RU2789059C2 - BENZIMIDAZOLE DERIVATIVES AS MODULATORS OF RETINOID-RELATED ORPHAN RECEPTOR GAMMA (RORγ) AND THEIR PHARMACEUTICAL USE - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: group of inventions relates to pharmaceutical chemistry and includes benzimidazole derivatives of the formula (I), their production methods, intermediate compounds of formulas (IA), (IC), (ID), a pharmaceutical composition, an inhibition method, and the use. In the formula (I), ring A is selected from a group consisting of phenyl, piperidinyl, and thienyl; R₁, R₂, and R₃, each independently, is selected from a group consisting of a hydrogen atom, halogen, and C_1-6 alkyl; R₄, in each case, is independently selected from a group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 halogenalkyl, C_1-6 alkoxy, C_1-6 halogenalkoxy, cyano, and -NR₁₁R₁₂, while the specified C_1-6 alkoxy is possibly substituted with C_1-6 alkoxy groups in a number from one to three; R_5a is hydrogen; R_5b is selected from a group consisting of a hydrogen atom, C_1-6 alkyl, hydroxy, C_1-6 hydroxyalkyl, -(CH₂)_xNR₁₀COR₉, -NR₁₀COCH₂OR₈, -(CH₂)_xC(O)OR₈, -(CH₂)_xCONR₁₁R₁₂, and -(CH₂)_xNR₁₁R₁₂, while the specified C_1-6 alkyl is possibly substituted with one morpholinyl; or R_5a and R_5b together form

R₆ is selected from a group consisting of C_1-6 alkyl, C_1-6 halogenalkyl, and -NR₁₁R₁₂, while the specified C_1-6 alkyl is possibly substituted with groups in a number from one to three, selected from a group consisting of C_1-6 alkoxy and 3-6-element cycloalkyl; R₇, in each case, is independently a hydrogen or halogen atom; R₈ is selected from a group consisting of a hydrogen atom and C_1-6 alkyl; R₉ is selected from a group consisting of C_1-6 alkyl and 5-element heteroaryl containing two heteroatoms, which are N and O, while the specified C_1-6 alkyl and 5-element heteroaryl, each, is possibly substituted with C_1-6 alkyl groups in a number from one to three; R₁₀ is a hydrogen atom; R₁₁ and R₁₂, each independently, are selected from a group consisting of a hydrogen atom, C_1-6 alkyl, and 3-6-element cycloalkyl; n, s, x are equal to 0, 1, 2, 3, or 4.

EFFECT: benzimidazole derivatives of the formula (I) as inhibitors of a retinoid-related orphan receptor gamma (RORγ).

18 cl, 1 tbl, 173 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) based on U.S. Provisional Application No. 62/666312, filed May 3, 2018, the disclosure of which is incorporated herein by reference throughout its completeness.

FIELD OF THE INVENTION

The present invention relates to retinoid-associated orphan receptor gamma (RORγ) modulators and uses as therapeutic agents for the treatment of RORγ-mediated diseases or conditions, including various inflammatory and autoimmune diseases and cancers.

PRIOR ART

Nuclear receptors are ligand-regulated transcription factors that regulate development, immunity, and cellular metabolism, and are one of the main classes of drug targets in the treatment of diseases in humans. The retinoid-related orphan receptor gamma (RORγ) is a member of the nuclear receptor subfamily 1 (NR1) and exhibits a typical nuclear receptor domain structure that includes a DNA-binding domain, a ligand-binding domain, a hinge domain, and an activation function domain-2 (Benoit G., et al., Pharmacological Reviews, 58 (4): 798-836, 2006; Zhang, Y., et al., Acta Pharmacogica Sinica, 36: 71-87, 2015). RORγ is involved in recognition and binding as a monomer, unlike most other nuclear receptors, which bind as dimers. It binds to specific DNA sequences, usually composed of TAAA/TNTAGGTCA, called ROR response elements (RORE).

There are two isoforms of RORγ, RORγ1 and RORγ2, which are products of the same RORC gene, probably as a result of the selection of alternative promoters (Villey I., et al., Eur, J, Immunol., 29(12): 4072-80, 1999). RORγ2 (also known as RORγt) is formed from a messenger RNA (mRNA) identical to that of RORγ1, except that the alternative exon is replaced by two 5'-most exons, resulting in a truncated form of RORγ1. These two isoforms show different patterns of tissue-specific expression. Preferably, RORγt is expressed in the thymus and various cell types of the immune system, while RORγ1 is expressed in many tissues, thymus, lung, kidney, muscle and liver.

RORγt is a master regulator of T-helper cell type 17 (Th17 cells) development (Ruan, Q., et al., J. Exp. Med., 208(11): 2321-2333, 2011; Ivanov, I. I. et al. ., Cell, 126: 1121-1133, 2006). Th17 cells produce numerous cytokines, including interleukin-17 (IL-17), which are known to increase inflammation. In addition, RORγt has been shown to play a critical role in non-Th17 lymphoid cells expressing Thy1 (thymocyte differentiation antigen 1), SCA-1 (stem cell antigen 1), and IL-23R (IL-23 receptor) proteins (Buonocore, S., et al., Nature, 464: 1371-1375, 2010). RORγt plays an important role in the development of secondary lymphoid tissues, in thymopoiesis, in the development of lymphocytes (Jetten, A.M., Nucl. Recep.Signal, 7: e300, DOI:10.1621/nrs.07003, 2009). RORγ1 appears to be involved in the regulation of circadian rhythms (Guillaumond, F. et al., J. Biol. Rhythms, 20 (5): 391-403, 2005; Akashi M. and Takumi T., Nat. Struct. Mol. Biol., 12 (5): 441-448, 2005).

RORγ has been identified as a key mediator in the pathogenesis of several diseases such as rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, Sjögren's syndrome and asthma, etc. (Louten et al., J. Allergy Clin. Immunol., 123: 1004-1011, (2009); Annuziato, F., et al., Nat. Rev. Rheumatol., 5(6): 325-331, 2009 ; Lizuka, M., et al., J. Immunol., 194: 56-67, 2014). Some other diseases, such as chronic disease dry eye syndrome, Kawasaki disease, mucosal leishmaniasis, and Hashimoto's thyroiditis, are characterized by higher levels of Th17 and/or elevated levels of Th17-specific cytokines such as IL-17, IL-22, and IL. -23 (Chen, Y., et al., Mucosal. Immunol., 7(1): 38-45, 2014; Jia, S., et al., Clin. Exp. Immunol., 162: 131-137, 2010; Boaventura, V. S., et al., Eur. J. Immunol., 40: 2830-2836, 2010; Figueroa-Vega, N., et al., J. Clin. Endocrinol. Metab., 95: 953-62 , 2010). In each of the examples mentioned above, inhibition can be enhanced by simultaneous inhibition of RORα. RORγt inhibitors are currently under development for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis. See Jun R. Huh and Dan R. Littman, Eur. J. Immunol., 42(9): 2232-2237 (2012), WO 2012/027965, WO 2013/029338 and US 2015/291607.

The present invention describes a number of new compounds that exhibit a strong inhibitory effect against RORγ, so they can provide a possible therapeutic approach to the treatment of RORγ-mediated diseases or conditions.

BRIEF DESCRIPTION OF THE INVENTION

According to one aspect, the present invention relates to a compound of formula (I):

or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof,

where:

выбран из одинарной связи и двойной связи, когда

представляет собой двойную связь, тогда

представляет собой одинарную связь, R_a отсутствует и R_b представляет собой атом водорода; когда

представляет собой двойную связь, тогда

представляет собой одинарную связь, R_a представляет собой атом водорода, и R_b отсутствует;

selected from a single bond and a double bond when

is a double bond, then

represents a single bond, R _a is absent and R _b represents a hydrogen atom; when

is a double bond, then

represents a single bond, R _a represents a hydrogen atom, and R _b is absent;

ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ₁ , R ₂ and R ₃ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

all R ₄ are the same or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - OR ₈ , -C(O)OR ₈ , -COR ₉ , -NR ₁₀ COR ₉ , -S(O) ₂ R ₉ , -NR ₁₀ S(O) ₂ R ₉ , -CONR ₁₁ R ₁₂ , -NR ₁₁ R ₁₂ and -S(O) ₂ NR ₁₁ R ₁₂ , wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen, alkyl , alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R _5a and R _5b are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ₈ , - NR ₁₀ COR ₉ , -NR ₁₀ COCH ₂ OR ₈ , -(CH ₂ ) _x C(O)OR ₈ , -(CH ₂ ) _x CONR ₁₁ R ₁₂ and -(CH ₂ ) _x NR ₁₁ R ₁₂ , while said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, -CONR ₁₁ R ₁₂ , -NR ₁₀ COR ₉ , cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R _5a and R _5b together form

R ₆ is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and NR ₁₁ R ₁₂ , wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

all R ₇ are the same or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ₈ , -C(O)OR ₈ , -COR ₉ , -NR ₁₀ COR ₉ , -S(O) ₂ R ₉ , -NR ₁₀ S(O) ₂ R ₉ , -CONR ₁₁ R ₁₂ , -NR ₁₁ R ₁₂ and -S(O) ₂ NR ₁₁ R ₁₂ , wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of a halogen atom , alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ₈ is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl, said alkyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen and alkoxy;

R ₉ is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of atom halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ₁₀ is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl;

R ₁₁ and R ₁₂ are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, -COR ₁₃ , aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ₁₁ and R ₁₂ together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl has one or more heteroatoms selected from the group consisting of O, N and S and is optionally substituted with one or more groups selected from a group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ₁₃ is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of atom halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

n is 0, 1, 2, 3, or 4;

s is 0, 1, 2, 3, or 4; and

x is 0, 1, 2, 3, or 4.

According to another aspect, the present invention relates to a compound of formula (IA):

or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is an intermediate for the synthesis of a compound of formula (I),

where:

,

, R_a, R_b, R₁ - R₃, R_5a, R_5b, R₆, R₇ и n являются такими, как определено в формуле (I).

,

, R _a , R _b , R ₁ - R ₃ , R _5a , R _5b , R ₆ , R ₇ and n are as defined in formula (I).

According to another aspect, the present invention relates to a compound of formula (IC) or formula (ID) as an intermediate for the synthesis of compounds of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

where:

R _a and R _b represents a hydrogen atom;

ring A, R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (I).

According to another aspect, the present invention relates to various processes for the preparation of a compound of formula (I).

According to another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipient.

