C ₃ alkyl,

R5 is -C1-C3 alkyl,

or a pharmaceutical acceptable salt thereof.

In a representative configuration of compounds of Formula (IV) or Formula (V), R ₂ is - NH-(CH ₂ ) _n -R3.

Preferably R ₃ is -NR4R5 or a heterocycloalkyl selected from morpholino, 1 -piperidyl, or piperazin-1-yl, where the heterocycloalkyl is unsubstituted or substituted with -C1-C ₃ alkyl, R ₄ is -C1-C ₃ alkyl, and R5 is -C1-C ₃ alkyl.

Typically, the bond a is a trans double bond (E). Most preferably the compound is selected from the group consisting of:

4-[2-(2,4-dichlorophenyl)ethyl]-N-[2-(dimethylamino)ethyl ]benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[2-(dimethylamino)e thyl]benzamide,

N-[2-(dimethylamino)ethyl]-4-[(E)-2-(2,4,6-trichloropheny l)vinyl]benzamide;methane,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[2-(dimethylamino)ethyl ]benzamide,

4-[(E)-2-(3,5-dibromophenyl)vinyl]-N-[2-(dimethylamino)ethyl ]benzamide,

N-[2-(dimethylamino)ethyl]-4-[(E)-2-[4-(trifluoromethyl)phen yl]vinyl]benzamide,

4-[(E)-2-[2,4-bis(trifluoromethyl)phenyl]vinyl]-N-[2-(dimeth ylamino)ethyl]benzamide,

4-[(E)-2-[3,5-bis(trifluoromethyl)phenyl]vinyl]-N-[2-(dimeth ylamino)ethyl]benzamide,

4-[2-(2,4-dichlorophenyl)butyl]-N-[2-(dimethylamino)ethyl]be nzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[2-(4-methylpiperazin- 1-yl)ethyl]benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[3-(4-methylpiperazin- 1-yl)propyl]benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-(2-morpholinoethyl)ben zamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-(3-morpholinopropyl)be nzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[2-(1-piperidyl)ethyl] benzamide,

4-[(E)-2-(2,4-dichlorophenyl)vinyl]-N-[3-(1-piperidyl)propyl ]benzamide,

[4-[(E)-2-(2,4-dichlorophenyl)vinyl]phenyl]-(4-morpholino-1- piperidyl)methanone,

[4-[(E)-2-(2,4-dichlorophenyl)vinyl]phenyl]-[4-(4-ethylpiper azin-1-yl)-1-piperidyl]methanone,

N-[2-(4-methylpiperazin-1-yl)ethyl]-4-[(E)-2-(2,4,6-trich lorophenyl)vinyl]benzamide,

N-[3-(4-methylpiperazin-1-yl)propyl]-4-[(E)-2-(2,4,6-trichlo rophenyl)vinyl]benzamide,

N-(2-morpholinoethyl)-4-[(E)-2-(2,4,6-trichlorophenyl)vinyl] benzamide,

N-(3-morpholinopropyl)-4-[(E)-2-(2,4,6-trichlorophenyl)vinyl ]benzamide,

N-[3-(1-piperidyl)propyl]-4-[(E)-2-(2,4,6-trichlorophenyl)vi nyl]benzamide,

(4-morpholino-1-piperidyl)-[4-[(E)-2-(2,4,6-trichlorophenyl) vinyl]phenyl]methanone,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[2-(4-methylpiperazin-1 -yl)ethyl]benzamide,

4-[(E)-2-(3,5-dibromophenyl)vinyl]-N-[3-(4-methylpiperazin-1 -yl)propyl]benzamide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-(2-morpholinoethyl)benz amide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-(3-morpholinopropyl)ben zamide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[2-(1-piperidyl)ethyl]b enzamide,

4-[(E)-2-(2,4-dibromophenyl)vinyl]-N-[3-(1-piperidyl)propyl] benzamide,

[4-[(E)-2-(2,4-dibromophenyl)vinyl]phenyl]-(4-morpholino-1-p iperidyl)methanone,

[4-[(E)-2-(2,4-dibromophenyl)vinyl]phenyl]-[4-(4-ethylpipera zin-1-yl)-1-piperidyl]methanone, and

[4-(4-ethylpiperazin-1-yl)-1-piperidyl]-[4-[(E)-2-(2,4,6- trichlorophenyl)vinyl]phenyl]methanone. The invention further provides pharmaceutical compositions comprising a compound according to Formula (IV) or Formula (V) in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.

The invention further provides a compound according to Formula (IV) or Formula (V) for use in medicine.

The invention further provides a compound according to Formula (IV) or Formula (V) or a pharmaceutical composition thereof according to the invention for use in treatment, prophylaxis or prevention of fungal infections, preferably Candida infections.

The present invention further provides a method for the prophylaxis, prevention and/or the treatment of fungal infections, preferably Candida infections which comprises the

administration of a therapeutically active amount of a compound according to Formula (IV) or Formula (V).

Definitions

The term "alkyl", as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals such as "C1 -C3 alkyl", "C1 -C6 alkyl," or "C1 -C12 alkyl", containing between one and three, one and six, or one and twelve carbon atoms, respectively. Examples of C1 -C3 alkyl radicals include methyl, ethyl, propyl and isopropyl radicals.

The term "heterocycloalkyl," as used herein, refers to a non-aromatic 5-, 6- or 7- membered ring or a bi-or tri-cyclic group fused system, where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5- membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds,

(iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above rings may be fused to a benzene ring, and (v) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted.

Representative heterocycloalkyl groups include, but are not limited to, [l,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl.

The term "substituted heterocycloalkyl", as used herein, refers to a heterocycloalkyl group, as previously defined, substituted by one, two, three or more aliphatic substituents.

As used herein, the term“pharmaceutically acceptable salts” includes acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo or by freeze-drying). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion using a suitable ion exchange resin.

In the context of the present specification, the term“treat” also includes“prophylaxis” unless there are specific indications to the contrary. The term“treat” within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring condition and continued therapy for chronic disorders.

The compounds of the present invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly, vaginaly, rectaly and by injection into the joints.

The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.

For preparing pharmaceutical compositions from the compounds of the present invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersable granules, capsules, cachets, and

suppositories.

A solid carrier can be one or more substances, which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.

In powders, the carrier is a finely divided solid, which is in mixture with the finely divided compound of the present invention. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogenous mixture is then poured into conveniently sized molds and allowed to cool and solidify.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.

The term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavouring agents, stabilizers, and thickening agents as desired. Aqueous solutions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

Depending on the mode of administration, the pharmaceutical composition will according to one embodiment of the present invention include 0.05% to 99% weight (percent by weight), according to an alternative embodiment from 0.10 to 50% weight, of the compound of the present invention, all percentages by weight being based on total composition.

A therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.

The above-mentioned subject-matter for a pharmaceutical composition comprising a compound according to the present invention is applied analogously for a pharmaceutical composition comprising a combination according to the present invention. Another object of the present invention is a compound as disclosed above for use in medicine.

Another object of the present invention is a pharmaceutical formulation comprising a compound as disclosed above in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.

It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein.

The use of the word“a” or“an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean“one,” but it is also consistent with the meaning of “one or more,”“at least one,” and“one or more than one.”

These, and other, embodiments of the invention will be better appreciated and understood when considered in conjunction with the following description and the

accompanying drawings. It should be understood, however, that the following description, while indicating various embodiments of the invention and numerous specific details thereof, is given by way of illustration and not of limitation. Many substitutions, modifications, additions and/or rearrangements may be made within the scope of the invention without departing from the spirit thereof, and the invention includes all such substitutions, modifications, additions and/or rearrangements.

EXAMPLES

A method to screen large chemical compound libraries for Y-H transition inhibitors was developed. The ideal compounds are those that prevent C. albicans morphotype transition from yeast form to hyphal form without affecting the cellular viability of fungal cells. The method is based on automated microscopic imaging of labeled fungal cells and thereafter quantitative image analysis, referred to as high-content analysis (HCA). Using HCA, we calculated the mean object shape (MOS) and length/width ratio (LWR) of fungal cells. MOS and LWR were selected to define and quantify the Y-H transition.

To verify the method, farnesol, a natural quorum-sensing molecule secreted by C.

albicans was used. Farnesol blocks hyphal growth without affecting the proliferation as yeast- form cells C. albicans (Ramage G., Saville S. P., Wickes B. L. Inhibition of Candida albicans Biofilm Formation by Farnesol, a Quorum-Sensing Molecule. Appl. Environ. Microbiol. 2002, 68, 5459-5463). In addition, knockout-mutant strains that are restricted to yeast-form growth, namely, Aedtl 10 and Aefgl (Lo H. J. et al. Nonfilamentous C. albicans Mutants Are Aviruient. Cell 1997, 90, 939-949) were used. These transcription factor knockout strains are unable to switch from yeast form to hyphal growth, even when growing in otherwise hypha-inducing conditions.

Microbiological methods

Media, conditions for cultivation of fungi and cell concentrations were based on the guidelines for antifungal susceptibility testing (AFST) set by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Compound screen

Compounds were screened for their ability to block morphological switching in Candida albicans SC5314 (C. albicans). The screen was performed largely as in Stylianou M et al. Novel High-Throughput Screening Method for Identification of Fungal Dimorphism Blockers. J Biomol Screen 20(2), 285-91 , 2015. Briefly, C. albicans was grown over night in synthetic complete dropout medium with 2% glucose (SC) by shaking at 30 °C. Subcultures were inoculated to 10 ⁷ cells/ml in fresh media and grown as above for 4 h. Cells were pelleted and diluted to a concentration of 5 x 10 ⁵ C. albicans cells/ml in phosphate-buffered saline (PBS). Experiments were performed in black, 96-well plate with transparent bottom (Costar, Fisher Scientific, Waltham, MA). To improve microscopic imaging the cells were kept at the bottom of the wells by treating the plates with 0.001% Poly-L-lysine lysine (Sigma-Aldrich, St. Louis, MO) for 15 min followed by two washes with PBS before use. To each well of the black plates 130 ml RPMI 1640 growth medium (Lonza, Basel, Switzerland) was added. The compounds to be tested were diluted to 1.25 mM, 0.63 mM, 0.31 mM and 0.16 mM in DMSO (Sigma-Aldrich) and added to the experimental plates to the final concentrations of 12.5 mM, 6.3 mM, 3.1 mM and 1.6 mM. RPMI and compounds/DMSO for hyphal controls were incubated together for 1 h, shaking, at room temperature to allow even distribution of compound in the media before the addition of 10 ⁴ C. albicans cells/well, making a total volume of 150 mI/well. Controls were present as hyphal form controls containing RPMI, DMSO and C. albicans (as above), but no compounds, as yeast form controls containing RPMI, DMSO and dead yeast form C. albicans (volumes as above). Yeast form controls were killed by a 15-min incubation with 0.1 % w/v Thimerosal (Sigma- Aldrich) and serve as morphological references for a blockage of morphotype switching as well as for fungicidal activity. Plates were run in four identical copies and were incubated at 37 °C with 5% CO ₂ to stimulate hyphal formation. After 6 and 24 h respectively plates were analyzed for morphological determination by array scan analysis. The inhibitory effect of a tested compound is expressed as the lowest concentration of the compound that effects inhibition of Y- H transition in average of the replicates, i.e. the lowest concentration of the test compound at which the fungi remains in yeast form. The results are summarized in Tables 1 , 2 and 3. Determination of morphology by HCA

Morphology of the fungi was determined at 6 and 24 h by analyzing the plates using an automated microscope (HCA-Cellomics ArrayScan VTI, Thermo Scientific) at the Laboratories for Chemical Biology Umea (LCBU), Chemical Biology Consortium Sweden (CBCS). Prior to analysis the fungal cells were fixed with 1.4% Paraformaldehyde (PFA) and stained with 0.1% calcofluor white (CFW, Sigma-Aldrich), a chitin specific fluorescent dye. Using the information from the HCA microscopy the morphological form of the individual fungal cells was determined by measurements of mean hyphal average length and mean object average intensity at 6 and 24 h respectively. Mean object average intensity was used at 24 h as the wells are by this time overgrown with hyphae if the compounds have not been able to block morphological switching. The assay was performed with three technical replicates each of at least two biological replicates.