According to another aspect, the present invention relates to a method for inhibiting retinoid-related orphan receptor gamma (RORγ) or treating a disease or disorder mediated by retinoid-related orphan receptor gamma (RORγ) in a subject using a therapeutically effective amount of a compound of formula (I) or a tautomer, a mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Other aspects and advantages of the present invention will be better understood by the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, the present invention relates to a compound of formula (I):

or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof,

where:

выбран из одинарной связи и двойной связи, когда

представляет собой двойную связь, тогда

представляет собой одинарную связь, R_a отсутствует, и R_b представляет собой атом водорода; когда

представляет собой двойную связь, тогда

представляет собой одинарную связь, R_a представляет собой атом водорода, и R_b отсутствует;

selected from a single bond and a double bond when

is a double bond, then

represents a single bond, R _a is absent, and R _b represents a hydrogen atom; when

is a double bond, then

represents a single bond, R _a represents a hydrogen atom, and R _b is absent;

ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ₁ , R ₂ and R ₃ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

all R ₄ are the same or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - OR ₈ , -C(O)OR ₈ , -COR ₉ , -NR ₁₀ COR ₉ , -S(O) ₂ R ₉ , -NR ₁₀ S(O) ₂ R ₉ , -CONR ₁₁ R ₁₂ , -NR ₁₁ R ₁₂ and -S(O) ₂ NR ₁₁ R ₁₂ , wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen, alkyl , alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R _5a and R _5b are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ₈ , - NR ₁₀ COR ₉ , -NR ₁₀ COCH ₂ OR ₈ , -(CH ₂ ) _x C(O)OR ₈ , -(CH ₂ ) _x CONR ₁₁ R ₁₂ and -(CH ₂ ) _x NR ₁₁ R ₁₂ , while said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, -CONR ₁₁ R ₁₂ , -NR ₁₀ COR ₉ , cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R _5a and R _5b together form

R ₆ is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and NR ₁₁ R ₁₂ , wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

all R ₇ are the same or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ₈ , -C(O)OR ₈ , -COR ₉ , -NR ₁₀ COR ₉ , -S(O) ₂ R ₉ , -NR ₁₀ S(O) ₂ R ₉ , -CONR ₁₁ R ₁₂ , -NR ₁₁ R ₁₂ and -S(O) ₂ NR ₁₁ R ₁₂ , wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of a halogen atom , alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ₈ is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl, said alkyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen and alkoxy;

R ₉ is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of atom halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ₁₀ is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl;

R ₁₁ and R ₁₂ are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, -COR ₁₃ , aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ₁₁ and R ₁₂ together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl has one or more heteroatoms selected from the group consisting of O, N and S and is optionally substituted with one or more groups selected from a group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ₁₃ is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of atom halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

n is 0, 1, 2, 3, or 4;

s is 0, 1, 2, 3, or 4; and

x is 0, 1, 2, 3, or 4.

In some embodiments of the present invention, the compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is a compound of formula (Ia) or formula (Ib):

where:

R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (I).

In some embodiments of the present invention, in a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, ring A is selected from the group consisting of phenyl, C _3-6 cycloalkyl, and 5 - or 6-membered heteroaryl, preferably piperidinyl, phenyl, thienyl, furyl and pyridinyl.

In some embodiments of the present invention, a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is a compound of formula (II):

where:

,

, R_a, R_b, R₁ - R₄, R_5a, R_5b, R₆, R₇, n и s являются такими, как определено в формуле (I).

,

, R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (I).

In some embodiments of the present invention, a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is a compound of formula (IIa):

where:

,

, R_a, R_b, R₁ - R₄, R_5a, R_5b, R₆, R₇ и n являются такими, как определено в формуле (I).

,

, R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ and n are as defined in formula (I).

In some embodiments of the present invention, a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is a compound of formula (III):

where:

,

, R_a, R_b, R₁ - R₄, R_5a, R_5b, R₆, R₇, n и s являются такими, как определено в формуле (I).

,

, R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (I).

In some embodiments of the present invention, a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is a compound of formula (IIIa):

where:

R _4a and R _4b are the same or different and are each independently selected from the group consisting of halogen atom, hydrogen atom, alkyl and haloalkyl;

,

, R_a, R_b, R₁ - R₃, R_5a, R_5b, R₆, R₇ и n являются такими, как определено в формуле (I).

,

, R _a , R _b , R ₁ - R ₃ , R _5a , R _5b , R ₆ , R ₇ and n are as defined in formula (I).

In some embodiments of the present invention, in a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, all R ₄ are the same or different and each is independently selected from the group consisting of the atom hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -OR ₈ and -NR ₁₁ R ₁₂ ;

R ₈ , R ₁₁ and R ₁₂ are as defined in formula (I).

In some embodiments of the present invention, in a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R ₁ , R ₂ and R ₃ are the same or different and are each independently selected from a group consisting of a hydrogen atom, a halogen and an alkyl.

In some embodiments of the present invention, in a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R _5a and R _5b are the same or different and are each independently selected from the group consisting of from a hydrogen atom, hydroxy, hydroxyalkyl, -OR ₈ , -NR ₁₀ COR ₉ , -NR ₁₀ COCH ₂ OR ₈ , -(CH ₂ ) _x C(O)OR ₈ , -(CH ₂ ) _x CONR ₁₁ R ₁₂ and -(CH ₂ ) _x NR ₁₁ R ₁₂ ;

; R₈ - R₁₂ и x являются такими, как определено в формуле (I).or R _5a and R _5b together form

; R ₈ - R ₁₂ and x are as defined in formula (I).

In some embodiments of the present invention, in a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R6 is selected from the group consisting _of alkyl, haloalkyl, cycloalkyl, heterocyclyl, and - NR ₁₁ R ₁₂ , wherein said alkyl is optionally substituted with one or more groups selected from the group consisting of alkoxy and cycloalkyl.

In some embodiments of the present invention, in a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R ₇ is selected from the group consisting of hydrogen, halogen and alkyl.

Exemplary compounds of the present invention include, but are not limited to, the following.

According to another aspect, the present invention relates to a compound of formula (IA),

or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is an intermediate for the synthesis of a compound of formula (I),

where:

R_a, R_b, R₁ - R₃, R_5a, R_5b, R₆, R₇ и n являются такими, как определено в формуле (I).

R _a , R _b , R ₁ - R ₃ , R _5a , R _5b , R ₆ , R ₇ and n are as defined in formula (I).

According to another aspect, the present invention provides a compound of formula (IC) or formula (ID) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof,

where:

R _a and R _b represents a hydrogen atom;

ring A, R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (I).

In some embodiments of the present invention, in a compound of formula (IC) or formula (ID), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring A is selected from the group consisting _of phenyl, C3 _-6 cycloalkyl and 5- or 6-membered heteroaryl, preferably piperidinyl, phenyl, thienyl, furyl and pyridinyl.

Exemplary intermediates of the present invention include, but are not limited to, those listed in the following table.

According to another aspect, the present invention relates to a process for preparing a compound of formula (I) comprising the step of coupling a compound of formula (IA) with a compound of formula (IB) under basic conditions in the presence of a catalyst to obtain a compound of formula (I):

where:

или

G is a leaving group, preferably a boronic acid or borate group, and more preferably

or

R_a, R_b, R₁ - R₄, R_5a, R_5b, R₆, R₇, n и s являются такими, как определено в формуле (I).ring A,

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (I).

According to another aspect, the present invention relates to a process for preparing a compound of formula (I) comprising the step of cyclizing a compound of formula (IC) or (ID) to obtain a compound of formula (I):

where:

R_a, R_b, R₁ - R₄, R_5a, R_5b, R₆, R₇, n и s являются такими, как определено в формуле (I).ring A,

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (I).

According to another aspect, the present invention relates to a process for preparing a compound of formula (II), comprising the step of cyclizing a compound of formula (IIC) or formula (IID) to obtain a compound of formula (II):

where:

R_a, R_b, R₁ - R₄, R_5a, R_5b, R₆, R₇, n и s являются такими, как определено в формуле (II).

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (II).

According to another aspect, the present invention relates to a process for preparing a compound of formula (III), comprising the step of cyclizing a compound of formula (IIIC) or formula (IIID), which is subjected to an intramolecular transformation reaction to obtain a compound of formula (III):

where:

R_a, R_b, R₁ - R₄, R_5a, R_5b, R₆, R₇, n и s являются такими, как определено в формуле (III).

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (III).

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers. , diluent or excipient.

According to another aspect, the present invention relates to a method of inhibiting retinoid-related orphan receptor gamma (RORγ) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. , a solvate, or a prodrug.

According to another aspect, the present invention relates to a method of treating a disease or disorder mediated by retinoid-related orphan receptor gamma (RORγ) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or their a mixture or a pharmaceutically acceptable salt, solvate or prodrug thereof.

According to another aspect, the present invention relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the preparation of a medicament for inhibiting RORγ.

According to another aspect, the present invention relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the preparation of a medicament for the treatment of a RORγ protein-mediated disease or disorder.

According to another aspect, the present invention also relates to a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a drug.

In another aspect, the present invention also relates to a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a RORγ inhibitor.

According to another aspect, the present invention also relates to a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of a RORγ protein-mediated disease or disorder.

RORγ protein-mediated diseases or disorders include, but are not limited to, inflammatory and autoimmune diseases and cancers, while inflammatory and autoimmune diseases include, but are not limited to, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoarthritis, regional enteritis, ulcerative colitis, ankylosing spondylitis, autoimmune diabetes, type I diabetes, autoimmune eye disease, autoimmune thyroid disease, autoimmune polyendocrine syndrome type I, autoimmune polyendocrine syndrome type II, multiple sclerosis, inflammatory bowel disease, irritable bowel syndrome, juvenile idiopathic arthritis, Sjögren's syndrome, Crohn's disease, asthma, Kawasaki disease, Hashimoto's thyroiditis, infectious diseases, ankylosing spondylitis, chronic obstructive pulmonary disease (COPD), pulmonary disease, glomerulonephritis, myocarditis, thyroiditis, dry eye syndrome, SW eitis, Behçet's disease, asthma, atopic dermatitis, contact dermatitis, allograft rejection, polymyositis, graft-versus-host disease, acne, ulcerative colitis, systemic lupus erythematosus, scleroderma, bronchitis, dermatomyositis, and allergic rhinitis; and while cancers include, but are not limited to, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma of the nervous system, hepatocellular carcinoma, mastoid tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.

DEFINITIONS

Unless otherwise indicated, the terms used in this description have the following meanings.

"Alkyl" means a linear or branched saturated aliphatic hydrocarbon group having 1-20 carbon atoms, preferably C ₁ -C ₁₂ alkyl, more preferably C ₁ -C ₆ alkyl, sometimes more preferably C ₁ -C ₄ alkyl. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5- dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n- nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and their branched isomers. More preferably, the alkyl group is a lower alkyl having 1-6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl propyl, 1,1,2-trimethylpropyl, 1 ,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted. If substitution is present, the group(s) to be substituted may/may be substituted at any available point of attachment. The substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl, and a carboxylic ester group.

The term "alkylene" refers to alkyl in which a hydrogen atom is also substituted. For example, to methylene (-CH ₂ -), 1,2-ethylene (-CH ₂ CH ₂ -), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -) and the like.

"Alkenyl" means alkyl as defined above, which has at least two carbon atoms, preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms, sometimes more preferably 2-4 carbon atoms, and at least one carbon -carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is/are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, and heterocyclylthio.

"Cycloalkyl" means a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3-20 carbon atoms, preferably 3-12 carbon atoms, more preferably 3-8 carbon atoms and most preferably 3-6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl includes cycloalkyl having a spiro ring, a fused ring, or a bridged ring.

"Spiro-cycloalkyl" means a 5-20 membered polycyclic group containing rings connected through one common carbon atom (called a spiro atom), wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, preferably 6-14 membered spiro-cycloalkyl and more preferably 7-10 membered spiro-cycloalkyl. Depending on the number of common spiro atoms, spiro-cycloalkyls can be subdivided into mono-spiro-cycloalkyl, di-spiro-cycloalkyl or poly-spiro-cycloalkyl and preferably mono-spiro-cycloalkyl or di-spiro-cycloalkyl, more preferably 4-membered /4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono-spiro-cycloalkyl. Non-limiting examples of spiro-cycloalkyls include, but are not limited to:

"Fused cycloalkyl" means a 5 to 20 membered all-carbon polycyclic group, wherein each ring in such a system shares an adjacent pair of carbon atoms with another ring, one or more of the rings may contain one or more double bonds, but neither one of the rings does not have a fully conjugated π electron system, preferably a 6-14 membered fused cycloalkyl, more preferably a 7-10 membered fused cycloalkyl. Depending on the number of said rings, fused cycloalkyls can be subdivided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic, tricyclic or tetracyclic fused cycloalkyl, and more preferably bicyclic or tricyclic. Non-limiting examples of fused cycloalkyl include, but are not limited to:

"Bridged cycloalkyl" means a 5 to 20 membered all-carbon polycyclic group, wherein every two rings in this system share two non-conjugated atoms, which rings may have one or more double bonds, but neither ring has fully conjugated π-electron system, preferably means 6-14-membered bridged cycloalkyl and more preferably 7-10-membered bridged cycloalkyl. Depending on the number of said rings, bridged cycloalkyls can be subdivided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl and preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl and more preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyls include, but are not limited to:

Said cycloalkyl includes the aforementioned cycloalkyl fused to aryl, heteroaryl or heterocyclyl, wherein the ring associated with the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl may optionally be substituted or unsubstituted. When substituted, the substituent(s) group(s) is/are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl, carboxylic ester group.

"Heterocyclyl" means a 3-20 membered saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more heteroatoms selected from the group consisting of N, O and S(O) _m (where m is an integer, selected from 0-2) as ring atoms, but excluding -O-O-, -OS- or -SS- in the ring, and the rest of the ring atoms are carbon atoms. Preferably, the heterocyclyl has 3-12 atoms with 1-4 heteroatoms, more preferably 3-6 atoms. Non-limiting examples of monocyclic heterocyclyl include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl includes heterocyclyl having a spiro ring, a fused ring, or a bridged ring.

"Spiro-heterocyclyl" means a 5 to 20-membered polycyclic heterocyclyl containing rings linked through a single common atom (referred to as a spiro atom), said rings having one or more heteroatoms selected from the group consisting of N, O and S (O) _m (where m is an integer selected from 0-2) as ring atoms, with the remaining ring atoms being carbon atoms, where one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system; preferably means 6-14 membered spiro-heterocyclyl and more preferably 7-10 membered spiro-heterocyclyl. Depending on the number of common spiro atoms, spiro-heterocyclyls can be subdivided into mono-spiro-heterocyclyl, di-spiro-heterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiro-heterocyclyl or di-spiro-heterocyclyl and more preferably 4-membered /4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono-spiro-heterocyclyl. Non-limiting examples of spiro-heterocyclyls include, but are not limited to:

"Fused heterocyclyl" means a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in such a system shares an adjacent pair of carbon atoms with the other ring, where one or more rings may contain one or more double bonds, but none of rings does not have a fully conjugated π-electron system, and said rings have one or more heteroatoms selected from the group consisting of N, O and S(O) _m (where m is an integer selected from 0-2) as atoms in the ring, and while the remaining atoms in the ring are carbon atoms; preferably means 6-14 membered fused heterocyclyl and more preferably 7-10 membered fused heterocyclyl. Depending on the number of said rings, fused heterocyclyls can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic fused heterocyclyl, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl include, but are not limited to:

"Bridged heterocyclyl" means a 5- to 14-membered polycyclic heterocyclyl group, wherein every two rings in this system share two non-conjugated atoms, which rings may have one or more double bonds, but neither ring has a fully conjugated π-electron system, and the rings have one or more heteroatoms selected from the group consisting of N, O and S(O) _m (where m is an integer selected from 0-2) as atoms in the ring, and when the remaining atoms in the ring are carbon atoms; preferably means 6-14 membered bridged heterocyclyl and more preferably 7-10 membered bridged heterocyclyl. Depending on the number of said rings, bridged heterocyclyls can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably bicyclic or tricyclic bridged heterocyclyl. Non-limiting examples of bridged heterocyclyl o's include, but are not limited to:

Said heterocyclyl includes the aforementioned heterocyclyl fused to aryl, heteroaryl or cycloalkyl, wherein the ring associated with the parent structure is heterocyclyl. Non-limiting examples include, but are not limited to:

и так далее.

and so on.

The heterocyclyl may optionally be substituted or unsubstituted. When substituted, the substituent(s) group(s) is/are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl, carboxylic ester group.

"Aryl" means a 6- to 14-membered all-carbon monocyclic ring or polycyclic fused ring (i.e., each ring in such a system shares an adjacent pair of carbon atoms with another ring in the system) having a fully conjugated π- electronic system; preferably means 6-10 membered aryl, more preferably phenyl and naphthyl, and most preferably phenyl. Aryl includes the aforementioned aryl fused to heteroaryl, heterocyclyl or cycloalkyl, wherein the ring associated with the parent structure is aryl. Non-limiting examples include, but are not limited to:

и

; предпочтительно

.

and

; preferably

.

Aryl may optionally be substituted or unsubstituted. When substituted, the substituent(s) group(s) preferably is(are) one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano , cycloalkyl, heterocyclyl a, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, and a carbon ether group.

"Heteroaryl" means a 5-14 membered aryl having 1-4 heteroatoms selected from the group consisting of O, S and N as ring atoms, with the remaining ring atoms being carbon atoms; preferably 5-10 membered heteroaryl, more preferably 5- or 6-membered heteroaryl such as imidazolyl, furyl, thienyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, pyrazolyl , pyrimidinyl or thiadiazole; more preferably pyrazolyl. Heteroaryl includes the aforementioned heteroaryl fused to aryl, heterocyclyl or cycloalkyl, wherein the ring associated with the parent structure is heteroaryl. Non-limiting examples include, but are not limited to:

и

предпочтительно

. Гетероарил возможно может быть замещенным или незамещенным. При наличии замещения замещающей(ими) группой(ами) предпочтительно являет(ют)ся одна или более групп, независимо выбранных из группы, состоящей из алкила, алкенила, алкинила, алкокси, алкилтио, алкиламино, галогена, тиола, гидрокси, нитро, циано, циклоалкила, гетероциклила, арила, гетероарила, циклоалкокси, гетероциклического алкокси, циклоалкилтио, гетероциклилтио, карбоксила и группы карбонового эфира.

and

preferably

. Heteroaryl may optionally be substituted or unsubstituted. When substituted, the substituent(s) group(s) preferably is(are) one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclylthio, carboxyl, and a carboxylic ester group.

"Alkoxy" means a -O-(alkyl) or -O-(unsubstituted cycloalkyl) group, where alkyl is as defined above. Non-limiting examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like. Alkoxy may optionally be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , heterocyclic alkoxy, cycloalkylthio, heterocyclylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, and a carbon ether group.

"Haloalkyl" means alkyl substituted with one or more halogen atoms, alkyl being as defined above.

"Haloalkoxy" means alkoxy substituted with one or more halogen atoms, alkoxy being as defined above.

"Hydroxyalkyl" means alkyl substituted with a hydroxy group, alkyl being as defined above.

"Hydroxy" means a -OH group.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Amino" means a -NH ₂ group.

"Cyano" means a -CN group.

"Nitro" means a -NO ₂ group.

"Oxo" means the =O group.

"Carboxyl" means a -C(O)OH group.

"Carboxylic ester group" means a -C(O)O(alkyl) or -C(O)O(cycloalkyl) group, where alkyl and cycloalkyl are as defined above.

"Possible" or "possible" means that the event or circumstance described subsequently may occur, but does not necessarily occur, and such descriptions include a situation in which the event or circumstance may or may not occur. For example, "heterocyclic group optionally substituted with alkyl" means that an alkyl group may be present but need not be present, and such descriptions include the situation where the heterocyclic group is substituted with alkyl and the situation where the heterocyclic group is not substituted with alkyl.

The term "substituted" refers to the situation where one or more hydrogen atoms in a group, preferably up to and including 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with an appropriate number of substituents. It goes without saying that the substituents are only in their chemically possible position. One skilled in the art is able to determine, experimentally or theoretically, whether or not substitution is possible without undue effort. For example, a structure in which an amino or hydroxy group with a free hydrogen atom is bonded to carbon atoms having unsaturated bonds (such as olefins) may be unstable.

As for any of the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclylthio, and carboxylic ether substituents mentioned throughout this application, any alkyl is preferably C ₁ -C ₆ alkyl, sometimes more preferably C ₁ -C ₄ alkyl; any alkenyl is preferably C ₂ -C ₆ alkenyl, sometimes more preferably C ₁ -C ₄ alkenyl; any alkynyl is preferably C ₂ -C ₆ alkynyl, sometimes more preferably C ₁ -C ₄ alkynyl; any cycloalkyl is preferably C ₃ -C ₆ cycloalkyl; any heterocyclyl is preferably 5-10 membered, sometimes more preferably 5- or 6-membered heterocyclyl; any aryl is preferably C ₆ -C ₁₀ aryl, more preferably phenyl; any heteroaryl is 5-10 membered, sometimes more preferably 5- or 6-membered, heteroaryl; and any carboxylic ether is preferably a C ₁ -C ₄ alkyl ether, sometimes more preferably a methyl or ethyl ester.

"Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or its(their) physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the introduction of the compound into the body and the absorption of the active ingredient and, thus, the manifestation of biological activity.

The compounds of the present invention may exist as pharmaceutically acceptable salts or solvates. The pharmaceutically acceptable salts may be any acid addition salt formed by reacting a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, nitric , sulfonic, p-toluenesulfonic, methanesulfonic acid or the like.