Determination of morphology by manual microscopy

Morphology of the fungi was determined at 6 and 24 h by analyzing the plates under an inverted light microscope at 20x magnification. Prior to analysis the fungal cells were fixed with 1.4% Paraformaldehyde (PFA) and stained with 0.1% calcofluor white (CFW, Sigma-Aldrich), a chitin specific fluorescent dye. The morphology of the fungi of each well was assessed and categorized as either yeast, affected growth or hyphae. To be classified as“yeast” the vast majority of the fungi had to have retained their circular, non-hyphenated morphology, whilst “affected growth” was defined as being fungi with clearly stunted hyphal growth. The assay was performed with six technical replicates, distributed equally on duplicate plates, for each biological replicate. At least two biological replicates were analyzed per compound used. The results of the six technical replicates were combined into one result before comparing the outcome of the biological replicates. Where there were discrepancies between the biological replicates, the combined result was defined as the more conservative of the results for cases with two biological replicates, i.e if one biological replicate showed“yeast” and the other “affected growth”, the overall result was defined as“affected growth”. In cases where more than two biological replicates had been studied, the final result was based on the outcome of the majority of the biological replicates.

Statistical analysis and Determination of positive hits

The morphological data from 6 and 24 h were combined to determine what compounds affect the fungal ability to switch from yeast to hyphal form. To be considered a positive hit compounds must cause the morphological form to be yeast at both 6 and 24 h. Results

The compound A (ID: 7551581) was identified as a positive hit and used as the

starting point for further synthesis of new compounds for evaluation for their ability to block morphological switching in Candida albicans SC5314 (C. albicans).

Compounds were tested for their ability to block morphological switching in Candida albicans SC5314 (C. albicans) as described above at increasing concentrations. The lowest concentration of compound as an average of replicates causing complete blockages of morphological switching and keeping the fungal cell in the yeast form was determined at 6h and 24h and was taken as a measure of the activity of the compound.

Table 1. Lowest active concentration of compound as an average of replicates effecting inhibition of Y-H transition

Table 2. Lowest active concentration of compound as an average of replicates for inhibition of Y-H transition

Table legend: (-) = not determined

Table 3. Lowest active concentration of compound as an average of replicates for inhibition of Y-H transition

Chemical synthesis and Analytical data

General synthesis schemes

Experimental procedures 1-52

Compound 1 : To a solution of methyl 4-hydroxybenzoate (250 mg, 1.64 mmol) in acetone (10 mL) were added K ₂ CO ₃ (1.4 g, 9.8 mmol, 6 equiv) and 2,4-dichloro-1-(chloromethyl)benzene (481 mg, 2.47 mmol). The resultant reaction mixture was refluxed for 14 h. Then it was allowed to cool to room temperature, filtered and washed with acetone (2 x 10 mL). Filtrate was concentrated under reduced pressure and the residue was purified over silica gel column chromatography (5- 10% EtOAc/pet ether) to get compound 51 a (299 mg, 73%) as a white solid; Mp 146-149 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.01 (d, J = 8.9 Hz, 2H), 7.47 (d, J = 8.3 Hz, 1 H), 7.43 (d, J = 2.1 Hz, 1 H), 7.28 (dd, J = 8.3, 2.1 Hz, 1 H), 6.99 (d, J = 8.9 Hz, 2H), 5.17 (s, 2H), 3.89 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.8, 162.0, 134.5, 133.4, 132.8, 131.8, 129.7, 129.5, 127.5, 123.4, 1 14.5,

66.8, 52.1.

To the above obtained compound 54a (270 mg, 0.87 mmol) was added MeOH:THF (1 :1 , 10 mL) followed by 50% aqueous NaOH (0.5 mL) and heated at 60 °C for 2 h (monitored by TLC). Then all volatiles were removed under reduced pressure and the residue was dissolved in water (10 mL) and made acidic till pH 1-2 by using cone. HCI. Then it was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to get the carboxylic acid as a white solid. And it was proceeded for the next step. T o the white solid, toluene (1 mL) and SOCb (1 mL) was added and heated at 90 °C for 5 h and then all volatiles were removed under reduced pressure and the residue was co-evaporated with anhydrous toluene (2 mL). The residues was taken in anhydrous THF (2 mL) and then it was added to a cooled 0 °C solution of N,N-dimethylethylenediamine (77 mg, 0.87 mmol), Et ₃ N (96 mg, 0.95 mmol) in anhydrous THF (2 mL). Reaction solution was allowed to warm to room temperature and stirred at room temperature for 12 h. Then reaction solution was concentrated under reduced pressure and the residue was taken in EtOAc (20 mL) and washed with 5% aqueous Na ₂ C0 ₃ (2 x 20 mL), water, brine, dried over Na ₂ SO ₄ , concentrated. The residue was purified over silica gel column chromatography (2-15% MeOH/CH2Cb with 1 % EtsN) to get compound 1 (275 mg, 86%) as a white solid; Mp 102-104 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.78 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.3 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.28 (dd, 1 H, J = 8.3, 1.9 Hz, merged with CHCb), 6.98 (d, J = 8.8 Hz, 2H), 6.85 (br s, 1 H), 5.15 (s, 2H), 3.52 (q, J = 5.3 Hz, 2H), 2.55 (t, J = 5.9 Hz, 2H), 2.30 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.0, 160.7, 134.5, 133.3, 133.0, 129.7, 129.4, 129.1 ,

127.8, 127.5, 114.6, 66.7, 58.0, 45.2, 37.1 ; IR (neat) 3441 , 3074, 2945, 2821 , 1636, 1504, 1468, 1305, 1248, 1182, 1041 , 844, 766 cm ^-1 ; HRMS ealed for C ₁₈ H _2i Cl ₂ N ₂ 0 ₂ (M+H), 367.0980; found, 367.0988; Purity by LCMS 99.7%.

Compound 5: Experimental procedure is similar to that for compound 1. After column purification the product 5 (643 mg, 43% in four steps) was obtained as a white solid; Mp 115-116 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.76 (d, J = 8.8 Hz, 2H), 7.48-7.28 (m, 5H), 6.99 (d, J = 8.8 Hz, 2H), 6.74 (br s, 1 H), 5.10 (s, 2H), 3.59-3.43 (m, 2H), 2.50 (t, J = 5.9 Hz, 2H), 2.26 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.0, 161.3, 136.5, 128.9, 128.8, 128.3, 127.6, 127.4, 1 14.7, 70.2, 57.9, 45.3, 37.2; IR (neat) 3326, 3051 , 2941 , 2820, 2786, 1635, 1503, 1456, 1305, 1265, 1179, 1039, 844, 736 cm ^-1 ; HRMS calcd for C ₁₈ H ₂₃ N ₂ 0 ₂ (M+H), 299.1760; found, 299.1758; Purity by LCMS 98.0%.

Compound 4: To a solution of methyl 4-(bromomethyl)benzoate 55 (750 mg, 3.27 mmol) in acetone (15 mL) were added K2CO3 (2.7 g, 19.8 mmol) and phenol (740 mg, 7.87 mmol). The resultant reaction mixture was refluxed for 12 h. Then it was allowed to cool to room temperature, filtered and washed with acetone (2 x 15 mL). Filtrate was concentrated under reduced pressure and the residue was purified over silica gel column chromatography (2-6% EtOAc/pet ether) to get phenyl benzyl ether compound. And then it was dissolved in MeOH:THF:H ₂ 0 (1 :3: 1 , 34 mL) and then added LiOH.H2O (1.0 g, 23.8 mmol) and stirred at room temperature for overnight. Reaction solution was acidified till pH 1 by using cone. HCI. Then it was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to get the carboxylic acid. And it was taken in CH2CI2 (10 mL) and SOCI2 (10 mL) and DMF (0.1 mL) was added and heated at reflux for 10 h and stirred at room temperature for two days, then all volatiles were removed under reduced pressure and the residue was co evaporated with anhydrous CH2CI2 (10 mL) to get a yellowish oil. The residues was taken in anhydrous THF (3 mL) and then it was added to a cooled 0 °C solution of L/,L/- dimethylethylenediamine (77 mg, 0.87 mmol), Et ₃ N (96 mg, 0.95 mmol) in anhydrous THF (4 mL). Reaction solution was allowed to warm to room temperature and stirred at room temperature for overnight. Then reaction solution was concentrated under reduced pressure and the residue was taken in EtOAc (30 mL) and washed with 5% aqueous Na ₂ C0 ₃ (30 mL), water, brine, dried over Na ₂ SO ₄ , concentrated. The residue was purified over silica gel column chromatography (2-15% MeOH/CHaC ) to get compound 4 (220 mg, 22% in four steps) as a white solid; Mp 91-92 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.79 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.32-7.20 (m, 2H), 6.98-6.91 (m, 3H), 6.89 (br s, 1 H), 5.09 (s, 2H), 3.57-3.44 (m, 2H), 2.52 (t, J = 5.9 Hz, 2H), 2.26 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.2, 158.6, 140.7, 134.2, 129.6, 127.4, 127.3, 121.3, 1 14.9, 69.4, 57.8, 45.2, 37.2; IR (neat) 3441 , 3074, 2945, 2821 , 1636, 1504, 1468, 1305, 1248, 1 182, 1041 , 844, 766 cm ^-1 ; HRMS calcd for C ₁₈ H ₂₃ N ₂ 0 ₂ (M+H), 299.1760; found, 299.1759; Purity by LCMS 99.0%.

Carboxylic acid 57: Experimental procedure is similar to that for compound 1. To a solution of methyl 4-(bromomethyl)benzoate 55 (0.92 g, 4.0 mmol) in acetone (20 mL) were added K ₂ CO ₃ (3.30 g, 24.0 mmol) and 2,4-dichlorophenol (0.85 g, 5.2 mmol). The resultant reaction mixture was stirred at 60 °C for 10 h. Then it was allowed to cool to room temperature, filtered and washed with acetone (2 x 10 mL). Filtrate was concentrated under reduced pressure and the residue was taken in MeOH HF (1 : 1 , 40 mL) and added 50% aqueous NaOH (1.6 mL). Resultant reaction solution was stirred at room temperature for 6 h and then all volatiles were removed under reduced pressure and the residue was dissolved in water (15 mL) and extracted with Et ₂ 0 (3 x 15 mL) to remove impurities. Aqueous phase was made acidic till pH 1-2 by using cone. HCI and saturated with solid NaCI. Then it was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to get the carboxylic acid 57 ⁷ (1.09 g, 92%) as a white solid. Mp 205-207 °C; ¹ H NMR (400 MHz, DMSO-d ₆ ) d 12.99 (s, 1 H), 7.98 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 2.6 Hz, 1 H), 7.57 (d, J = 8.3 Hz, 2H), 7.37 (dd, J = 8.9, 2.6 Hz, 1 H), 7.24 (d, J = 8.9 Hz, 1 H), 5.31 (s, 2H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) d 167.0, 152.5,

141.2, 130.4, 129.5, 129.4, 128.1 , 127.2, 124.8, 122.6, 115.5, 69.7.

Compound 7551581 : To a suspension of compound 57 (200 mg, 0.67 mmol) in anhydrous toluene (0.7 mL) was added thionyl chloride (SOCI ₂ , 0.7 mL). The resultant solution was heated at 90 °C for 6 h and then all volatiles were removed under reduced pressure and the residue was co-evaporated with anhydrous toluene (2 mL). The residues was taken in anhydrous THF (1 mL) and then it was added to a cooled 0 °C solution of N,N-dimethylethylenediamine (59 mg, 0.67 mmol), Et ₃ N (75 mg, 0.74 mmol) in anhydrous THF (1 mL). Reaction solution was allowed to warm to room temperature and stirred at room temperature for 9 h. Then reaction solution was concentrated under reduced pressure and the residue was taken in EtOAc (20 mL) and washed with 5% aqueous Na ₂ C0 ₃ (2 x 20 mL), water, brine, dried over Na ₂ SO ₄ , concentrated. The residue was purified over silica gel column chromatography (5-12% MeOH/CH ₂ CI ₂ ) to get 7551581 ⁶ (226 mg, 91 %) as a white solid. Mp 134-136 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.83 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 2.5 Hz, 1 H), 7.14 (dd, J = 8.8, 2.5 Hz, 1 H), 6.96 (s, 1 H), 6.84 (d, J = 8.8 Hz, 1 H), 5.16 (s, 2H), 3.54 (dt, = 6.1 , 5.1 Hz, 2H), 2.56 (t, J = 5.9 Hz, 2H), 2.30 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.1 , 152.8, 139.6, 134.5, 130.3, 127.7, 127.6, 127.1 , 126.4,

124.2, 1 14.8, 70.6, 57.9, 45.2, 37.2.

Compound 8: Experimental procedure is similar to that for compound 7551581. After column purification the product 8 (278 mg, 98%) was obtained as a white solid; Mp 155-156 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.79 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 2.6 Hz, 1 H), 7.14 (dd, J = 8.8, 2.6 Hz, 1 H), 6.85 (d, J = 8.8 Hz, 1 H), 6.83 (s, 1 H), 5.16 (s, 2H), 3.53 (td, J = 6.0, 4.8 Hz, 2H), 2.60 (t, J = 6.0 Hz, 2H), 2.57-2.34 (m, 8H), 2.29 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.0, 152.8, 139.6, 134.6, 130.3, 127.7, 127.4, 127.1 , 126.4, 124.22, 1 14.8, 70.6, 56.3, 55.3, 52.9, 46.2, 36.4; IR (neat) 3285, 2934, 1621 , 1545, 1331 , 1284, 1 165, 1060, 866, 742 cm ^-1 ; HRMS ealed for C ₂₁ H ₂₆ CI ₂ N ₃ 0 ₂ (M+H), 422.1402; found, 422.1400; Purity by LCMS 99.1 %.