"Solvate" refers to the physical association of a compound of this invention with one or more, preferably one to three, solvent molecules, whether organic or inorganic. Such physical association includes attachment via hydrogen bonds. In some cases, it will be possible to isolate the solvate, for example, in which one or more, preferably one to three, solvent molecules are incorporated into the crystal lattice of the crystalline substance. Representative solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Generally, solvation methods are known in the art.

"Therapeutically effective amount" means the total amount of each active ingredient that is sufficient to demonstrate a measurable benefit to the patient, such as a significant reduction in viral load. When used in relation to an individual active ingredient administered as monotherapy, the term refers to that ingredient only. When used in relation to a combination, this term refers to the combined amounts of active ingredients that result in a therapeutic effect, regardless of the route of administration: in combination, sequentially or jointly.

"Pharmaceutical acceptable" refers to those compounds, substances, compositions and/or dosage forms that are medically suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction, or other problem or other complication in accordance with reasonable benefit/risk ratio and are effective for their intended use.

The term "patient" or "subject" includes both humans and other mammals, including, but not limited to, cats, dogs, cows, horses, or the like.

The term "treatment" or "treatment" refers to: (1) suppression of a disease, disorder, or condition, i.e. suspension of its development; and (2) alleviate the disease, disorder, or condition, i.e. causing remission of the disease, disorder and/or condition. In some embodiments, the present invention also includes the use of a compound of any of the described embodiments for preventing the onset of a disease, disorder, or condition in a patient who may be predisposed to the disease, disorder, and/or condition, but who has not yet been diagnosed as having it.

All terms used in this application, unless specifically defined, will take on the usual meanings that are understood by a person of ordinary skill in the art. All references mentioned in this specification are incorporated by reference in their entirety.

SYNTHESIS METHOD OF THE PRESENT INVENTION

In order to accomplish the object of the present invention, the following technical solutions are applied in the synthesis of the present invention:

a process for preparing a compound of formula (I) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Scheme 1

step 1, the compound of formula (I-1) is subjected to a condensation reaction with a compound of formula (I-2) under basic conditions to obtain a compound of formula (I-3) or formula (I-3');

step 2, the compound of formula (I-3) or formula (I-3') is subjected to an intramolecular transformation reaction in the presence of an acid to obtain a compound of formula (IA);

step 3, a compound of formula (IA) is coupled with a compound of formula (IB) under basic conditions in the presence of a catalyst to give a compound of formula (I);

where:

X is halogen, preferably bromine;

или

G is a leaving group, preferably a boronic acid or borate group; more preferably

or

R_a, R_b, R₁ - R₄, R_5a, R_5b, R₆, R₇, n и s являются такими, как определено в формуле (I).ring A,

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (I).

Alkaline reagents include an organic base and an inorganic base, said organic base including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium t-butoxide, or potassium t-butoxide, when this said inorganic base includes, but is not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.

Phosphine palladium catalysts include, but are not limited to, 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, tris(dibenzylideneacetone) dipalladium(0), palladium diacetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, triphenylphosphine and tetrakis(triphenylphosphine)palladium.

The above reactions are preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof;

a process for preparing a compound of formula (I) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Scheme 2

the compound of formula (IC) or formula (ID) is subjected to an intramolecular transformation reaction in the presence of an acid to obtain a compound of formula (I);

where:

R_a, R_b, R₁ - R₄, R5a, R_5b, R₆, R₇, n и s являются такими, как определено в формуле (I).ring A,

R _a , R _b , R ₁ - R ₄ , R5a, R _5b , R ₆ , R ₇ , n and s are as defined in formula (I).

Acidic reagents include, but are not limited to, acetic acid, pyridine hydrobromide, trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid, and methanesulfonic acid, preferably pyridine hydrobromide or hydrochloric acid.

The above reactions are preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof;

a process for preparing a compound of formula (II) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, comprising the following steps:

Scheme 3

a compound of formula (IIC) or formula (IID) is subjected to an intramolecular transformation reaction in the presence of an acid to obtain a compound of formula (II);

where:

R_a, R_b, R₁ - R₄, R_5a, R_5b, R₆, R₇, n и s являются такими, как определено в формуле (II).

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (II).

Acidic reagents include, but are not limited to, acetic acid, pyridine hydrobromide, trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid, and methanesulfonic acid, preferably pyridine hydrobromide or hydrochloric acid.

The above reactions are preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof;

a process for preparing a compound of formula (III) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixtures thereof or pharmaceutically acceptable salts thereof, comprising the following steps:

Scheme 3

a compound of formula (IIIC) or formula (IIID) is subjected to an intramolecular transformation reaction in the presence of an acid to obtain a compound of formula (III);

where:

R_a, R_b, R₁ - R₄, R_5a, R_5b, R₆, R₇, n и s являются такими, как определено в формуле (III).

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in formula (III).

Acidic reagents include, but are not limited to, acetic acid, pyridine hydrobromide, trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid, and methanesulfonic acid, preferably pyridine hydrobromide or hydrochloric acid.

The above reactions are preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof.

Hereinafter, the present invention will be described using the following examples, however, these examples should not be construed as limiting the scope of the present invention.

EXAMPLES

Compound structures were identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR spectra were determined using AVANCE-400 or AVANCE III 500 from Bruker. Solvents used were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ) and deuterated methanol (CD ₃ OD) with tetramethylsilane (TMS) as internal standard. Chemical shifts of the NMR spectra (δ) are given in 10 ^-6 ( ^ppm ).

High performance liquid chromatography (HPLC) data were determined on an Agilent 1200DAD high pressure liquid chromatography spectrometer (Sunfire C18 chromatographic column, 150 x 4.6 mm) and a Waters 2695-2996 high pressure liquid chromatography spectrometer (Gemini C18 chromatographic column, 150 x 4 .6 mm).

Chiral High Performance Liquid Chromatography (HPLC) data were determined on an LC-10A-VP instrument (Shimadzu) or an Analytical Supercritical Liquid Chromatography (SFC) instrument (Berger Instruments Inc.)

Mass spectrum (MS) was determined on a SHIMADZU mass spectrometer (electrospray ionization (ESI)) combined with liquid chromatography (LCMS) (manufacturer: Shimadzu, type: LC-20AD, LCMS-2020).

Known starting materials for the present invention were obtained by methods conventionally used for synthesis in the art, or purchased from Aldrich Chemical Company, Fisher Scientific or Combi-Blocks, and so on.

Unless otherwise indicated, the reactions were carried out under nitrogen or argon atmosphere.

The term "nitrogen atmosphere" or "argon atmosphere" means that the reaction flask was equipped with a 1 liter nitrogen or argon cylinder.

The term "hydrogen atmosphere" means that the reaction flask was equipped with a 1 liter hydrogen bottle.

Unless otherwise indicated, the reaction temperature in the reaction mixtures refers to room temperature, and the temperature range was from 20°C to 30°C.

The progress of the reaction was monitored by thin layer chromatography (TLC), and the developed solvent system included: A: dichloromethane and methanol, B: hexane and ethyl acetate. The ratio of solvent volumes was adjusted according to the polarity of the compounds. The elution system for purifying compounds on the CombiFlash Rapid Column Chromatography, TLC and Flash chromatography instrument includes: A: dichloromethane and methanol, B: hexane and ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compounds, and sometimes a small amount of a basic reagent such as ammonia or an acidic reagent such as acetic acid was added.

The final compounds were purified by preparative HPLC on a Shimadzu instrument (LC-20AD, SPD20A) (Gemini-NX column, C18, 5 μm, 21.2×100 mm, from Phenomenex) using the elution system: C: 0.075% TFA (trifluoroacetic acid ) in water and 0.075% TFA in MeOH or D: 0.075% TFA in water and 0.075% TFA in CH ₃ CN.

The following abbreviations have been used:

TEA means triethylamine,

DIPEA means N,N-diisopropylethylamine,

EDCI means N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride,

HOBt means 1-hydroxybenzotriazole hydrate,

DCM means dichloromethane,

HBTU stands for O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate,

DMF means N,N-dimethylformamide,

NMR stands for Proton Nuclear Magnetic Resonance and

MS is mass spectroscopy with (+) meaning positive ion mode, which typically results in M+1 (or M+H), where M is the mass of the molecular ion.

Preparative HPLC stands for Preparative High Performance Liquid Chromatography.

Example 1

Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-phenyl-1H-benzo[d]imidazole

Stage 1. Obtaining ethyl 2- (4- (ethylthio) phenyl) acetate

To a solution of 2-(4-mercaptophenyl)acetic acid (3.4 g; 0.02 mol) in N,N-dimethylformamide (DMF) (20 ml) was added K ₂ CO ₃ (11 g; 0.04 mol) and iodoethane (6.4 g; 0.06 mol). The reaction mixture was stirred at RT. After 2.5 hours, the starting material was completely consumed. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic phase was washed with water (30 ml) and brine (20 ml), dried over sodium sulfate, filtered and concentrated to give the desired product ethyl-[4-(ethylthio)phenyl]acetate (3.6 g; 80%) as a pale -yellow solid, MS (+) ES: 225 (M+H) ⁺ .

Stage 2. Preparation of ethyl 2-(4-(ethylsulfonyl)phenyl)acetate

Ethyl 2-(4-(ethylthio)phenyl)acetate (5.5 g; 0.0245 mol) and dichloromethane (82.5 ml) were added to a 250 ml round bottom flask. The reaction mixture was cooled to 0°C. To the same flask at 0°C was added m-chloroperbenzoic acid (12.6 g; 0.073 mol). The reaction mixture was stirred at room temperature for 12 hours. The resulting suspension was filtered through a pad of celite. The filtrate was washed with water. The organic layer was separated, washed with saturated sodium bicarbonate solution, then with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography using hexane/ethyl acetate to give the title compound as an oil which solidified on standing (4.7 g; 75%), MS (+) ES: 257 (M+H) ⁺ .

Stage 3. Obtaining 2-(4-(ethylsulfonyl)phenyl)acetic acid

Ethyl 2-(4-(ethylsulfonyl)phenyl)acetate (2.56 g; 0.01 mol) and ethanol (18 ml) were added to a 50 ml round bottom flask. A solution of sodium hydroxide in water (1.42 g; 0.0355 mol in 18 ml of water) was added to the same flask. The reaction mixture was stirred at room temperature for 12 hours. The volatiles were evaporated under reduced pressure. The residue was acidified to pH 5.0 using 1 N. HCl solution, and was extracted with ethyl acetate (15 ml × 3). The organic layer was separated and combined, washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a colorless oil which solidified on standing (2.0 g; 85%), MS (+) ES: 229 (M+H) ⁺ .

Stage 4. Obtaining 2-bromo-1,3-dichloro-4,5-dinitrobenzene

2-Bromo-1,3-dichloro-5-nitrobenzene (2.7 g; 0.01 mol) was carefully added to a previously prepared solution of fuming nitric acid (10 ml) and concentrated sulfuric acid (10 ml) with stirring. After the addition, the mixture was heated to 50°C in a water bath for two hours to complete the reaction (monitoring using LCMS). The mixture was then cooled and poured onto ice. The yellow precipitate was collected by filtration, washed thoroughly with water and dried to give the product as a yellow solid (3 g; 95%), MS (+) ES: 314 (M+H) ⁺ .

Stage 5. Obtaining 4-bromo-3,5-dichlorobenzene-1,2-diamine

In a stirred mixture of AcOH (50 ml) and EtOH (100 ml) were suspended 2-bromo-1,3-dichloro-4,5-dinitrobenzene (3.1 g; 0.01 mol) and iron powder (4.4 g; 0.08 mol). The reaction mixture was slowly heated to a gentle boil (reflux) and left to stir for 1 hour. Then the reaction mixture was cooled to room temperature, was added diethyl ether (50 ml) and water (50 ml). The solution was carefully neutralized by adding solid sodium carbonate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (20 ml). The organic phases were combined and washed with saturated NaHCO ₃ (2×30 ml), H ₂ O (2×30 ml) and brine (1×30 ml), then dried over MgSO ₄ , filtered and concentrated to dryness under vacuum, obtaining specified in title compound as an off-white solid (2.0 g; 78%), MS (+) ES: 255 (M+H) ⁺ .

Step 6. Preparation of N-(6-amino-3-bromo-2,4-dichlorophenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

1-Ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride (2.0 g; 0.01 mol) and benzotriazol-1-ol (1.35 g; 0.01 mol) were added portionwise to the chilled ( in an ice water bath) a solution of 4-bromo-3,5-dichlorobenzene-1,2-diamine (2.55 g; 0.01 mol) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (from step 3 ; 2.28 g; 0.01 mol) in DMF (10 ml) for 30 min. After the addition was complete, the mixture was stirred for 60 minutes and allowed to warm to room temperature, stirred overnight. The mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic phase was separated and dried over MgSO ₄ , filtered. The solvent was evaporated under reduced pressure to give an off-white solid which was purified by flash chromatography using hexane/ethyl acetate to give the product as an off-white solid (3.5 g; 75%), MS (+) ES: 466 (M+ H) ⁺ .

Step 7. Preparation of 5-bromo-4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-1H-benzo[d]imidazole

N-(6-Amino-3-bromo-2,4-dichlorophenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide (from step 6) (3.5 g; 0.0075 mol) was mixed with acetic acid ( 25 ml) and the mixture was heated to 100°C for 4 hours, cooled. The solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, dried over MgSO ₄ . This product was purified by flash chromatography using hexane/ethyl acetate to give the product as a white solid (2.7 g; 80%), MS (+) ES: 448 (M+H) ⁺ .

Step 8. Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-phenyl-1H-benzo[d]imidazole

Mixture of 5-bromo-4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-1H-benzo[d]imidazole (step 7) (448 mg; 1 mmol), phenylboronic acid (363 mg; 3 mmol) , tris-(dibenzylideneacetone)dipalladium(0) (60 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (60 mg) and sodium carbonate (2 M solution) in 1,4-dioxane (3 ml) were degassed, sealed and heated to 100° C. under microwave irradiation for 1 h. Volatile solvents were removed under reduced pressure. The residue was loaded directly onto a solid cartridge from ISCO and eluted rapidly with hexane/ethyl acetate to give a white solid (320 mg; 72% yield), MS (+) ES: 445 (M+H) ⁺ .

Example 2

Preparation of (4,6-dichloro-5-phenyl-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

Stage 1. Obtaining (4,6-dichloro-5-phenyl-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanone

4,6-Dichloro-2-(4-(ethylsulfonyl)benzyl)-5-phenyl-1H-benzo[d]imidazole (Example 1) (4.5 mg; 0.01 mmol) was dissolved in 1,4-dioxane (0.5 ml), was added MnO ₂ (5 mg; 0.058 mmol) at room temperature. The mixture was stirred and heated to 60°C for 60 min to complete the reaction (monitoring using LCMS). After cooling, the solid was filtered off and the product was purified by flash chromatography using hexane/ethyl acetate to give a white solid (4 mg; 87%), MS (+) ES: 459 (M+H) ⁺ .

Stage 2. Preparation of (4,6-dichloro-5-phenyl-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

(4,6-Dichloro-5-phenyl-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)-methanone (example 3, step 1) (4 mg; 0.0087 mmol) was dissolved in methanol (0.5 ml), sodium borohydride (1.6 mg; 0.044 mmol) was added and the mixture was stirred for 30 minutes to complete the reaction. The product was purified by preparative HPLC using System C as eluent to give a white solid (3.3 mg; 82%), MS (+) ES: 461 (M+H) ⁺ .

Example 3

Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)phenyl)-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole

According to the synthetic route of Example 1, the starting material, phenylboronic acid, was replaced in step 8 with 2-trifluoromethylphenylboronic acid, respectively, the title compound was obtained as a white solid, MS (+) ES: 513 (M+H) ⁺ .

Example 4

Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

4,6-Dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole (5.3 mg; 0.01 mmol) was dissolved in 0. 1 ml anhydrous DMSO, paraformaldehyde (0.6 mg; 0.02 mmol) was added with stirring, then sodium ethoxide powder (1.2 mg; 0.02 mmol) was added. The mixture was stirred at room temperature for 60 minutes. The mixture was treated with a small amount of dilute HCl and directly purified by prep HPLC using System C as eluent to give the product as a white solid (3.8 mg; 70% yield), MS (+) ES: 559 (M+H) ⁺ .

Example 5

Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 545 (M+H) ⁺ .

Example 6

Preparation of 2-(4,6-dichloro-5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same manner as in example 4, obtaining the product as a white solid, MS (+) ES: 505 (M+H) ⁺ .

Example 7

Preparation of (4,6-dichloro-5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 491 (M+H) ⁺ .

Example 8

Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, except using 2-isopropyloxyphenylboronic acid instead of phenylboronic acid in step 8, obtaining the product as a white solid, MS (+) ES: 503 (M+H ) ⁺ .

Example 9

Preparation of 2-(4,6-dichloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 533 (M+H) ⁺ .

Example 10

Preparation of (4,6-dichloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This product was obtained in essentially the same manner as in example 2, obtaining the product as a white solid, MS (+) ES: 519 (M+H) ⁺ .

Example 11

Preparation of 2-(4,6-dichloro-5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 493 (M+H) ⁺ .

Example 12

Preparation of (4,6-dichloro-5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 479 (M+H) ⁺ .

Example 13

Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-(methoxymethoxy)phenyl)-1H-benzo[d]imidazole

This compound was prepared using essentially the same method as in Example 1 except using 2-methoxymethoxyphenylboronic acid in place of phenylboronic acid in Step 8 to give the product as a white solid, MS (+) ES: 505 (M+H ) ⁺ .

Example 14

Preparation of 2-(4,6-dichloro-5-(2-methoxymethoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 535 (M+H) ⁺ .

Example 15

Preparation of (4,6-dichloro-5-(2,5-dichlorophenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 534 (M+H) ⁺ .

Example 16

Preparation of 4,6-dichloro-5-(2-ethoxyphenyl)-2-(4-(ethylsulfonyl)benzyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, except for the use of 2-ethoxyphenylboronic acid instead of phenylboronic acid in step 36, obtaining the product as a white solid, MS (+) ES: 489 (M+H ) ⁺ .

Example 17

Preparation of 2-(4,6-dichloro-5-(2-ethoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 519 (M+H) ⁺ .

Example 18

Preparation of (4,6-dichloro-5-(2-ethoxyphenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 505 (M+H) ⁺ .

Example 19

Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-(2-methoxyethoxy)phenyl)-1H-benzo[d]imidazole

This compound was prepared using essentially the same method as in Example 1 except using (2-(2-methoxyethoxy)phenyl)boronic acid in place of phenylboronic acid in Step 8 to give the product as a white solid, MS (+ ) ES: 519 (M+H) ⁺ .

Example 20

Preparation of 2-(4,6-dichloro-5-(2-(2-methoxyethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 549 (M+H) ⁺ .

Example 21

Preparation of (4,6-dichloro-5-(2-(2-methoxyethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 535 (M+H) ⁺ .

Example 22

Preparation of 2-(4,6-dichloro-2-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-1H-benzo[d]imidazol-5-yl)benzonitrile

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 500 (M+H) ⁺ .

Example 23

Preparation of 2-(4,6-dichloro-2-((4-(ethylsulfonyl)phenyl)(hydroxy)methyl)-1H-benzo[d]imidazol-5-yl)benzonitrile

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 486 (M+H) ⁺ .

Example 24

Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(thiophen-3-yl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, except for the use of 3-thiophenylboronic acid instead of phenylboronic acid in step 8, obtaining the product as a white solid, MS (+) ES: 451 (M+H ) ⁺ .

Example 25

Preparation of 2-(4,6-dichloro-5-(thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 481 (M+H) ⁺ .

Example 26

Preparation of (4,6-dichloro-5-(thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 467 (M+H) ⁺ .

Example 27

Preparation of 2-(4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-1H-benzo[d]imidazol-5-yl)-N,N-dimethylaniline

This compound was prepared using essentially the same method as in Example 1 except using (2-(dimethylamino)phenyl)boronic acid in place of phenylboronic acid in Step 8 to give the product as a white solid, MS(+)ES : 488 (M+H) ⁺ .

Example 28

Preparation of 4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-2-(4-(ethylsulfonyl)benzyl)-1H-benzo[d]imidazole

This compound was prepared using essentially the same method as in Example 1 except using 2-difluoromethoxyphenylboronic acid pinacol ester in place of phenylboronic acid in Step 8 to give the product as a white solid, MS (+) ES: 511 (M +Н) ⁺ .

Example 29

Preparation of 2-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 541 (M+H) ⁺ .

Example 30

Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 527 (M+H) ⁺ .

Example 31

Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-(2,2,2-trifluoroethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, except using 4,4,5,5-tetramethyl-2-(2-(2,2,2-trifluoroethoxy)phenyl)-1,3 ,2-dioxaborolane instead of phenylboronic acid in step 8 to give the product as a white solid, MS (+) ES: 543 (M+H) ⁺ .

Example 32

Preparation of 2-(4,6-dichloro-5-(2-(2,2,2-trifluoroethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl) ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 573 (M+H) ⁺ .

Example 33

Preparation of (4,6-dichloro-5-(2-(2,2,2-trifluoroethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 559 (M+H) ⁺ .

Example 34

Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-(3,3,3-trifluoropropyl)phenyl)-1H-benzo[d]imidazole

This compound was prepared using essentially the same method as in Example 1 except using 4,4,5,5-tetramethyl-2-(2-(3,3,3-trifluoropropyl)phenyl)-1,3 ,2-dioxaborolane instead of phenylboronic acid in step 8 to give the product as a white solid, MS (+) ES: 541 (M+H) ⁺ .