Compound 9: Experimental procedure is similar to that for compound 7551581. After column purification the product 9 (283 mg, 96%) was obtained as a white solid; Mp 99-102 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.25 (br s, 1 H), 7.88 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 2.5 Hz, 1 H), 7.15 (dd, J = 8.8, 2.5 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 5.18 (s, 2H), 3.65-3.53 (m, 2H), 2.91-2.39 (m, 10H), 2.33 (s, 3H), 1.85 (p, J = 6.1 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.9, 152.7, 139.4, 134.5, 130.1 , 127.6, 126.9, 126.3, 124.1 , 1 14.8, 70.5, 57.6, 54.4, 52.8, 45.8,

40.1 , 24.2; IR (neat) 3285, 2934, 1621 , 1545, 1331 , 1284, 1 165, 1060, 866, 742 cm ^-1 ; HRMS calcd for C22H2 ₈ CI2N ₃ O2 (M+H), 436.1559; found, 436.1564; Purity by LCMS 99.1 %.

Synthesis of ethyl-4-[(diethoxyphophinyl)methyl]benzoate 59: A mixture of ethyl 4- (bromomethyl)benzoate (10 g, 41 mmol) and triethyl phosphite (P(OEt)3, 30 mL) was heated at reflux for overnight and then all volatiles were removed under reduced and the residue was purified over silica gel column chromatography (20-100% EtOAc/pet ether) to get phosphonate 59 ⁸ (1 1.8 g, 96%) as a colorless oil; ¹ H NMR (400 MHz, CDCI ₃ ) d 7.97 (d, J = 7.4 Hz, 2H), 7.35 (dd, J = 8.4, 2.5 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.08-3.91 (m, 4H), 3.18 (d, J = 22.2 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 6H); ¹³ C NMR (100 MHz, CDCI ₃ ) d 166.5, 137.1 , 129.9, 129.8, 129.2, 62.4, 62.3, 61.0, 34.8, 33.4, 16.5, 16.4, 14.4.

General procedure for making unsaturated esters 60a-h: To a cooled 0 °C solution of phosphonate 59 (3.25 mmol, 1.3 equiv.) in anhydrous THF (8 mL) was added NaH (120 mg, 3.0 mmol) and stirred for 15 min. Then a solution of aldehydes 58a-h (2.5 mmol, 1.0 equiv.) in anhydrous THF (4 mL) was added dropwise. The resulting solution was allowed to warm to room temperature until completion of starting of aldehydes 58a-h (monitored by TLC). Then reaction solution was quenched by adding saturated aqueous NH4CI (15 mL) and then extracted with EtOAc (3 x 15 mL). Combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated. The residue was purified over silica gel column chromatography (1-5% or 5-20% EtOAc/pet ether) to get compounds 60a-h.

Data of ester 60a: The ester 60a was obtained as a white solid (3.34 g, 91 %); Mp 101-103 °C; ¹ H NMR (400 MHz, CDCI ₃ ) d 8.04 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.5 Hz, 1 H), 7.58 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 16.3 Hz, 1 H), 7.42 (d, J = 2.1 Hz, 1 H), 7.30-7.21 (m, 1 H), 7.07 (d, J = 16.3 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCI ₃ ) d 166.4,

141.1 , 134.3, 134.2 133.6, 130.7, 130.2, 130.0, 129.8, 127.5, 127.4, 126.8, 126.1 , 61.2, 14.5; IR (neat) 2986, 1701 , 1632, 1508, 1468, 1307, 1276, 1 107, 1048, 834, 765 cm ^-1 ; HRMS calcd for C ₁₇ H ₁₄ ³⁵ CI ³⁷ CINa0 ₂ (M+Na), 345.0239; found, 345.0230.

Data of ester 60b: The ester 60b was obtained as a white solid (240 mg, 68%); Mp 75-77 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.05 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.38 (s, 2H), 7.20 (d, J = 16.7 Hz, 1 H), 7.13 (d, J = 16.7 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.4, 140.9, 136.5, 135.2, 133.4, 132.9, 130.3, 130.2, 128.8, 126.8, 124.1 , 61.18, 14.49; IR (neat) 2984, 1717, 1607, 1370, 1276, 1106, 970, 889, 764 cm ^-1 ; HRMS calcd for C^H ^C C NaC (M+Na), 378.9849; found, 378.9844. Data of ester 60c: The ester 60c was obtained as a white solid (463 mg, 75%); Mp 86-88 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.05 (d, J= 8.4 Hz, 2H), 7.76 (d, J= 2.0 Hz, 1H), 7.58 (d, J= 8.3 Hz, 2H), 7.54 (d, J= 8.4 Hz, 1H), 7.47 (d, J= 16.2 Hz, 1H), 7.46-7.43 (m, 1H), 7.05 (d, J= 16.2 Hz, 1H), 4.39 (q, J= 7.1 Hz, 2H), 1.41 (t, J= 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.4, 141.1, 135.8, 135.6, 131.0, 130.2, 130.1, 128.8, 127.8, 126.8, 124.8, 122.2, 61.2, 14.5; IR (neat) 1706, 1641, 1463, 1278, 1104, 808, 764 cm ^-1 ; HRMS calcd for C ₁₇ H ₁₄ ⁸¹ Br ⁷⁹ BrNa0 ₂ (M+Na), 432.9238; found, 432.9228.

Data of ester 60d: The ester 60d was obtained as a white solid (422 g, 69%); Mp 136-138 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.04 (d, J= 8.4 Hz, 2H), 7.57 (dd, J= 6.6, 1.7 Hz, 3H), 7.53 (d, J = 8.4 Hz, 2H), 7.11 (d, J= 16.3 Hz, 1H), 7.01 (d, J= 16.3 Hz, 1H), 4.39 (q, J= 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.3, 140.6, 140.5, 133.3, 130.6, 130.2, 128.4,

128.1, 126.7, 123.4, 61.2, 14.5; IR (neat) 2986, 1711, 1606, 1546, 1283, 1108, 957, 762 cm ^-1 ; HRMS calcd for C ₁₇ H ₁₄ ⁸¹ Br ⁷⁹ BrNa0 ₂ (M+Na), 432.9238; found, 432.9241.

Data of ester 60e: The ester 60e was obtained as a white solid (740 mg, 95%); Mp 136-138 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.03 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 16.2 Hz, 1H), 7.09 (d, J = 16.3 Hz, 1H), 6.69 (s, 2H), 6.43 (t, = 2.3Hz, 1H), 4.39 (q, =7.1 Hz, 2H), 3.84 (s, 6H), 1.41 (t, J= 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.5, 161.2, 141.6, 138.9,

131.2, 130.1, 129.5, 128.3, 126.5, 105.0, 100.7, 61.1, 55.6, 14.5; IR (neat) 2995, 2838, 1699, 1591, 1457, 1308, 1244, 1154, 1067, 852, 763 cm ^-1 ; HRMS calcd for C ₁₉ H ₂₁ O ₄ (M+H), 313.1440; found, 313.1444.

Data of ester 60f: The ester 60f was obtained as a white solid (302 mg, 63%); Mp 129-131 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.05 (d, J= 8.4 Hz, 2H), 7.62 (s, 4H), 7.58 (d, J= 8.4 Hz, 2H), 7.21 (s, 2H), 4.39 (q, J= 7.1 Hz, 2H), 1.41 (t, J= 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.4, 141.0, 140.3, 130.2, 130.05, 129.6, 127.0, 126.7, 125.8, 61.2, 14.5; IR (neat) 3055, 2986, 2305, 1712, 1614, 1325, 1266, 1168, 1110, 1016, 739 cm ^-1 ; HRMS calcd for C ₁₉ H ₂₃ CI ₂ N ₂ 0 (M+H), 365.1187; found, 365.1192.

Data of ester 60g: The ester 60g was obtained as a white solid (486 mg, 83%); Mp 112-114 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.00 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 10.7 Hz, 2H), 7.73 (d, J = 8.6 Hz, 1 H), 7.52 (d, J= 8.4 Hz, 2H), 7.47 (dd, J= 16.2, 2.3 Hz, 1H), 7.11 (d, J= 16.1 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.3, 140.4, 139.6, 134.1, 130.7, 130.3, 129.9, 128.9, 128.5, 127.9, 127.1, 125.3, 123.6,61.26, 14.47; IR (neat) 2986, 2907, 2305, 1716, 1622, 1346, 1281, 1086, 972, 850, 743 cm ^-1 ; HRMS calcd for C ₁₉ H ₂₃ CI ₂ N ₂ 0 (M+H), 365.1187; found, 365.1192. Data of ester 60h: The ester 60h was obtained as a white solid (360 mg, 62%); Mp 151-153 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.00 (d, J= 8.5 Hz, 2H), 7.86 (s, 2H), 7.70 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.18 (d, J= 16.0 Hz, 1H), 7.17 (d, J= 16.0 Hz, 1H), 4.32 (q, J= 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.3, 140.3, 139.0, 132.6, 132.0, 131.6, 130.6, 130.3, 127.9, 126.9, 126.5, 124.8, 121.4, 61.2, 14.5; IR (neat) 2990, 2254, 1711, 1607, 1380, 1280, 1180, 910, 742 cm ^-1 ; HRMS calcd for C ₁₉ H ₂₃ CI ₂ N ₂ O (M+H), 365.1187; found, 365.1192.

General procedure for ester hydrolysis to get carboxylic acids 61a-h: To a stirred solution of esters 60a-h (1.0 mmol) in MeOH:THF (1:1, 10 mL) was added 50% aqueous NaOH (0.5 mL) and heated at 60 °C for 30-50 min (monitored by TLC). Then all volatiles were removed under reduced pressure and the residue was dissolved in water (10 mL) and made acidic till pH 1-2 by using cone. HCI. Then it was extracted with EtOAc (3x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to get the carboxylic acids 60a-h as a white solid.

Data of acid 61a: The acid 61a was obtained as a white solid (2.65 g, 97%); Mp 270-273 °C; ¹ H NMR (400 MHz, DMSO-d ₆ ) d 12.99 (s, 1H), 7.94 (t, J= 8.8 Hz, 3H), 7.73 (d, J= 8.4 Hz, 2H), 7.65 (d, J= 2.1 Hz, 1H), 7.50 (d, J= 16.7 Hz, 1H), 7.48-7.45 (m, 1H), 7.42 (d, J= 16.3 Hz, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) d 166.9, 140.5, 133.4, 133.2, 133.1, 131.5, 130.2, 129.8, 129.1, 128.3, 127.8, 126.9, 124.8; IR (neat) 3059, 2827,2668, 1692, 1605, 1469, 1425, 1294, 1182, 1103, 936, 867, 765 cm ^-1 ; HRMS calcd for C19H23CI2N2O (M+H), 365.1187; found, 365.1192.

Data of acid 61b: The acid 61b was obtained as a white solid (0.52 g, 99%); Mp 75-77 °C; ¹ H NMR (400 MHz, DMSO-d ₆ ) d 13.01 (s, 1H), 7.96 (d, J= 8.3 Hz, 2H), 7.75 (s, 3H), 7.73 (s, 1H), 7.24 (d, J= 16.7 Hz, 1H), 7.16 (d, J= 16.7 Hz, 1H); ¹³ C NMR (100 MHz, DMSO) d 166.9, 140.0, 136.3, 134.4, 133.0, 132.7, 130.5, 129.8, 128.5, 126.9, 123.8; IR (neat) 2984, 1717, 1607, 1370, 1276, 1106, 970, 889, 764 cm ^-1 ; HRMS calcd for C ₁₉ H ₂₃ CI ₂ N ₂ 0 (M+H), 365.1187; found, 365.1192.

Data of acid 61 c: The acid 61 c was obtained as a white solid (1.86 g, quantitative); Mp 285-287 °C; ¹ H NMR (400 MHz, DMSO-d ₆ ) d 12.98 (br s, 1H), 7.96 (d, J= 8.4 Hz, 2H), 7.93 (d, J= 2.0 Hz, 1 H), 7.84 (d, J= 8.5 Hz, 1H), 7.73 (d, J= 8.4 Hz, 2H), 7.64 (dd, J= 8.5, 2.0 Hz, 1H), 7.45 (d, J = 16.3 Hz, 1H), 7.39 (d, J= 16.3 Hz, 1H); ¹³ C NMR (100 MHz, DMSO) d 166.9, 140.5, 135.4, 134.8, 131.6, 131.1, 130.2, 129.9, 128.7, 127.6, 126.9, 124.1, 121.6; IR (neat) 2815, 2666, 1678, 1603, 1571, 1428, 1291, 1182, 956, 809, 766 cm ^-1 ; HRMS calcd for C19H23CI2N2O (M+H), 365.1187; found, 365.1192.

Compound 2: To a stirred solution of compound 3 (30 mg, 0.08 mmol) in MeOH (1 mL) were added Ph ₂ S (0.15 mg, 1 mmol%) and Pd/C (10% w/w, 3 mg). The resultant solution was stirred under H ₂ atmosphere at room temperature for 63 h (reaction monitored by LCMS). Reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified over silica gel column chromatography (2-13% MeOH/CH ₂ CI ₂ ) to get compound 2 (24.6 mg, 82%) as a colorless oi; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.76 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 2.1 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 2H), 7.15 (br s, 1 H), 7.1 1 (dd, J = 8.2, 2.1 Hz, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 3.59 (q, J = 5.5 Hz, 2H), 2.98 (ddd, J = 8.6, 6.0, 2.0 Hz, 2H), 2.91 (ddd, J = 8.7, 5.9, 1.9 Hz, 2H), 2.67 (t, J = 5.8 Hz, 2H), 2.39 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.5, 144.9, 137.4,

134.6, 132.6, 132.4, 131.4, 129.4, 128.8, 127.4, 127.1 , 58.1 , 45.0, 36.8, 35.7, 35.0; IR (neat) 3441 , 3074, 2945, 2821 , 1636, 1504, 1468, 1305, 1248, 1182, 1041 , 844, 766 cm ^-1 ; HRMS calcd for C1 ₉ H2 ₃ CI2N2O (M+H), 365.1187; found, 365.1 192; Purity by LCMS 99.7%.

Compound 3: To a suspension of carboxylic acid 61 a (284 mg, 0.97 mmol) in anhydrous toluene (5 mL) was added SOCI2 (1.5 mL) and heated at 100 °C for 10 h and then all volatiles were removed under reduced pressure and the residue was co-evaporated with anhydrous toluene (2 mL). The residues was taken in anhydrous THF (2 mL) and then it was added to a cooled 0 °C solution of N,N-dimethylethylenediamine (86 mg, 0.98 mmol), EΐbN (108 mg, 1.07 mmol) in anhydrous THF (1 mL). Reaction solution was allowed to warm to room temperature and stirred at room temperature for 14 h. Then reaction solution was concentrated under reduced pressure and the residue was taken in EtOAc (15 mL) and washed with 5% aqueous Na2CC (2 x 10 mL), water, brine, dried over Na ₂ SC>4, concentrated. The residue was purified over silica gel column chromatography (2-13% MeOH/CH2Ch) to get compound 3 (283 mg, 81 %) as a white solid; Mp 132-134 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.81 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.5 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 16.3 Hz, 1 H), 7.40 (d, J = 2.1 Hz, 1 H), 7.24 (dd, J = 8.6, 1.9 Hz, 1 H), 7.06 (d, J = 16.3 Hz, 1 H), 6.98 (d, J = 5.2 Hz, 1 H), 3.62-3.47 (m, 2H), 2.58 (t, J = 5.9 Hz, 2H), 2.32 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.0, 139.8, 134.2, 134.0, 133.7, 130.7, 129.8,

127.7, 127.5, 127.4, 126.9, 125.4, 57.9, 45.2, 37.2; IR (neat) 3293, 2820, 1635, 1548, 1468, 1303, 1 191 , 1 100, 867, 739 cm ^-1 ; HRMS calcd for C ₁₉ H ₂₁ CI ₂ N ₂ 0 (M+H), 363.1031 ; found, 363.1033; Purity by LCMS 98.5%.

Compound 6: To a stirred solution of compound 7 (94 mg, 0.32 mmol) in MeOH (12 mL) was added Pd/C (10% w/w, 23 mg). The resultant solution was stirred under H ₂ atmosphere at room temperature for 10 h. Reaction solution was filtered and the filtrate was concentrated under reduced pressure to get compound 2 (93.7 mg, 99%) as a colorless oil; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.73 (d, J = 8.2 Hz, 2H), 7.27 (m, 2H), 7.24-7.18 (m, 3H), 7.17-7.12 (m, 2H), 6.97 (br s, 1 H), 3.56 (dt, J = 6.1 , 5.1 Hz, 2H), 3.01-2.88 (m, 4H), 2.60 (t, J = 5.8 Hz, 2H), 2.34 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.6, 145.5, 141.4, 132.3, 128.7, 128.6, 128.5, 127.3, 126.2, 58.1 , 45.2, 37.8, 37.7, 37.0; IR (neat) 3316, 2926, 2856, 1639, 1544, 1500, 1304, 1 189, 1028, 848 cm ^-1 ; HRMS calcd for C ₁₉ H ₂₅ N ₂ 0 (M+H), 297.1967; found, 297.1975; Purity by LCMS 98.1 %. Compound 7: Experimental procedure is similar to that for compound 3. After column purification the product 7 (263.7 mg, 90%) was obtained as a white solid; Mp 146-147 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.80 (d, J = 8.4 Hz, 2H), 7.60-7.48 (m, 4H), 7.37 (t, J = 7.5 Hz, 2H), 7.31-7.26 (m, 1 H), 7.18 (d, J = 16.3 Hz, 1 H), 7.11 (d, J = 16.3 Hz, 1 H), 6.91 (br s, 1 H), 3.54 (q, J = 5.4 Hz, 2H), 2.56 (t, J = 5.9 Hz, 2H), 2.30 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.2, 140.4, 137.0, 133.4, 130.6, 128.9, 128.2, 127.7, 127.6, 126.8, 126.6, 57.9, 45.3, 37.2; IR (neat) 3312, 2772, 1631 , 1545, 1263, 1161 , 969, 832, 749 cm ^-1 ; HRMS calcd for C ₁₉ H ₂₃ N ₂ 0 (M+H), 295.1810; found, 295.1809; Purity by LCMS 99.2%.

Compound 10: To a stirred solution of esters 60b (215 mg, 0.66 mmol) in MeOH:THF (1 : 1 , 12 mL) was added 50% aqueous NaOH (0.6 mL) and heated at 60 °C for 30 min (monitored by TLC). Then all volatiles were removed under reduced pressure and the residue was dissolved in water (10 mL) and made acidic till pH 1-2 by using cone. HCI. Then it was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to get the carboxylic acids as a white solid, which was proceeded for next step.

To the above obtained compound was added anhydrous CH ₂ CI ₂ (7 mL) followed by EDCI.HCI (139 mg, 0.72 mmol) and HOBT (107 mg, 0.79 mmol) and stirred for 15 min at room temperature. Then a solution of N,N-dimethylethylenediamine (61 mg, 0.69 mmol) in anhydrous CH ₂ CI ₂ (3 mL) was added dropwise. Resultant reaction solution was stirred at room temperature for 9 h. Then reaction solution was diluted with CH ₂ CI ₂ (15 mL) and washed with saturated aqueous NaHCCb (10 mL), water (10 mL), brine, dried over Na ₂ SO ₄ , concentrated. The residue was purified over silica gel column chromatography (5-15% MeOH/CH ₂ CI ₂ ) to get compounds 10 (158.2 mg, 66%, 2 steps) as a white solid; Mp 127-129 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.82 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.38 (s, 2H), 7.18 (d, J = 16.7 Hz, 1 H), 7.10 (d, J = 16.7 Hz, 1 H), 6.90 (br s, 1 H), 3.59-3.47 (m, 2H), 2.55 (t, J = 5.9 Hz, 2H), 2.29 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.0, 139.5, 136.5, 135.1 , 134.4, 133.3, 133.0, 128.7, 127.6, 126.9, 123.5, 57.8, 45.3, 37.3; IR (neat) 3270, 2938, 2771 , 1628, 1538, 1434, 1366, 1309, 1190, 1042, 852, 793 cm ^-1 ; HRMS calcd for C ₁₉ H ₂₀ CbN ₂ O (M+H), 397.0641 ; found, 397.0640; Purity by LCMS 98.5%.

Compound 11 : Experimental procedure is similar to that for compound 10. After column purification the product 11 (377.4 mg, 74%, 2 steps) was obtained as a white solid; Mp 137-139 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.80 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 2.0 Hz, 1 H), 7.56 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.4 Hz, 1 H), 7.46-7.39 (m, 2H), 7.03 (d, J = 16.2 Hz, 1 H), 6.91 (t, J = 5.0 Hz, 1 H), 3.59-3.47 (m, 2H), 2.55 (t, J = 5.9 Hz, 2H), 2.29 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.0, 139.7, 135.8, 135.5, 134.2, 131.0, 130.9, 128.2, 127.8, 127.7, 127.0, 124.7, 122.0, 57.8, 45.3, 37.3; IR (neat) 3229, 3053, 2975, 2779, 1640, 1545, 1462, 1306, 1034, 962, 827, 732 cm ^-1 ; HRMS calcd for C ₁₉ H ₂₁ Br ₂ N ₂ 0 (M+H), 451.0021 ; found, 451.0023; Purity by LCMS 98.5%. Compound 12: Experimental procedure is similar to that for compound 10. After column purification the product 12 (362 mg, 86%, 2 steps) was obtained as a white solid; Mp 149-151 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.81 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 1.7 Hz, 2H), 7.55 (t, J = 1.7 Hz, 1 H), 7.52 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 16.3 Hz, 1 H), 6.98 (d, J = 16.3 Hz, 2H), 3.55 (q, J = 5.4 Hz, 2H), 2.57 (t, J = 5.9 Hz, 2H), 2.31 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.0, 140.6, 139.3, 134.2, 133.2, 130.6, 128.4, 127.7, 127.5, 126.9, 123.4, 57.9, 45.2, 37.2; IR (neat) 3229, 3053, 2975, 2779, 1640, 1545, 1462, 1306, 1034, 962, 827, 732 cm ^-1 ; HRMS calcd for C ₁₉ H _2i Br ₂ N ₂ 0 (M+H), 451.0021 ; found, 451.0029; Purity by LCMS 98.5%.

Compound 130Me: Experimental procedure is similar to that for compound 10. After column purification the product 13 (604 mg, 77%, 2 steps) was obtained as a white solid; Mp 107-109 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.72 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.01 (s, 2H), 6.90 (t, J = 4.8 Hz, 1 H), 6.60 (d, J = 2.3 Hz, 2H), 6.34 (t, J = 2.2 Hz, 1 H), 3.76 (s, 6H), 3.54-3.41 (m, 2H), 2.51 (t, J = 5.9 Hz, 2H), 2.25 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.2, 161.1 , 140.2, 139.0, 133.5, 130.6, 128.3, 127.6, 126.6, 104.9, 100.5, 57.9, 55.5, 45.2, 37.2; IR (neat) 3229, 3053, 2975, 2779, 1640, 1545, 1462, 1306, 1034, 962, 827, 732 cm ^-1 ; HRMS calcd for C21 H27N2O3 (M+H), 355.2022; found, 355.2026; Purity by LCMS 98.5%.

Compound 13: To a cooled -40 °C solution of compound 130Me (330 mg, 0.93 mmol) in anhydrous CH2CI2 (10 mL) was added BBr3 (1.0 M in THF, 2.80 mL, 2.80 mmol). Resultant reaction solution was slowly allowed to warm to 0 °C and stirred for 7 h. Then reaction solution was quenched with water and stirred at 0 °C for 15 min then it was concentrated under reduced pressure. The residue was purified over silica gel column chromatography (5-20% MeOH/CHaCh) to get compounds 13 (235.6 mg, 77%) as a yellowish white solid; Mp 260-265 °C; ¹ H NMR (400 MHz, DMSO-d ₆ ) d 9.29 (s, 2H), 8.74 (s, 1 H), 7.90 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 16.4 Hz, 1 H), 7.08 (d, J = 16.3 Hz, 1 H), 6.47 (s, 2H), 6.21 (s, 1 H), 3.59 (d, J = 6.0 Hz, 2H), 3.17 (d, J = 8.0 Hz, 2H), 2.76 (s, 6H); ¹³ C NMR (100 MHz, DMSO) d 166.3, 158.5, 140.0, 138.4, 132.4, 130.9, 127.8, 126.9, 126.2, 104.9, 102.8, 56.2, 42.9, 34.9; IR (neat) 3270, 2938, 2771 , 1628, 1538, 1434, 1366, 1309, 1 190, 1042, 852, 793 cm ^-1 ; HRMS calcd for C19H20CI3N2O (M+H), 397.0641 ; found, 397.0640; Purity by LCMS 98.5%.