Example 35

Preparation of (4,6-dichloro-5-(2-(3,3,3-trifluoropropyl)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 557 (M+H) ⁺ .

Example 36

Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-isopropylphenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, except for the use of 2-isopropylphenylboronic acid instead of phenylboronic acid in step 8, obtaining the product as a white solid, MS (+) ES: 487 (M+H ) ⁺ .

Example 37

Preparation of 2-(4,6-dichloro-5-(2-isopropylphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 517 (M+H) ⁺ .

Example 38

Preparation of (E,Z)-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanone oxime

A mixture of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanone (52 mg; 0.1 mmol) and hydroxylamine hydrochloride (14 mg; 0.2 mmol) in anhydrous pyridine (1 ml) was heated to 70° C. for 2 hours. After cooling, the solvent was evaporated under reduced pressure to dryness. The product was purified by flash chromatography using hexane/ethyl acetate to give the product as a white solid (42 mg; 78%) MS (+) ES: 540 (M+H) ⁺ .

Example 39

Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanamine

Mixture of (E,Z)-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanone oxime (42 mg; 0.078 mmol) was dissolved in anhydrous THF (2 ml). To this solution was added a 1 M solution of borohydride in THF (4 ml) and the mixture was stirred at room temperature overnight. Volatile solvents were evaporated under reduced pressure and the residue was directly purified by preparative HPLC using System C to elute to give a white solid (18 mg; 45%), MS (+) ES: 526 (M+H) ⁺ .

Example 40

Preparation of N-((4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyl)acetamide

A solution of acetyl chloride (in DCM) (1 eq.) was added to a chilled (in ice water bath) solution of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazole-2- yl)(4-(ethylsulfonyl)phenyl)methanamine (Example 39) (4 mg; 0.0076 mmol) and triethylamine (1 eq.) in dichloromethane (0.5 ml). The mixture was stirred for 30 minutes, after which the dichloromethane was evaporated. The residue was directly separated by preparative HPLC using System C to elute giving a white solid (2.6 mg; 42%), MS (+) ES: 568 (M+H) ⁺ .

Example 41

Preparation of N-((4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyl)-2-methoxyacetamide

An analogous method to Example 40 was used to give the product as a white solid, MS (+) ES: 598 (M+H) ⁺ .

Example 42

Preparation of N-((4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyl)-3,5-dimethylisoxazole -4-carboxamide

An analogous method to Example 40 was used to give the product as a white solid, MS (+) ES: 649 (M+H) ⁺ .

Example 43

Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanamine

An analogous method to Example 39 was used to give the product as a white solid, MS (+) ES: 544 (M+H) ⁺ .

Example 44

Preparation of N-((4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyl)acetamide

An analogous method to Example 40 was used to give the product as a white solid, MS (+) ES: 586 (M+H) ⁺ .

Example 45

Preparation of 4,6-dichloro-2-(4-(methylsulfonyl)benzyl)-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, obtaining the product as a white solid, MS (+) ES: 499 (M+H) ⁺ .

Example 46

Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(methylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 529 (M+H) ⁺ .

Example 47

Preparation of 4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-2-(4-(methylsulfonyl)benzyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 28, obtaining the product as a white solid, MS (+) ES: 497 (M+H) ⁺ .

Example 48

Preparation of 2-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(methylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 29, obtaining the product as a white solid, MS (+) ES: 527 (M+H) ⁺ .

Example 49

Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(methylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 30, obtaining the product as a white solid, MS (+) ES: 513 (M+H) ⁺ .

Example 50

Preparation of 4,6-dichloro-2-(4-(propylsulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, obtaining the product as a white solid, MS (+) ES: 543 (M+H) ⁺ .

Example 51

Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(propylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 6, obtaining the product as a white solid, MS (+) ES: 573 (M+H) ⁺ .

Example 52

Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(propylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 7, obtaining the product as a white solid, MS (+) ES: 559 (M+H) ⁺ .

Example 53

Preparation of 4,6-dichloro-2-(4-((2-methoxyethyl)sulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, obtaining the product as a white solid, MS (+) ES: 559 (M+H) ⁺ .

Example 54

Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((2-methoxyethyl)sulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 6, obtaining the product as a white solid, MS (+) ES: 589 (M+H) ⁺ .

Example 55

Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-((2-methoxyethyl)sulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 7, obtaining the product as a white solid, MS (+) ES: 575 (M+H) ⁺ .

Example 56

Preparation of 4,6-dichloro-2-(4-(methylsulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, obtaining the product as a white solid, MS (+) ES: 515 (M+H) ⁺ .

Example 57

Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(methylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 6, obtaining the product as a white solid, MS (+) ES: 545 (M+H) ⁺ .

Example 58

Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(methylsulfonyl)phenyl)methanol

This product was obtained in essentially the same way as in example 7, obtaining the product as a white solid, MS (+) ES: 531 (M+H) ⁺ .

Example 59

Preparation of 4,6-dichloro-2-(4-((2,2,2-trifluoroethyl)sulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, obtaining the product as a white solid, MS (+) ES: 583 (M+H) ⁺ .

Example 60

Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((2,2,2-trifluoroethyl)sulfonyl )phenyl)ethanol

This compound was obtained in essentially the same way as in example 6, obtaining the product as a white solid, MS (+) ES: 613 (M+H) ⁺ .

Example 61

Preparation of 4,6-dichloro-2-(4-((2-fluoroethyl)sulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, obtaining the product as a white solid, MS (+) ES: 547 (M+H) ⁺ .

Example 62

Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((2-fluoroethyl)sulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 577 (M+H) ⁺ .

Example 63

Preparation of 4,6-dichloro-2-(4-((2-fluoroethyl)sulfonyl)benzyl)-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, obtaining the product as a white solid, MS (+) ES: 531 (M+H) ⁺ .

Example 64

Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((2-fluoroethyl)sulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 561 (M+H) ⁺ .

Example 65

Preparation of 4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-2-(4-((trifluoromethyl)sulfonyl)benzyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, obtaining the product as a white solid, MS (+) ES: 553 (M+H) ⁺ .

Example 66

Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, obtaining the product as a white solid, MS (+) ES: 555 (M+H) ⁺ .

Example 67

Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 585 (M+H) ⁺ .

Example 68

Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 571 (M+H) ⁺ .

Example 69

Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, obtaining the product as a white solid, MS (+) ES: 539 (M+H) ⁺ .

Example 70

Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 569 (M+H) ⁺ .

Example 71

Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 555 (M+H) ⁺ .

Example 72

Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained using essentially the same method as in example 1, obtaining the product as a white solid, MS (+) ES: 537 (M+H) ⁺ .

Example 73

Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 567 (M+H) ⁺ .

Example 74

Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 519 (M+H) ⁺ .

Example 75

Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)methanol

This product was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 505 (M+H) ⁺ .

Example 76

Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

Stage 1. Obtaining methyl-(2-fluoro-4-nitrophenyl)acetate

To 2-(2-fluoro-4-nitrophenyl)acetic acid (4.0 g; 0.02 mol) in methanol (20 ml) was added concentrated sulfuric acid (1 ml). The solution was heated to reflux overnight. After cooling, the mixture was concentrated to a small volume and partitioned between ether (30 ml) and water. The ethereal phase was separated and washed with saturated sodium bicarbonate solution (30 ml). Then the organic phase was once again separated and washed with water, dried over MgSO ₄ . The solid was filtered off and the solvent was evaporated to give a product pure enough to carry out the next step (3.8 g; 88%), MS (+) ES: 214 (M+H) ⁺ .

Step 2. Preparation of methyl 2-(4-amino-2-fluorophenyl)acetate

Methyl 2-(2-fluoro-4-nitrophenyl)acetate (3.8 g; 0.018 mol) and ethyl acetate (30 ml) were added to a 50 ml round bottom flask. 10% palladium on activated charcoal (0.5 g) was added to the same flask. The reaction mixture was stirred under hydrogen gas (using a balloon) for 5 hours. The reaction mixture was filtered through a pad of celite. The filtrate was evaporated under reduced pressure to give the title compound (2.8 g; 86%) MS (+) ES: 184 (M+H) ⁺ .

Stage 3. Obtaining 2-(2-fluoro-4-mercaptophenyl)acetic acid

A solution of sodium nitrite (1.06 g; 0.015 mol) in 16 ml of water was added dropwise at 0°C to a stirred suspension of methyl 2-(4-amino-2-fluorophenyl)acetate (2.8 g; 0.015 mol) in 50 ml of water and 3.8 ml of concentrated hydrochloric acid. After completion of the addition, the reaction mixture was stirred at the same temperature for another 60 minutes. This cold diazonium salt solution was then added dropwise at room temperature to a mixture of potassium O-ethyl carbonodithioate (2.8 g), 50 ml of water and 16 ml of 2 M sodium carbonate solution and heated to 45° C. until gas evolution ceased. The mixture was cooled to room temperature and the pH was adjusted to 1 with concentrated hydrochloric acid. The oily ester of xanthic acid was extracted with ether. The solvent was evaporated to give a dark red liquid, 2-(4-(ethoxycarbonothioyl)thio)-2-fluorophenyl)acetic acid methyl ester (3.5 g), MS (+) ES: 288 (M+H) ⁺ .

The above oily product was dissolved in ethanol (10 ml), a solution of KOH (1.8 g) in water (10 ml) was added and the mixture was heated to reflux overnight. The mixture was concentrated to a small volume and acidified with concentrated HCl. The product was extracted with ethyl acetate (10 ml x3). The combined organic phase was dried over MgSO ₄ , the solid was filtered off. Evaporation of the solvent gave the crude product (2.5 g; 89%), MS (+) ES: 187 (M+H) ⁺ .

Stage 4. Preparation of ethyl 2-(4-(ethylthio)-2-fluorophenyl)acetate

2-(2-Fluoro-4-mercaptophenyl)acetic acid (2.5 g, 0.013 mol) was dissolved in DMF (25 ml), then cesium carbonate (13.0 g, 0.039 mol) was added. The mixture was stirred for 10 minutes, after which iodoethane (6 g; 0.039 mol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (30 ml). The organic phase was separated and dried over MgSO ₄ . The solid was filtered off and the solvent was evaporated to dryness. This product was purified by flash chromatography using hexane/ethyl acetate to give an oil (2.8 g; 86%), MS (+) ES: 243 (M+H) ⁺ .

Stage 5. Preparation of ethyl 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetate

Ethyl 2-(4-(ethylthio)-2-fluorophenyl)acetate (2.8 g; 0.012 mol) was dissolved in DCM (50 ml). The solution was cooled to 0°C using an ice bath. MCPBA (6.0 g) was added in portions. The reaction mixture was stirred at room temperature overnight and then filtered to remove a solid. The filtrate was washed with sat. sodium carbonate solution (30 ml x2), water (30 ml), brine (30 ml), dried over magnesium sulfate and concentrated. The residue was purified by column chromatography using hexane/ethyl acetate to give the title compound ethyl 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetate (2.0 g; 64%), MS (+) ES: 275 (M+ H) ⁺ .

Stage 6. Obtaining 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetic acid

To a solution of ethyl 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetate (2.0 g; 7.3 mmol) in ethanol (30 ml) was added a solution of NaOH (1.0 g) in water (10 ml) . The reaction mixture was stirred at room temperature overnight. Ethanol was removed under reduced pressure and 20 ml of water was added. The aqueous phase was acidified to pH 1 using 6 M HCl solution and then extracted with ethyl acetate (50 ml x3). The combined organic phases were washed with brine (50 ml), dried over magnesium sulfate and concentrated to give an oil which solidified on standing (1.6 g; 90%), MS(+) ES: 247 (M+H) ⁺ .

Step 7: Preparation of N-(6-amino-3-bromo-2,4-dichlorophenyl)-2-(4-(ethylsulfonyl)-2-fluorophenyl)acetamide

1-Ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride (1.0 g; 5 mmol) and benzotriazol-1-ol (0.7 g; 5 mmol) were added in portions to the chilled (in an ice bath). water) solution of 4-bromo-3,5-dichlorobenzene-1,2-diamine (1.28 g; 5 mmol) and 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetic acid (Example 93, step 6; 1.23 g; 5 mmol) in DMF (10 ml). After the addition was complete, the mixture was stirred for 60 minutes and allowed to warm to room temperature, stirred overnight. The mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic phase was separated and dried over MgSO ₄ , filtered. The solvent was evaporated under reduced pressure to give an off-white solid which was purified by flash chromatography using hexane/ethyl acetate to give the product as a solid (1.7 g; 70%), MS (+) ES: 484 (M+H ) ⁺ .

Step 8. Preparation of 5-bromo-4,6-dichloro-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-1H-benzo[d]imidazole

N-(6-Amino-3-bromo-2,4-dichlorophenyl)-2-(4-(ethylsulfonyl)-2-fluorophenyl)acetamide (step 7) (1.7 g; 3.5 mmol) was mixed with acetic acid (10 ml), the mixture was heated to 100°C for 4 hours and cooled. The solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution and dried over MgSO ₄ . This product was purified by flash chromatography using hexane/ethyl acetate to give the product as a white solid (1.2 g; 73%), MS (+) ES: 466 (M+H) ⁺ .

Step 9. Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

5-Bromo-4,6-dichloro-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-1H-benzo[d]imidazole mixture (step 8) (47 mg; 0.1 mmol), 2-trifluoromethoxyphenylboronic acid (62 mg; 0.3 mmol), tris-(dibenzylideneacetone) dipalladium(0) (6 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (6 mg) and sodium carbonate (2 M solution) in 1,4-dioxane (0.6 ml) was degassed and heated to 100°C under microwave irradiation for 1 hour. Volatile solvents were removed under reduced pressure. The residue was applied directly to a solid cartridge from ISCO and eluted rapidly with hexane/ethyl acetate to give a white solid (38 mg; 70% yield), MS (+) ES: 547 (M+H) ⁺ .

Example 77

Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)-2-fluorophenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 577 (M+H) ⁺ .

Example 78

Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)-2-fluorophenyl)methanol

This compound was obtained in essentially the same way as in example 2, obtaining the product as a white solid, MS (+) ES: 563 (M+H) ⁺ .

Example 79

Preparation of (4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)-2-fluorophenyl)methanol

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 547 (M+H) ⁺ .

Example 80

Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)-2-fluorobenzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained in a manner essentially similar to that of example 76, obtaining the product as a white solid, MS (+) ES: 573 (M+H) ⁺ .

Example 81

Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)-2-fluorophenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl) ethanol

This compound was obtained in a manner essentially similar to that of example 77, obtaining the product as a white solid, MS (+) ES: 603 (M+H) ⁺ .

Example 82

Preparation of (4-((cyclopropylmethyl)sulfonyl)-2-fluorophenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 589 (M+H) ⁺ .

Example 83

Preparation of 4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-1H-benzo[d]imidazole

This compound was prepared in essentially the same manner as in Example 76 by using 2-difluorophenylboronic acid in place of 2-trifluoromethoxyphenylboronic acid in Step 9 to give the product as a white solid, MS (+) ES: 529 (M+H) ⁺ .

Example 84

Preparation of 2-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)-2-fluorophenyl)ethanol

This compound was obtained in a manner essentially similar to that of example 77, obtaining the product as a white solid, MS (+) ES: 559 (M+H) ⁺ .

Example 85

Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)-2-fluorophenyl)methanol

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 545 (M+H) ⁺ .

Example 86

Preparation of 4,6-dichloro-2-(2-chloro-4-(ethylsulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained in a manner essentially similar to that of example 76, obtaining the product as a white solid, MS (+) ES: 563 (M+H) ⁺ .

Example 87

Preparation of 2-(2-chloro-4-(ethylsulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in a manner essentially similar to that of example 77, obtaining the product as a white solid, MS (+) ES: 593 (M+H) ⁺ .

Example 88

Preparation of (2-chloro-4-(ethylsulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 579 (M+H) ⁺ .

Example 89

Preparation of 4,6-dichloro-2-(2-chloro-4-(ethylsulfonyl)benzyl)-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained in a manner essentially similar to that of example 76, obtaining the product as a white solid, MS (+) ES: 545 (M+H) ⁺ .

Example 90

Preparation of 4,6-dichloro-2-(2-chloro-4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained in a manner essentially similar to that of example 76, obtaining the product as a white solid, MS (+) ES: 589 (M+H) ⁺ .

Example 91

Preparation of 2-(2-chloro-4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl )ethanol

This compound was obtained in a manner essentially similar to that of example 77, obtaining the product as a white solid, MS (+) ES: 619 (M+H) ⁺ .

Example 92

Preparation of (2-chloro-4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 605 (M+H) ⁺ .

Example 93

Preparation of 4,6-dichloro-5-(2-chlorophenyl)-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-1H-benzo[d]imidazole

This compound was obtained in a manner essentially similar to that of example 76, obtaining the product as a white solid, MS (+) ES: 505 (M+H) ⁺ .

Example 94

Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-chlorophenyl)-1H-benzo[d]imidazol-2-yl)methanol

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 521 (M+H) ⁺ .

Example 95

Preparation of 2-(4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-1H-benzo[d]imidazol-5-yl)benzonitrile

This compound was obtained in a manner essentially similar to that of example 76, obtaining the product as a white solid, MS (+) ES: 496 (M+H) ⁺ .

Example 96

Preparation of 2-(4,6-dichloro-2-(1-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-hydroxyethyl)-1H-benzo[d]imidazol-5-yl)benzonitrile

This compound was obtained in a manner essentially similar to that of example 77, obtaining the product as a white solid, MS (+) ES: 526 (M+H) ⁺ .

Example 97

Preparation of 2-(4,6-dichloro-2-((4-((cyclopropylmethyl)sulfonyl)phenyl)(hydroxy)methyl)-1H-benzo[d]imidazol-5-yl)benzonitrile

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 512 (M+H) ⁺ .

Example 98

Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)-2-fluorobenzyl)-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained in a manner essentially similar to that of example 76, obtaining the product as a white solid, MS (+) ES: 555 (M+H) ⁺ .

Example 99

Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)-2-fluorophenyl)-2-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl) ethanol

This compound was obtained in a manner essentially similar to that of example 77, obtaining the product as a white solid, MS (+) ES: 585 (M+H) ⁺ .

Example 100

Preparation of (4-((cyclopropylmethyl)sulfonyl)-2-fluorophenyl)(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 571 (M+H) ⁺ .

Example 101

Preparation of 4,6-dichloro-2-(2-chloro-4-(methylsulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained in a manner essentially similar to that of example 76, obtaining the product as a white solid, MS (+) ES: 549 (M+H) ⁺ .

Example 102

Preparation of 2-(2-chloro-4-(methylsulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in a manner essentially similar to that of example 77, obtaining the product as a white solid, MS (+) ES: 579 (M+H) ⁺ .

Example 103

Preparation of (2-chloro-4-(methylsulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 565 (M+H) ⁺ .

Example 104

Preparation of 4,6-dichloro-2-(4-((isopropylsulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

This compound was obtained in a manner essentially similar to that of example 76, obtaining the product as a white solid, MS (+) ES: 543 (M+H) ⁺ .

Example 105

Preparation of 2-(4-((isopropyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in a manner essentially similar to that of example 77, obtaining the product as a white solid, MS (+) ES: 573 (M+H) ⁺ .

Example 106

Preparation of (4-((isopropyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 559 (M+H) ⁺ .

Example 107

Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((isopropylsulfonyl)phenyl)ethanol

This compound was obtained in essentially the same way as in example 4, obtaining the product as a white solid, MS (+) ES: 557 (M+H) ⁺ .

Example 108

Preparation of 2-(4-(ethylsulfonyl)benzyl)-4,6-difluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

Step 1. Preparation of N-(4-bromo-3,5-difluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide

KNO ₃ was added to a chilled (in ice water) solution of 4-bromo-3,5-difluoroaniline (2 g; 0.01 mol) in trifluoroacetic anhydride (10 ml) in one portion. The reaction mixture was then allowed to warm to room temperature with stirring overnight. The solvent was evaporated to dryness and the residue was taken up in ethyl acetate, washed with sat. sodium bicarbonate solution, water, dried over MgSO ₄ . The solid was filtered off and the solvent was evaporated. The product was purified by flash chromatography using hexane/ethyl acetate to give an off-white solid (1.8 g; 51%), MS (+) ES: 349 (M+H) ⁺ .

Stage 2. Obtaining 4-bromo-3,5-difluoro-2-nitroaniline

Mixture of K ₂ CO ₃ (0.95 g; 6.9 mmol) and N-(4-bromo-3,5-difluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide (2 g; 5.7 mmol ) in methanol (20 ml) was heated to 50° C. for 3 h. After cooling, water (50 ml) was added and the precipitate was collected by filtration, washed thoroughly with water and dried in vacuo to give the product as an off-white solid (1.4 g ; 98%), which was used directly in the next step without purification, MS (+) ES: 253 (M+H) ⁺ .

Stage 3. Obtaining 4-bromo-3,5-difluorobenzene-1,2-diamine

In a stirred mixture of AcOH (50 ml) and EtOH (100 ml) were suspended 4-bromo-3,5-difluoro-2-nitroaniline (2.5 g; 0.01 mol) and iron powder (4.4 g; 0. 08 mol). The reaction mixture was slowly heated to reflux and allowed to stir for 1 hour. The reaction mixture was cooled to room temperature, then diethyl ether (50 ml) and water (50 ml) were added. The solution was carefully neutralized by adding sodium carbonate. The combined organic extracts were washed with saturated NaHCO ₃ (2×30 ml), H ₂ O (2×30 ml) and brine (1×30 ml), then dried over Na ₂ SO ₄ , filtered and concentrated to dryness under vacuum, obtaining the indicated title compound as white solid (1.6 g; 71%), MS (+) ES: 223 (M+H) ⁺ .