Compound 14: Experimental procedure is similar to that for compound 10. After column purification the product 14 (92.8 mg, 69%, 2 steps) was obtained as a white solid; Mp 107-109 °C; ¹ H NMR (400 MHz, Benzene-d ₆ ) d 7.99 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 6.88 (br s, 1 H), 6.77 (d, J = 16.4 Hz, 1 H), 6.71 (d, J = 16.4 Hz, 1 H), 3.53-3.41 (m, 2H), 2.08 (t, J = 5.8 Hz, 2H), 1.87 (s, 6H); ¹³ C NMR (100 MHz, Benzene-d ₆ ) d 165.7, 140.4, 139.22, 134.59, 130.17, 128.42, 127.92, 127.80, 127.68, 127.56, 127.44, 126.73, 125.44, 125.41 , 99.99, 57.56, 44.39, 36.92; IR (neat) 3229, 3053, 2975, 2779, 1640, 1545, 1462, 1306, 1034, 962, 827, 732 cm ^-1 ; HRMS calcd for C ₂₀ H ₂₂ F ₃ N ₂ O (M+H), 363.1684; found, 363.1689; Purity by LCMS 98.5%.

Compound 15: Experimental procedure is similar to that for compound 10. After column purification the product 15 (465 mg, 87%, 2 steps) was obtained as a white solid; Mp 96-98 °C; ¹ H NMR (400 MHz, Benzene-d ₆ ) d 7.99 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 6.88 (br s, 1 H), 6.77 (d, J = 16.4 Hz, 1 H), 6.71 (d, J = 16.4 Hz, 1 H), 3.53-3.41 (m, 2H), 2.08 (t, J = 5.8 Hz, 2H), 1.87 (s, 6H); ¹³ C NMR (100 MHz, Benzene-d ₆ ) d 165.7, 140.4, 139.22, 134.59, 130.17, 128.42, 127.92, 127.80, 127.68, 127.56, 127.44, 126.73, 125.44, 125.41 , 99.99, 57.56, 44.39, 36.92; I R (neat) 3229, 3053, 2975, 2779, 1640, 1545, 1462, 1306, 1034, 962, 827, 732 cm ^-1 ; HRMS calcd for C ₁₉ H _2i Br ₂ N ₂ 0 (M+H), 451.0021 ; found, 451.0023; Purity by LCMS 98.5%.

Compound 16: Experimental procedure is similar to that for compound 10. After column purification the product 16 (50 mg, 90%) was obtained as a white solid. Mp 96-98 °C; ¹ H NMR (400 MHz, Benzene-d ₆ ) d 7.99 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 6.88 (br s, 1 H), 6.77 (d, J = 16.4 Hz, 1 H), 6.71 (d, J = 16.4 Hz, 1 H), 3.53-3.41 (m, 2H), 2.08 (t, J = 5.8 Hz, 2H), 1.87 (s, 6H); ¹³ C NMR (100 MHz, Benzene-d ₆ ) d 165.7, 140.4, 139.22, 134.59, 130.17, 128.42, 127.92, 127.80, 127.68, 127.56, 127.44, 126.73, 125.44, 125.41 , 99.99, 57.56, 44.39, 36.92;IR (neat) 3229, 3053, 2975, 2779, 1640, 1545, 1462, 1306, 1034, 962, 827, 732 cm ^-1 ; HRMS calcd for C ₁₉ H _2i Br ₂ N ₂ 0 (M+H), 451.0021 ; found, 451.0023; Purity by LCMS 98.5%.

Compound 17: To a solution of phosphonate 59 (3.25 mmol, 1.3 equiv.) in anhydrous toluene (8 mL) was added NaH (120 mg, 3.0 mmol) and stirred for 15 min. Then a solution of 2-(2,4- dichlorophenyl)oxirane 60 (2.5 mmol, 1.0 equiv.) in anhydrous toluene (4 mL) was added dropwise. The resulting solution was refluxed for 8 h. Then reaction solution was quenched by adding saturated aqueous NH4CI (15 mL) and then extracted with EtOAc (3 x 15 mL). Combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated. The residue was purified over silica gel column chromatography (5-20% EtOAc/pet ether) and then reverse phase preparative HPLC to get compound 63 and 64 (50 mg, 90%).

Data for 63: It was obtained as a white solid; Mp 96-98 °C; ¹ H NMR (400 MHz, Benzene-d ₆ ) d 7.99 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 6.88 (br s, 1 H), 6.77 (d, J = 16.4 Hz, 1 H), 6.71 (d, J = 16.4 Hz, 1 H), 3.53-3.41 (m, 2H), 2.08 (t, J = 5.8 Hz, 2H), 1.87 (s, 6H); ¹³ C NMR (100 MHz, Benzene-d ₆ ) d 165.7, 140.4, 139.22, 134.59, 130.17, 128.42, 127.92, 127.80, 127.68, 127.56, 127.44, 126.73, 125.44, 125.41 , 99.99, 57.56, 44.39, 36.92;IR (neat) 3229, 3053, 2975, 2779, 1640, 1545, 1462, 1306, 1034, 962, 827, 732 cm ^-1 ; HRMS calcd for C ₁₉ H _2i Br ₂ N ₂ 0 (M+H), 451.0021 ; found, 451.0023; Purity by LCMS 98.5%. Data for 64: It was obtained as a white solid; Mp 96-98 °C; ¹ H NMR (400 MHz, Benzene-d ₆ ) d 7.99 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 6.88 (br s, 1 H), 6.77 (d, J = 16.4 Hz, 1 H), 6.71 (d, J = 16.4 Hz, 1 H), 3.53-3.41 (m, 2H), 2.08 (t, J = 5.8 Hz, 2H), 1.87 (s, 6H); ¹³ C NMR (100 MHz, Benzene-d ₆ ) d 165.7, 140.4, 139.22, 134.59, 130.17, 128.42, 127.92, 127.80, 127.68, 127.56, 127.44, 126.73, 125.44, 125.41 , 99.99, 57.56, 44.39, 36.92;IR (neat) 3229, 3053, 2975, 2779, 1640, 1545, 1462, 1306, 1034, 962, 827, 732 cm ^-1 ; HRMS calcd for C ₁₉ H _2i Br ₂ N ₂ 0 (M+H), 451.0021 ; found, 451.0023; Purity by LCMS 98.5%.

Compound 64 was used to synthesize compound 17 using protocol same as for compound 10. After column purification compound 17 was obtained as a white solid; Mp 96-98 °C; ¹ H NMR (400 MHz, Benzene-d ₆ ) d 7.99 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 6.88 (br s, 1 H), 6.77 (d, J= 16.4 Hz, 1 H), 6.71 (d, J = 16.4 Hz, 1 H), 3.53- 3.41 (m, 2H), 2.08 (t, J = 5.8 Hz, 2H), 1.87 (s, 6H); ¹³ C NMR (100 MHz, Benzene-d ₆ ) d 165.7, 140.4, 139.22, 134.59, 130.17, 128.42, 127.92, 127.80, 127.68, 127.56, 127.44, 126.73, 125.44, 125.41 , 99.99, 57.56, 44.39, 36.92;IR (neat) 3229, 3053, 2975, 2779, 1640, 1545, 1462, 1306, 1034, 962, 827, 732 cm ^-1 ; HRMS calcd for C ₁₉ H _2i Br ₂ N ₂ 0 (M+H), 451.0021 ; found, 451.0023; Purity by LCMS 98.5%.

Synthesis of compounds 18-52

General procedure for acid and amine coupling: To a suspension of acid (100 mg, 0.34 mmol, 1.0 equiv.) in anhydrous CH2CI2 (1 mL) were added EDChHCI (72 mg, 0.58 mmol) and HOBT (56 mg, 0.58 mmol) and stirred for 15 min at room temperature and then a solution of amine (1.0 equiv.) in anhydrous CH2CI2 (1.4 mL) was added dropwise. Resultant solution was stirred overnight or till complete consumption of starting material. Then reaction solution was diluted with CH2CI2 (15 mL) and washed with saturated aqueous NaHCC>3 (10 mL), water (10 mL), brine, dried over Na2SC>4, concentrated. The residue was purified over silica gel column chromatography (5- 15% MeOH/CHaCL) to get compounds 18-51.

Compound 18: The product SA-1 19 was obtained as a white solid (106 mg, 74%); Mp 134-136 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.80 (d, 2H, J = 8.3 Hz), 7.63-7.59 (m, 3H), 7.50 (d, 1 H, J = 16.3 Hz), 7.42 (d, 1 H, J = 2.0 Hz), 7.32-7.21 (m, 1 H, merged with CHCL), 7.08 (d, 1 H, J = 16.1 Hz), 6.91 (br s, 1 H), 3.57 (q, J = 5.6 Hz, 2H), 2.65 (t, 2H, J = 6.0 Hz), 2.63-2.41 (m, 8H), 2.33 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.8, 139.7, 134.1 , 134.0, 133.6, 130.6, 129.7, 127.5, 127.4, 127.3, 126.9, 125.4, 56.3, 55.0, 52.7, 45.9, 36.3; IR (neat) 3423, 2815, 1636, 1548, 1468, 1304, 1 152, 1012, 963, 866 cm ^-1 ; HRMS calcd for C22H26CI2N3O (M+H), 418.1453; found, 418.1464; Purity by LCMS 97.9%.

Compound 19: The product SA-120 was obtained as a white solid (128 mg, 87%); Mp 129-131 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.28 (br s, 1H), 7.86 (d, 2H, J= 8.3 Hz), 7.62 (d, 2H, J= 8.5 Hz), 7.58 (d, 2H, J= 8.3 Hz), 7.50 (d, 1H, J= 16.3 Hz), 7.42 (d, 1H, J = 2.2 Hz), 7.27-7.25 (m, 1H, merged with CHCh), 7.08 (d, 1 H, J = 16.3 Hz), 3.59 (q, 2H, J = 5.4 Hz), 2.62 (t, 2H, J = 6.0 Hz), 2.70-2.41 (m, 8H), 2.33 (s, 3H), 1.82 (quintet, 2H, J = 5.8 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.8, 139.6, 134.2, 134.1, 133.9, 133.6, 130.7, 129.7, 127.7, 127.4, 127.3, 126.8, 125.3, 58.2,

54.9, 53.2, 46.1. IR (neat) 3423, 2818, 1639, 1551, 1467, 1308, 1150, 1010, 963, 867 cm ^-1 ; HRMS calcd for C ₂₂ H ₂₈ CI ₂ N ₃ O (M+H), 432.1609; found, 432.1620; Purity by LCMS 98.7%.

Compound 20: The product SA-121 was obtained as a white solid (124.6 g, 90%); Mp 163- 165 °C; ¹ H NMR (400 MHz, CDCl ₃ ) 7.79 (d, 2H, J= 8.0 Hz), 7.62-7.58 (m, 3H), 7.50 (d, 1H, J = 16.3 Hz), 7.41 (d, 1H, J= 1.5 Hz), 7.24 (d, 1H, J= 8 Hz), 7.07 (d, 1H, J= 16.3 Hz), 6.84 (br s, 1 H), 3.74 (s, 4H), 3.57 (q, 2H, J = 5.4 Hz), 2.62 (t, 2H, J = 5.8 Hz), 2.52 (s, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.8, 139.8, 134.1, 134.0, 133.9, 133.5, 130.5, 129.7, 127.45, 127.40, 127.2,

126.9, 125.5, 67.0, 56.9, 53.3, 36.0; IR (neat) 3443, 1640, 1548, 1469, 1306, 1115, 936, 835 cm ^-1 ; HRMS calcd for C21H2 ₃ CI2N2O2 (M+H), 405.1137; found, 405.1150; Purity by LCMS 97.6%.

Compound 21: The product SA-122 was obtained as a white solid (127.6 mg, 89%); Mp 146- 148 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.05 (br s, 1H), 7.83 (d, 2H, J= 8.3 Hz), 7.62 (d, 1H, J= 8.5 Hz), 7.59 (d, 2H, J= 8.3 Hz), 7.50 (d, 1H, J= 16.3 Hz), 7.42 (d, 1H, J= 1.9 Hz), 7.26 (m, 1H), 7.07 (d, 1 H, J = 16.3 Hz), 3.74 (t, 4H, J = 4.4 Hz), 3.59 (q, 2H, J = 5.6 Hz), 2.58 (t, 2H, J = 5.8 Hz), 2.56-2.47 (m, 4H), 1.81 (quintet, 2H, J= 5.9 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) d D166.8, 139.6, 134.2, 134.1, 134.0, 133.6, 130.6, 129.7, 127.5, 127.4, 127.3, 126.8, 125.4, 67.0, 58.8,

53.9 IR (neat) 3443, 2957, 2818, 1640, 1547, 1469, 1305, 1116, 1012, 918, 808 cm ^-1 ; HRMS calcd for C22H25CI2N2O2 (M+H), 419.1293; found, 419.1298; Purity by LCMS 97.3%.

Compound 22: The product SA-149 was obtained as a white solid (116.3 mg, 85%); Mp 165- 167 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.79 (d, 2H, J= 8.5 Hz), 7.59 (d, 1H, J= 8.5 Hz), 7.55 (d, 3H, J= 8.0 Hz), 7.48 (d, 1H, J= 16.3 Hz), 7.40 (d, 1H, J= 2.2 Hz), 7.24 (dd, 1H, J= 8.5, 1.9 Hz), 7.06 (s, 1 H), 7.04 (br s, 1H), 7.00 (d, 1H, J= 16.3 Hz), 4.07 (t, 2H, J = 6.7 Hz), 3.47 (q, 2H, J = 6.5 Hz), 2.14 (quintet, 2H, J= 6.7 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.4, 139.9, 137.2, 134.1, 134.0, 133.51, 133.49, 130.5, 129.7, 129.4, 127.6, 127.4, 127.2, 126.9, 125.5, 119.0, 44.8, 37.3, 31.1; IR (neat) 3242, 3055, 2987, 1650, 1557, 1447, 1311, 1266, 1089, 833740 cm ^-1 ; HRMS calcd for C ₂₁ H ₂₀ CI ₂ N ₃ O (M+H), 400.0983; found, 400.0987; Purity by LCMS 99.4%.

Compound 23: The product SA-150 was obtained as a white solid (108.6 mg, 80%); Mp 153- 155 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.21 (s, 1H), 7.98 (s, 1H), 7.79 (d, 2H, J= 8.0 Hz), 7.60 (d, 1 H, J= 8.8 Hz), 7.57 (d, 2H, J= 8.3 Hz), 7.49 (d, 1H, J= 16.3 Hz), 7.41 (s, 1H), 7.25 (d, 1H, J = 8.5 Hz), 7.05 (d, 1H, J= 16.3 Hz), 6.94 (br s, 1H), 4.32 (t, 2H, J = 6.3 Hz), 3.51 (q, 2H, J = 5.9 Hz), 2.21 (quintet, 2H, J= 6.3 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) d 167.3, 152.1, 134.5, 140.0, 134.1, 134.0, 133.5, 130.4, 129.7, 127.5, 127.4, 127.2, 126.9, 125.6, 47.2, 37.1, 29.9; IR (neat) 3418, 1637, 1552, 1468, 1314, 1101, 1047, 965, 868 cm ¹ ; HRMS calcd for C20H19CI2N4O (M+H), 401.0936; found, 401.0938; Purity by LCMS 96.2%.

Compound 24: The product SA-167 was obtained as an off-white solid (105 mg, 77%); Mp 146- 148 °C; ¹ H NMR (600 MHz, CDCl ₃ ) d 7.90 (d, 2H, J= 8.1 Hz), 7.62 (d, 1H, J= 8.4 Hz), 7.60 (d, 2H, J= 8.4 Hz), 7.50 (d, 1H, J= 16.5 Hz), 7.42 (d, 1H, J= 1.8 Hz), 7.27-7.25 (m, 1H, merged with CHCl ₃ ), 7.07 (d, 1H, J= 16.5 Hz), 3.68-3.63 (m, 2H), 2.83-2.75 (m, 2H), 2.75-2.60 (m, 4H), 1.83- 1.72 (m,4H), 1.60-1.49 (m, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) d 166.9, 139.8, 134.1, 133.9, 133.64, 133.60, 130.7, 129.7, 127.7, 127.4, 127.3, 126.9, 125.4, 57.4, 54.4, 35.8, 25.0, 23.6; IR (neat) 3424, 2937, 1640, 1548, 1469, 1307, 1101, 1048, 964, 866 cm ^-1 ; HRMS calcd for C22H25CI2N2O (M+H), 403.1344; found, 403.1348; Purity by LCMS 99.6%.

Compound 25: The product SA-168 was obtained as a colorless oil (86.9 mg, 61%); ¹ H NMR (600 MHz, CDCl ₃ ) d 8.52 (t, 1H, J = 5.9 Hz), 8.04 (d, 2H, J = 8.2 Hz), 7.61 (d, 1H, J = 8.5 Hz), 7.58 (d, 2H, J= 8.3 Hz), 7.48 (d, 1H, J= 16.2 Hz), 7.41 (d, 1H, J= 2.1 Hz), 7.25 (dd, 1H, J= 8.5, 2.2 Hz), 7.06 (d, 1 H, J = 16.3 Hz), 3.64 (q, 2H, J = 5.9 Hz), 3.07 (t, 2H, J = 6.7 Hz), 2.21 (q, 2H, J = 6.5 Hz), 2.20-1.40 (m, 5H); ¹³ C NMR (150 MHz, CDCl ₃ ) d 167.4, 139.8, 134.1, 133.9, 133.6, 133.0, 130.7, 129.6, 128.0, 127.4, 127.3, 126.9, 125.3, 54.6, 53.5, 36.6, 23.3, 22.7, 22.2; IR (neat) 3418, 2956, 1638, 1550, 1469, 1311, 1101, 1014, 964, 868 cm ^-1 ; HRMS calcd for C23H27CI2N2O (M+H), 417.1500; found, 417.1504; Purity by LCMS 99.5%.

Compound 26: The product SA-169 was obtained as a colorless oil (109.2 mg, 72%); ¹ H NMR (600 MHz, CDCl ₃ ) d 7.62 (d, 1H, J= 8.4 Hz), 7.56 (d, 2H, J= 8.1 Hz), 7.47 (d, 1H, J= 16.1 Hz), 7.42-7.41 (m, 3H), 7.25 (d, 1H, J= 2.2 Hz), 7.06 (d, 1H, J= 16.5 Hz), 4.72 (br s, 1H), 3.85 (br s, 1 H), 3.74 (s, 4H), 3.03 (br s, 1H), 2.84 (br s, 1H), 2.57 (s, 4H), 2.46 (br s, 1H), 1.98 (br s, 1H), 1.84 (br s, 1H), 1.54 (brs, 1H), 1.46 (brs, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) d 169.9, 138.1, 135.6, 134.0, 133.9, 133.7, 130.7, 129.6, 127.5, 127.4, 127.2, 126.8, 124.9, 67.1, 62.0, 49.8, 46.9, 41.5,29.0,28.0; IR (neat) 3452, 2955, 2856, 1625, 1470, 1445, 1279, 1117, 1025, 978, 867, 756 cm ^-1 ; HRMS calcd for C24H27CI2N2O2 (M+H), 445.1450; found, 445.1470; Purity by LCMS 97.3%.

Compound 27: The product SA-211 was obtained as a colorless oil (42.9 mg, 75%); ¹ H NMR (600 MHz, CDCl ₃ ) d 7.80 (d, 2H, J= 8.1 Hz), 7.75 (d, 1H, J= 1.8 Hz), 7.67 (s, 1H), 7.55 (d, 2H, J= 8.4 Hz), 7.50 (d, 1H, J = 8.4 Hz), 7.43-7.41 (m, 2H), 7.08 (s, 1H), 7.00-7.02 (m, 2H), 6.93 (t, 1 H, J= 5.3 Hz), 4.08 (t, 2H, J= 6.8 Hz), 3.48 (q, 2H, J = 6.5 Hz), 2.15 (quintet, 2H, J= 6.7 Hz); ¹³ C NMR (150 MHz, CDCl ₃ ) d 167.4, 139.8, 137.2, 135.6, 135.4, 133.5, 130.8, 130.5, 129.2, 128.2, 127.63, 127.59, 126.9, 124.6, 122.0, 1 19.0, 44.9, 37.3, 31.1 ; IR (neat) 3452, 2947, 2814, 1627, 1469, 1443, 1247, 1 101 , 1026, 867, 756 cm ^-1 ; HRMS calcd for C26H32CI2N3O (M+H), 472.1922; found, 472.1923; Purity by LCMS 98%.

Compound 28: The product SA-151 was obtained as a white solid (168.3 mg, 76%); Mp 156- 158 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.82 (d, 2H, J = 8.3 Hz), 7.60 (d, 2H, J = 8.3 Hz), 7.39 (s, 2H), 7.19 (d, 1 H, J = 16.7 Hz), 7.1 1 (d, 1 H, J = 16.7 Hz), 6.97 (t, 1 H, = 4.9 Hz), 3.57 (q, 2H, J = 5.6 Hz), 2.66 (t, 2H, J = 6.0 Hz), 2.70-2.45 (m, 8H), 2.34 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d

166.8, 139.5, 136.4, 135.0, 134.2, 133.2 132.8, 128.6, 127.5, 126.9, 123.4, 56.3, 55.0, 52.6, 45.9, 36.3; IR (neat) 3407, 2949, 2817, 1639, 1538, 1461 , 1307, 1 151 , 1010, 970, 856 cm ^-1 ; HRMS calcd for C ₂₂ H ₂₅ CI ₃ N ₃ O (M+H), 452.1063; found, 452.1061 ; Purity by LCMS 96.0%.

Compound 29: The product SA-152 was obtained as a colorless oil (69.7 g, 75%); ¹ H NMR (400 MHz, CDCl ₃ ) d 8.29 (br s, 1 H), 7.87 (d, 2H, J = 8.3 Hz), 7.58 (d, 2H, J = 8.3 Hz), 7.39 (s, 2H), 7.19 (d, 1 H, J = 16.7 Hz), 7.1 1 (d, 1 H, J = 16.7 Hz), 3.58 (q, 2H, J = 5.6 Hz), 2.61 (t, 2H, J = 6.0 Hz), 2.80-2.38 (m, 8H), 2.32 (s, 3H), 1.82 (quintet, 2H, J= 5.9 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.8, 139.3, 136.4, 135.0, 134.5, 133.2, 132.8, 128.6, 127.7, 126.7, 123.3, 58.1 , 54.9, 53.2, 46.0, 40.7, 24.2; IR (neat) 3406, 2942, 2814, 1640, 1539, 1440, 1371 , 1163, 856, 732 cm ^-1 ; HRMS calcd for C23H27CI3N3O (M+H), 466.1220; found, 466.1222; Purity by LCMS 96.3%.

Compound 30: The product SA-153 was obtained as a white solid (65.8 mg, 76%); Mp 176-178 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.81 (d, 2H, J = 8.0 Hz), 7.60 (d, 2H, J = 8.3 Hz), 7.39 (s, 2H), 7.19 (d, 1 H, J = 16.7 Hz), 7.12 (d, 1 H, J = 16.7 Hz), 6.84 (t, 1 H, J = 5.0 Hz), 3.74 (t, 4H, J = 4.6 Hz), 3.58 (q, 2H, J = 5.4 Hz), 2.63 (t, 2H, J = 6.0 Hz), 2.57-2.50 (m, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.8, 139.5, 136.3, 135.0, 134.2, 133.2, 132.8, 128.6, 127.4, 126.9, 123.5, 67.0, 56.9, 53.3, 36.0; IR (neat) 3424, 2857, 1636, 1551 , 1442, 1306, 1 117, 1010, 913, 791 cm ^-1 ; HRMS calcd for C21 H22CI3N2O2 (M+H), 439.0747; found, 439.0746; Purity by LCMS 91.0%.

Compound 31 : The product SA-154 was obtained as a colorless oil (72.3 mg, 80%); ¹ H NMR (400 MHz, CDCl ₃ ) d 8.07 (br s, 1 H), 7.84 (d, 2H, J = 8.3 Hz), 7.59 (d, 2H, J = 8.3 Hz), 7.39 (s, 2H), 7.19 (d, 1 H, J = 16.7 Hz), 7.12 (d, 1 H, J = 16.7 Hz), 3.74 (t, 4H, J = 4.4 Hz), 3.59 (q, 2H, J = 5.8 Hz), 2.58 (t, 2H, J = 5.8 Hz), 2.55-2.45 (m, 4H), 1.81 (quintet, 2H, J = 6.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.8, 139.4, 136.4, 135.0, 134.4, 133.2, 132.8, 128.6, 127.5, 126.8, 123.4, 67.0,

58.8, 53.9, 40.7, 24.1; IR (neat) 3443, 1640, 1502, 1370, 1 116, 936 cm ^-1 ; HRMS calcd for C22H24CI3N2O2 (M+H), 453.0903; found, 453.0904; Purity by LCMS 94.5%. Compound 32: The product SA- 155 was obtained as a white solid (78.6 mg, 91%); Mp 155-157 °C; ¹ H NMR (600 MHz, CDCl ₃ ) d 7.81 (d, 2H, J= 8.1 Hz), 7.55 (d, 2H, J= 8.1 Hz), 7.52 (s, 1H), 7.37 (s, 2H), 7.17 (d, 1H, J= 16.0 Hz), 7.10 (d, 1H, J= 16.1 Hz), 7.09 (br s, 1H), 7.06 (s, 1H), 6.98 (s, 1 H), 4.06 (t, 2H, J= 6.8 Hz), 3.47 (m, 2H), 2.14 (quintet, 2H, J= 6.7 Hz); ¹³ C NMR (150 MHz, CDCl ₃ ) d 167.4, 139.6, 137.1, 136.3, 135.0, 133.8, 133.2, 132.7, 129.5, 128.6, 127.6, 126.8,

123.6, 119.0, 44.8, 37.3,31.1; I R (neat) 3423, 1638, 1506, 1439, 1307, 1082, 973, 887, 738 cm ^-1 ; HRMS calcd for C ₂₁ H ₁₉ CI ₃ N ₃ O (M+H), 434.0594; found, 434.0593; Purity by LCMS 97.9%.

Compound 33: The product SA-156 was obtained as a white solid (73 g, 84%); Mp 163-165 °C; ¹ H NMR (600 MHz, CDCl ₃ ) d 8.21 (s, 1H), 7.99 (s, 1H), 7.80 (d, 2H, J= 8.1 Hz), 7.59 (d, 2H, J= 7.7 Hz), 7.39 (s, 2H), 7.18 (d, 1H, J= 16.0 Hz), 7.12 (d, 1H, J= 16.0 Hz), 6.85 (br s, 1H), 4.33 (t, 2H, J = 6.2 Hz), 3.52 (q, 2H, J = 5.9 Hz), 2.22 (quintet, 2H, J = 6.3 Hz); ¹³ C NMR (150 MHz, CDCl ₃ ) d 167.2, 152.0, 143.5, 139.8, 136.2, 135.0, 133.8, 133.2, 132.8, 128.6, 127.4, 126.9,

123.7, 47.3, 37.1,29.9; IR (neat) 3423, 1638, 1539, 1509, 1438, 1370, 1141, 969, 857, 791 cm ^-1 ; HRMS calcd for C20H18CI3N4O (M+H), 435.0546; found, 435.0545; Purity by LCMS 98.6%.

Compound 34: The product SA-165 was obtained as a colorless oil (53 mg, 73%); ¹ H NMR (600 MHz, CDCl ₃ ) d 8.53 (t, 1H, J= 5.1 Hz), 8.04 (d, 2H, J= 8.1 Hz), 7.59 (d, 2H, J= 8.4 Hz), 7.38 (s, 2H), 7.17 (d, 1 H, J = 16.6 Hz), 7.11 (d, 1H, J= 16.6 Hz), 3.64 (q, 2H, J = 5.6 Hz), 3.25-2.70 (m, 4H), 3.04 (t, 2H, J= 6.4 Hz), 2.19 (quintet, 2H, J= 6.0 Hz), 2.10-1.90 (m, 4H), 1.80-1.50 (m, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) d 167.3, 139.6, 136.5, 135.0, 133.3, 133.1, 132.9, 128.6, 127.9,

126.8, 123.4, 54.9, 53.6, 36.8, 23.3, 22.9, 22.3; IR (neat) 3312, 3052, 2936, 2809, 1641, 1539, 1440, 1305, 1126, 970, 858, 737 cm ^-1 ; HRMS calcd for C23H26CI3N2O (M+H), 451.1111; found, 451.1112; Purity by LCMS 96.2%.

Compound 35: The product SA-166 was obtained as a colorless oil (59.3 mg, 76%); ¹ H NMR (600 MHz, CDCl ₃ ) d 7.56 (d, 2H, J= 8.1 Hz), 7.42 (d, 2H, J= 8.1 Hz), 7.39 (s, 2H), 7.16 (d, 1H, J= 16.7 Hz), 7.08 (d, 1H, J= 16.6 Hz), 4.73 (br s, 1H), 3.86 (br s, 1H), 3.75 (s, 4H), 3.03 (br s, 1 H), 2.84 (br s, 1 H), 2.59 (s, 4H), 2.48 (br s, 1 H), 1.98 (br s, 1 H), 1.85 (br s, 1 H), 1.55 (br s, 1 H), 1.46 (br s, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) d 169.8, 137.8, 136.5, 135.8, 135.0, 133.1, 132.9, 128.6, 127.5, 126.8, 122.9, 67.1, 62.0, 49.8, 46.9, 41.4,29.0,28.0; IR (neat) 3474, 3054, 2955, 2856, 1628, 1537, 1440, 1310, 1280, 1118, 1026, 973, 845, 734 cm ^-1 ; HRMS calcd for C24H26CI3N2O2 (M+H), 479.1060; found, 479.1047; Purity by LCMS 98.3%.

Compound 36: The product SA-157 was obtained as a white solid (123 mg, 91%); Mp 201-203 °C; ¹ H NMR (600 MHz, CDCl ₃ ) d 7.80 (d, 2H, J= 8.1 Hz), 7.76 (d, 1H, J= 1.5 Hz), 7.60 (d, 2H, J= 8.1 Hz), 7.54 (d, 1H, J= 8.4 Hz), 7.46-7.44 (m, 2H), 7.05 (d, 1H, J= 16.1 Hz), 6.93 (br s, 1H), 3.57 (q, 2H, J = 5.5 Hz), 2.66 (t, 2H, J = 5.9 Hz), 2.70-2.41 (m, 8H), 2.34 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) d 166.8, 139.7, 135.7, 135.4, 134.0, 130.8, 128.2, 127.7, 127.5, 126.9, 124.6, 121.9, 56.3, 55.0, 52.6, 45.9, 36.2; IR (neat) 3280, 2936, 1632, 1544, 1461, 1300, 1164, 960, 865 cm ^-1 ; HRMS calcd for CaaHaeBraNsO (M+H), 506.0443; found, 506.0438; Purity by LCMS 99.6%.

Compound 37: The product SA-158 was obtained as a colorless oil (130 mg, 95%); ¹ H NMR (600 MHz, CDCl ₃ ) d 8.26 (br s, 1H), 7.86 (d, 2H, J = 8.1 Hz), 7.76 (d, 1H, J= 1.8 Hz), 7.58 (d, 2H, J = 8.4 Hz), 7.54 (d, 1H, J= 8.4 Hz), 7.46-7.43 (m, 2H), 7.05 (d, 1H, J= 16.1 Hz), 3.59 (q, 2H, J= 5.5 Hz), 2.63 (t, 2H, J= 5.9 Hz), 2.90-2.40 (m, 8H), 2.34 (s, 3H), 1.83 (quintet, 2H, J= 5.8 Hz); ¹³ C NMR (150 MHz, CDCl ₃ ) d 166.8, 139.5, 135.8, 135.4, 134.2, 130.9, 130.8, 128.0, 127.74, 127.69, 126.8, 124.6, 121.9, 58.0, 54.8, 53.1, 46.0, 40.5, 24.2; IR (neat) 3356, 2943, 2810, 1639, 1546, 1462, 1307, 1190, 1012, 963, 807, 736 cm ^-1 ; HRMS calcd for CasHasBraNsO (M+H), 520.0599; found, 520.0604; Purity by LCMS 96.5%.

Compound 38: The product SA-159 was obtained as a white solid (118.3 g, 91%); Mp 167- 170 °C; ¹ H NMR (600 MHz, CDCl ₃ ) d 7.80 (d, 2H, J= 8.1 Hz), 7.76 (d, 1H, J= 1.8 Hz), 7.60 (d, 2H, J= 8.4 Hz), 7.54 (d, 1H, J= 8.4 Hz), 7.45 (d, 1H, J= 16.1 Hz), 7.45 (dd, 1H, J= 8.5, 2.1 Hz), 7.05 (d, 1 H, J= 16.1 Hz), 6.88 (br s, 1H), 3.76 (t, 4H, J = 4.0 Hz), 3.59 (q, 2H, J = 5.4 Hz), 2.65 (t, 2H, J= 5.7 Hz), 2.59-2.51 (m, 4H); ¹³ C NMR (150 MHz, CDCl ₃ ) d 166.8, 139.7, 135.7, 135.4, 133.9, 130.9, 130.8, 128.2, 127.7, 127.5, 126.9, 124.6, 121.9, 66.9, 57.0, 53.3, 35.9; IR (neat) 3287, 2814, 1633, 1501, 1462, 1375, 1281, 1115, 1008, 962, 865, 761 cm ^-1 ; HRMS calcd for C _2i H ₂₃ Br ₂ N ₂ 0 ₂ (M+H), 493.0126; found, 493.0125; Purity by LCMS 98.6%.

Compound 39: The product SA-160 was obtained as a white solid (125.2 mg, 94%); Mp 152- 154 °C; ¹ H NMR (600 MHz, CDCl ₃ ) d 8.05 (br s, 1H), 7.83 (d, 2H, J= 8.1 Hz), 7.76 (d, 1H, J= 1.8 Hz), 7.59 (d, 2H, J= 8.4 Hz), 7.53 (d, 1H, J= 8.4 Hz), 7.45 (d, 1H, J= 16.2 Hz), 7.45 (dd, 1H, J = 8.5, 2.2 Hz), 7.04 (d, 1H, J= 16.5 Hz), 3.79-3.71 (m, 4H), 3.59 (q, 2H, J= 5.6 Hz), 2.60 (t, 2H, J= 5.7 Hz), 2.58-2.49 (m, 4H), 1.83 (quintet, 2H, J= 6.0 Hz); ¹³ C NMR (150 MHz, CDCl ₃ ) d 166.8, 139.6, 135.7, 135.4, 134.2, 130.8, 128.1, 127.7, 127.5, 126.9, 124.6, 121.9, 66.9, 58.7, 53.8, 40.6, 24.1; IR (neat) 3331, 2955, 2817, 1639, 1545, 1462, 1305, 1117, 1033, 963, 865, 735 cm ^-1 ; HRMS calcd for C ₂₂ H ₂₅ Br ₂ N ₂ 0 ₂ (M+H), 507.0283; found, 507.0283; Purity by LCMS 99.8%.

Compound 40: The product SA-170 was obtained as a white solid (107.4 mg, 84%); Mp 168- 170 °C; ¹ H NMR (600 MHz, CDCl ₃ ) d 7.80 (d, 2H, J= 8.1 Hz), 7.75 (d, 1H, J= 1.8 Hz), 7.67 (s, 1 H), 7.55 (d, 2H, J= 8.4 Hz), 7.50 (d, 1H, J= 8.4 Hz), 7.43-7.41 (m, 2H), 7.08 (s, 1H), 7.00-7.02 (m, 2H), 6.93 (t, 1H, J= 5.3 Hz), 4.08 (t, 2H, J= 6.8 Hz), 3.48 (q, 2H, J = 6.5 Hz), 2.15 (quintet, 2H, J = 6.7 Hz); ¹³ C NMR (150 MHz, CDCl ₃ ) d 167.4, 139.8, 137.2, 135.6, 135.4, 133.5, 130.8, 130.5, 129.2, 128.2, 127.63, 127.59, 126.9, 124.6, 122.0, 119.0, 44.9, 37.3, 31.1; IR (neat) 3331, 2938, 1636, 1546, 1462, 1307, 1231, 1081, 962, 868 cm ^-1 ; HRMS calcd for C _2i H ₂ oBr ₂ N ₃ 0 (M+H), 487.9973; found, 487.9970; Purity by LCMS 98.9%.

Compound 41: The product SA-164 was obtained as a colorless oil (43.6 mg, 68%); ¹ H NMR (600 MHz, CDCl ₃ ) d 8.28 (s, 1H), 8.00 (s, 1H), 7.80 (d, 2H, J= 8.1 Hz), 7.76 (d, 1H, J= 1.8 Hz), 7.58 (d, 2H, J= 8.1 Hz), 7.52 (d, 1H, J = 8.4 Hz), 7.45-7.43 (m, 2H), 7.03 (d, 1H, J= 16.1 Hz), 6.89 (br s, 1H), 4.33 (t, 2H, J = 5.7 Hz), 3.52 (q, 2H, J = 5.6 Hz), 2.22 (m, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) d 167.3, 139.9, 135.6, 135.4, 133.5, 130.8, 130.7, 128.3, 127.7, 127.5, 127.0, 124.6, 122.0, 47.3, 37.1,29.9; IR (neat) 3385, 2941, 1638, 1546, 1462, 1308, 1140, 1034, 964, 869, 732 cm ^-1 ; HRMS calcd for CaoH^B^O (M+H), 488.9926; found, 488.9927; Purity by LCMS 95.8%.

Compound 42: The product SA-161 was obtained as an off-white solid (61.6 g, 63%); Mp 152- 154 °C; ¹ H NMR (600 MHz, CDCl ₃ ) d 7.81 (d, 2H, J= 8.1 Hz), 7.68 (d, 1H, J= 1.8 Hz), 7.52 (d, 2H, J= 8.1 Hz), 7.47 (d, 1H, J= 8.4 Hz), 7.37 (d, 1H, J= 16.1 Hz), 7.37 (dd, 1H, J= 8.4, 2.0 Hz), 6.97 (d, 1H, J= 16.5 Hz), 3.57 (q, 2H, J= 5.1 Hz), 2.71-2.65 (m, 2H), 2.63-2.49 (m, 4H), 1.71- 2.62 (m, 4H), 1.50-1.42 (m, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) d 165.8, 138.6, 134.7, 134.4, 132.7, 129.9, 129.8, 127.1, 126.7, 125.9, 123.6, 120.8, 56.3, 53.3, 34.9, 24.1, 22.7; IR (neat) 3330, 3052, 2934, 2810, 1642, 1545, 1462, 1307, 1156, 1035, 964, 868, 736 cm ^-1 ; HRMS calcd for C ₂₂ H ₂₅ Br ₂ N ₂ 0 (M+H), 491.0334; found, 491.0336; Purity by LCMS 98.6%.

Compound 43: The product SA-162 was obtained as colorless oil (103 mg, 78%); ¹ H NMR (600 MHz, CDCl ₃ ) d 8.47 (t, 1H, J= 5.0 Hz), 7.94 (d, 2H, J= 8.4 Hz), 7.68 (d, 1H, J= 1.8 Hz), 7.52 (d, 2H, J = 8.4 Hz), 7.46 (d, 1H, J= 8.4 Hz), 7.38-7.35 (m, 2H), 6.97 (d, 1H, J= 16.1 Hz), 3.56 (q, 2H, J= 5.5 Hz), 3.15-2.60 (m, 4H), 2.88 (t, 2H, J= 6.1 Hz), 2.08-2.03 (m, 2H), 1.96-1.80 (m, 4H), 1.65-1.45 (m, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) d 167.4, 139.8, 135.7, 135.4, 132.9, 130.9, 130.8, 128.0, 127.7, 126.9, 124.6, 121.8, 54.5, 53.4, 36.5, 23.3, 22.6, 22.1; IR (neat) 3385, 2954, 1636, 1547, 1462, 1311, 1034, 961, 869, 763 cm ^-1 ; HRMS calcd for C ₂₃ H ₂₇ Br ₂ N ₂ 0 (M+H), 505.0490; found, 505.0494; Purity by LCMS 95.6%.

Compound 44: The product SA-163 was obtained as colorless oil (116.7 mg, 83%); ¹ H NMR (600 MHz, CDCl ₃ ) d 7.76 (d, 1H, J= 2.2 Hz), 7.56 (d, 2H, J= 8.1 Hz), 7.53 (d, 1H, J = 8.4 Hz), 7.45 (dd, 1 H, J= 8.4, 1.8 Hz), 7.43-7.40 (m, 3H), 7.03 (d, 1H, J= 16.1 Hz), 4.72 (br s, 1H), 3.85 (br s, 1 H), 3.74 (s, 4H), 3.03 (br s, 1 H), 2.84 (br s, 1 H), 2.57 (s, 4H), 2.46 (br s, 1 H), 1.98 (br s, 1 H), 1.84 (br s, 1H), 1.54 (brs, 1H), 1.46 (br s, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) d 169.8, 138.1, 135.8, 135.6, 135.4, 131.0, 130.8, 127.7, 127.6, 126.9, 124.6, 121.8, 67.1, 62.0, 49.8, 46.9, 41.5, 29.0, 28.1; IR (neat) 3463, 2954, 2856, 1625, 1561, 1463, 1310, 1117, 1028, 966, 867, 761 cm ^-1 ; HRMS calcd for (M+H), 533.0447; found, 533.0439; Purity by LCMS 96.2%.

Compound 45: The product SA-210 was obtained as a colorless oil (42.9 mg, 75%); ¹ H NMR (600 MHz, CDCl ₃ ) d 7.80 (d, 2H, J= 8.1 Hz), 7.75 (d, 1H, J= 1.8 Hz), 7.67 (s, 1H), 7.55 (d, 2H, J = 8.4 Hz), 7.50 (d, 1H, J= 8.4 Hz), 7.43-7.41 (m, 2H), 7.08 (s, 1H), 7.00-7.02 (m, 2H), 6.93 (t, 1H, J = 5.3 Hz), 4.08 (t, 2H, J = 6.8 Hz), 3.48 (q, 2H, J = 6.5 Hz), 2.15 (quintet, 2H, J = 6.7 Hz); ¹³ C NMR (150 MHz, CDCl ₃ ) d 167.4, 139.8, 137.2, 135.6, 135.4, 133.5, 130.8, 130.5, 129.2, 128.2, 127.63, 127.59, 126.9, 124.6, 122.0, 119.0, 44.9, 37.3,31.1; IR (neat) 3423, 2944, 2813, 1627, 1463, 1443, 1280, 1166, 1027, 827 cm ^-1 ; HRMS calcd for CaeHsaBraNsO (M+H), 560.0912; found, 560.0916; Purity by LCMS 98%.

Compound 46: The product 46 was obtained as a colorless oil (22.8 g, 68%); ¹ H NMR (600 MHz, CDCl ₃ ) d 7.80 (d, 2H, J= 8.1 Hz), 7.75 (d, 1H, J= 1.8 Hz), 7.67 (s, 1H), 7.55 (d, 2H, J= 8.4 Hz), 7.50 (d, 1 H, J= 8.4 Hz), 7.43-7.41 (m, 2H), 7.08 (s, 1H), 7.00-7.02 (m, 2H), 6.93 (t, 1H, J = 5.3 Hz), 4.08 (t, 2H, J= 6.8 Hz), 3.48 (q, 2H, J= 6.5 Hz), 2.15 (quintet, 2H, J = 6.7 Hz); ¹³ C NMR (150 MHz, CDCl ₃ ) d 167.4, 139.8, 137.2, 135.6, 135.4, 133.5, 130.8, 130.5, 129.2, 128.2, 127.63, 127.59, 126.9, 124.6, 122.0, 119.0, 44.9, 37.3,31.1; IR (neat) 3423, 2945, 2815, 1628, 1537, 1440, 1371, 1283, 1167, 1026, 825, 732 cm ^-1 ; HRMS calcd for C ₂₆ H ₃₁ CI ₃ N ₃ O (M+H), 506.1533; found, 506.1521; Purity by LCMS 98%.

Compound 47: The product 47 was obtained as a colorless oil (10.3 mg, 61%); ¹ H NMR (600 MHz, CDCl ₃ ) d 7.80 (d, 2H, J= 8.1 Hz), 7.75 (d, 1H, J= 1.8 Hz), 7.67 (s, 1H), 7.55 (d, 2H, J= 8.4 Hz), 7.50 (d, 1 H, J= 8.4 Hz), 7.43-7.41 (m, 2H), 7.08 (s, 1H), 7.00-7.02 (m, 2H), 6.93 (t, 1H, J = 5.3 Hz), 4.08 (t, 2H, J= 6.8 Hz), 3.48 (q, 2H, J= 6.5 Hz), 2.15 (quintet, 2H, J = 6.7 Hz); ¹³ C NMR (150 MHz, CDCl ₃ ) d 167.4, 139.8, 137.2, 135.6, 135.4, 133.5, 130.8, 130.5, 129.2, 128.2, 127.63, 127.59, 126.9, 124.6, 122.0, 119.0, 44.9, 37.3,31.1; IR (neat) 3385, 2922, 1614, 1554, 1453, 1323, 1249, 1167, 1111, 1028, 840, 712 cm ^-1 ; HRMS calcd for C ₂₆ H ₂₇ F ₃ N ₃ O ₂ (M+H), 470.2055; found, 470.2054; Purity by LCMS 98.3%.

Compound 51.2-(4-Ethyl-piperazin-1-yl)-ethylamine was coupled with acid as above general procedure for acid and amine coupling. After purification by column chromatography on silica gel, the product was obtained as a white solid (108.6 mg, 79%); ¹ H NMR (400 MHz, CDCl ₃ ) d 7.80 (d, J= 8.4 Hz, 2H), 7.62 (d, J= 8.5 Hz, 1H), 7.60 (d, J= 8.4 Hz, 2H), 7.50 (d, J= 16.3 Hz, 1H), 7.42 (d, J= 2.1 Hz, 1H), 7.31 -7.22 (m, 1H), 7.08 (d, = 16.3 Hz, 1H), 6.90 (br s, 1H), 3.57 (q, =5.6 Hz, 2H), 2.87 - 2.53 (m, 8H), 2.49 (q, J = 7.2 Hz, 4H), 1.13 (t, J = 7.2 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.8, 139.7, 134.1, 134.0, 133.6, 130.6, 129.7, 127.5, 127.4, 127.3, 126.9, 125.4, 56.3, 52.7, 52.6, 52.3, 36.3, 11.8. Compound 52. 2-(4-isopropyl-piperazin-1-yl)-ethylamine was coupled with acid as above general procedure for acid and amine coupling. After purification by column chromatography on silica gel, the product was obtained as a white solid (101 mg, 72%); ¹ H NMR (400 MHz, CDCl ₃ ) d 7.80 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.5 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 16.3 Hz, 1 H), 7.42 (d, J = 2.1 Hz, 1 H), 7.31 - 7.22 (m, 1 H), 7.08 (d, = 16.3 Hz, 1 H), 6.90 (br s, 1 H), 3.57 (q, = 5.6 Hz, 2H), 2.87 - 2.53 (m, 8H), 2.81 (m, 1 H), 1.18 (d, J = 5.5 Hz, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.8, 139.7, 134.1 , 134.0, 133.6, 130.6, 129.7, 127.5, 127.4, 127.3, 126.9, 125.4, 56.3, 52.7, 52.6, 52.3, 36.3, 11.8.

Compound 50. A mixture of 2,4-dichloroiodobenzene 72 (682 mg, 2.5 mmol), methyl 4- ethynylbenzoate 71 (440 mg, 2.75 mmol), Cul (57 mg, 0.3 mmol) and Pd(PPh ₃ )2Cl2 (105 mg, 0.15 mmol) was evacuated and then filled with Argon 3 times. Then Et ₃ N (5 mL, anhydrous and degassed) and anhydrous THF (20 mL) were added and heated at 80°C for 2 h. Reaction solution was concentrated under reduced pressure and the residue was purified over silica gel column chromatography (2-10% EtOAc/pet ether) to get compound SA-287-1 (587 mg, 77%) as a white solid; Mp 102-104 °C; ¹ H NMR (400 MHz, CDCl ₃ ) d 8.03 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.3 Hz, 1 H), 7.46 (d, = 2.1 Hz, 1 H), 7.26 - 7.22 (m, 1 H), 3.93 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.4, 136.8, 135.1 , 133.9, 131.6, 130.0, 129.6, 129.4, 127.2, 127.1 , 121.3, 94.5, 87.9, 52.3.

To the above ester (635 mg, 2.08 mmol) was added MeOH:THF (1 : 1 , 21 mL) followed by 50% aqueous NaOH (1.7 mL) and then resultant solution was heated at 60 °C for 30 min. Then all volatiles were removed under reduced pressure and the residue was taken in water (20 mL) and acidified with cone. HCI till pH 1-2 and extracted with EtOAc (2 x 60 mL), and washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to get carboxylic acid (592 mg, 98%) as a white solid;

Above obtained acid was coupled with 4-methyl-1-piperazineethanamine according to the above general procedure. After purification by column chromatography on silica gel, the product 50 was obtained as a white solid (194.8 mg, 94%); ¹ H NMR (400 MHz, CDCl ₃ ) d 7.78 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.3 Hz, 1 H), 7.46 (d, J = 2.0 Hz, 1 H), 7.25 (dd, J = 8.3, 2.1 Hz, 1 H), 6.90 (br s, 1 H), 3.61 - 3.49 (m, 2H), 2.76 - 2.37 (m, 10H), 2.32 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.5, 136.8, 135.0, 134.5, 133.8, 131.8, 129.4, 127.1 , 127.0, 125.7, 121.4, 94.5, 87.3, 56.2, 55.1 , 52.7, 45.9, 36.3; Purity by LCMS 98%.

Synthesis of 49. Experimental procedure is similar to that for compound 50. After purification by column chromatography on silica gel, the product SA-267 was obtained (127.4 mg, 78% in two steps) as a yellowish solid; ¹ H NMR (400 MHz, CDCl ₃ ) d 7.81 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.05 (t, J = 4.9 Hz, 1 H), 6.80 (d, J = 1.9 Hz, 1 H), 6.63 (d, J = 1.9 Hz, 1 H), 4.55 (br s, 2H), 3.65 - 3.50 (m, 2H), 2.59 (t, J = 5.8 Hz, 2H), 2.33 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) d 166.6, 149.6, 137.0, 135.4, 134.2, 131.5, 127.2, 125.8, 1 18.4, 1 12.2, 106.2, 99.3, 84.3, 57.76, 45.07, 37.08; Purity by LCMS 99.1 %.