Step 4: Preparation of N-(6-amino-3-bromo-2,4-difluorophenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

1-Ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride (2.0 g; 0.01 mol) and benzotriazol-1-ol (1.35 g; 0.01 mol) in portions over 30 minutes was added to a chilled (in an ice water bath) solution of 4-bromo-3,5-difluorobenzene-1,2-diamine (2.2 g; 0.01 mol) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (example 1, step 3; 2.28 g; 0.01 mol) in DMF (10 ml). After the addition was complete, the mixture was stirred for 60 minutes at 0-5° C. and then allowed to warm to room temperature with stirring overnight. The mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic phase was separated and dried over MgSO ₄ , filtered. The solvent was evaporated under reduced pressure to give an off-white solid which was purified by flash chromatography using hexane/ethyl acetate to give the product as a solid (3.5 g; 80%), MS (+) ES: 433 (M+H ) ⁺ .

Step 5. Preparation of 5-bromo-2-(4-(ethylsulfonyl)benzyl)-4,6-difluoro-1H-benzo[d]imidazole

N-(6-Amino-3-bromo-2,4-difluorophenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide (step 4) (3.5 g; 0.0075 mol) was mixed with acetic acid (25 ml) and the mixture was heated to 100°C for 4 hours, cooled. The solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, dried over MgSO ₄ . This product was purified by flash chromatography using hexane/ethyl acetate to give the product as a white solid (2.8 g; 85%), MS (+) ES: 415 (M+H) ⁺ .

Step 6. Preparation of 2-(4-(ethylsulfonyl)benzyl)-4,6-difluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

Mixture of 5-bromo-2-(4-(ethylsulfonyl)benzyl)-4,6-difluoro-1H-benzo[d]imidazole (42 mg; 0.1 mmol), 2-trifluoromethoxyphenylboronic acid (62 mg; 0.003 mol) , tris-(dibenzylideneacetone)dipalladium (0) (6 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (6 mg) and sodium carbonate (2 M solution; 0.2 ml) in 1,4-dioxane (0.5 ml) was degassed, sealed and heated to 100°C under microwave irradiation for 1 hour. Volatile solvents were removed under reduced pressure. The residue was applied directly to a solid cartridge and flash chromatographed using hexane/ethyl acetate to give a white solid (34 mg; 68% yield), MS (+) ES: 497 (M+H) ⁺ .

Example 109

Preparation of 2-(4,6-difluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in a manner essentially similar to that of example 77, obtaining the product as a white solid, MS (+) ES: 527 (M+H) ⁺ .

Example 110

Preparation of (4,6-difluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 513 (M+H) ⁺ .

Example 111

Preparation of 2-(4-(ethylsulfonyl)benzyl)-4,6-difluoro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole

This compound was obtained in essentially the same way as in example 91, except for the use of 2-trifluoromethylphenylboronic acid instead of 2-trifluoromethoxyphenylboronic acid in step 6, obtaining the product as a white solid, MS (+) ES: 481 (M+H ) ⁺ .

Example 112

Preparation of 2-(4,6-difluoro-5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in a manner essentially similar to that of example 92, obtaining the product as a white solid, MS (+) ES: 461 (M+H) ⁺ .

Example 113

Preparation of (4,6-difluoro-5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

This compound was obtained in a manner essentially similar to that of example 93, obtaining the product as a white solid, MS (+) ES: 459 (M+H) ⁺ .

Example 114

Preparation of 2-(4,6-difluoro-5-phenyl-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in a manner essentially similar to that of example 92, obtaining the product as a white solid, MS (+) ES: 443 (M+H) ⁺ .

Example 115

Preparation of 2-(4-(ethylsulfonyl)benzyl)-4,6-dimethyl-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole

This compound was obtained in accordance with the same procedure as described in example 108, obtaining the product as a white solid, MS (+) ES: 473 (M+H) ⁺ .

Example 116

Preparation of 2-(4,6-dimethyl-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in a manner essentially similar to that of example 77, obtaining the product as a white solid, MS (+) ES: 503 (M+H) ⁺ .

Example 117

Preparation of 2-(4-(ethylsulfonyl)phenyl)-2-(5-(2-methoxyphenyl)-4,6-dimethyl-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in a manner essentially similar to that of example 77, obtaining the product as a white solid, MS (+) ES: 465 (M+H) ⁺ .

Example 118

Preparation of (4-(ethylsulfonyl)phenyl)(5-(2-methoxyphenyl)-4,6-dimethyl-1H-benzo[d]imidazol-2-yl)methanol

This compound was obtained in a manner essentially similar to that of example 78, obtaining the product as a white solid, MS (+) ES: 451 (M+H) ⁺ .

Example 119

Preparation of 2-(6-chloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

This compound was obtained in a manner essentially similar to that of example 4, obtaining the product as a white solid, MS (+) ES: 525 (M+H) ⁺ .

Example 120

Preparation of 2-(4-(ethylsulfonyl)phenyl)-2-(6-fluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in a manner essentially similar to that of example 4, obtaining the product as a white solid, MS (+) ES: 509 (M+H) ⁺ .

Example 121

Preparation of (4-(ethylsulfonyl)phenyl)(6-fluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

This compound was obtained in a manner essentially similar to that of example 2, obtaining the product as a white solid, MS (+) ES: 495 (M+H) ⁺ .

Example 122

Preparation of N-cyclopropyl-4-((4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)benzenesulfonamide

Stage 1. Obtaining 2-(4-(chlorosulfonyl)phenyl)acetic acid

To chlorosulfonic acid (35 ml) was added dropwise 2-phenylacetic acid (5 g; 36.724 mmol) at 0°C, the reaction mixture was stirred at 0°C for 1 hour and then at room temperature overnight. After completion of the reaction, the reaction mixture was slowly cooled to 0°C and carefully poured onto ice. The resulting solid was extracted with ethyl acetate (3×10 ml) and dried over MaSO ₄ . The solid was filtered off and the solvent was evaporated under reduced pressure to give the title compound as an off-white solid (6.8 g; 78%), MS (+) ES: 235 (M+H) ⁺ .

Stage 2. Obtaining 2-(4-(N-cyclopropylsulfamoyl)phenyl)acetic acid

To a stirred solution of 2-(4-(chlorosulfonyl)phenyl)acetic acid (234 mg; 1.0 mmol) and i-Pr ₂ NEt (0.52 ml; 2.86 mmol) in CH ₂ Cl ₂ (10 ml) cyclopropylamine (0.076 ml; 1.1 mmol) was added. The mixture was stirred overnight at RT, diluted with EtOAc (80 ml), washed with 5% aq. HCl solution (2x 10 ml) and brine (10 ml) and dried over Mg ₂ SO ₄ . After removal of the solvent, the product was obtained as a gummy solid (180 mg; 70%). MS (+) ES: 256 (M+H) ⁺ .

Step 3. Preparation of N-(2-amino-4-bromo-3,5-dichlorophenyl)-2-(4-(N-cyclopropylsulfamoyl)phenyl)acetamide

To 2-(4-(N-cyclopropylsulfamoyl)phenyl)acetic acid (255 mg; 1 mmol) in DMF was added 4-bromo-3,5-dichlorobenzene-1,2-diamine (255 mg; 1 mmol), HOBt ( 135 mg; 1 mmol), triethylamine (202 mg; 2 mmol), then EDCI (191 mg; 1 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 min, allowed to warm to room temperature and stirred overnight. The reaction solution was partitioned between ethyl acetate (15 ml) and water (15 ml). The organic phase was separated and dried over MgSO ₄ . Evaporation of the solvent gave a tan solid which was used directly in the next step without purification (490 mg; 99% yield), MS (+) ES: 492 (M+H) ⁺ .

Step 4. Preparation of 4-((5-bromo-4,6-dichloro-1H-benzo[d]imidazol-2-yl)methyl)-N-ethylbenzenesulfinamide

N-(2-Amino-4-bromo-3,5-dichlorophenyl)-2-(4-(N-cyclopropylsulfamoyl)-phenyl)-acetamide (490 mg; 1 mmol) in acetic acid (5 ml) was heated to 80 °C for 3 hours After cooling, the solvent was evaporated to dryness and dissolved in ethyl acetate (10 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO ₄ . Evaporation of the ethyl acetate gave a solid which was purified by flash chromatography using a hexane/ethyl acetate solvent mixture (containing 10% MeOH) to give the product as a white solid (288 mg; 60% yield), MS (+) ES: 474 ( M+H) ⁺ .

Step 5: Preparation of N-cyclopropyl-4-((4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)benzenesulfonamide (compound of Example 164)

A mixture of 4-((5-bromo-4,6-dichloro-1H-benzo[d]imidazol-2-yl)methyl)-N-cyclopropylbenzenesulfinamide (step 4) (238 mg; 0.5 mmol), 2-trifluoromethoxyphenylboronic acid (308 mg; 1.5 mmol), tris-(dibenzylideneacetone) dipalladium (0) (24 mg), tri (tert-butyl) phosphonium tetrafluoroboronate (24 mg) and sodium carbonate (1 ml; 2 M solution) in 1 ,4-dioxane (2.5 ml) was degassed, sealed and heated to 100°C under microwave irradiation for 1 hour. Volatile solvents were removed under reduced pressure. The residue was loaded directly onto a solid cartridge from ISCO and eluted rapidly with hexane/ethyl acetate to give a white solid (83 mg; 30% yield), MS (+) ES: 556 (M+H) ⁺ .

Example 123

Preparation of N-cyclopropyl-4-(1-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-hydroxyethyl)benzenesulfonamide

To N-cyclopropyl-4-((4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)benzenesulfonamide (5.7 mg; 0.01 mmol) in DMSO (0.05 ml) paraformaldehyde (0.6 mg; 0.02 mmol) was added followed by sodium ethoxide (1.3 mg; 0.002 mmol) at room temperature. The reaction mixture was stirred for 60 min and purified directly by preparative HPLC using System C as eluent to give the product as a white solid (3.8 mg; 66% yield), MS (+) ES: 586 (M+H) ⁺ .

Example 124

Preparation of 2-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanol

Stage 1. Obtaining cyclopropylmethyl-2-(4-((cyclopropylmethyl)thio)phenyl)acetate

To a solution of (4-mercaptophenyl)acetic acid (3.4 g; 0.02 mol) in N,N-dimethylformamide (DMF) (20 ml) was added K ₂ CO ₃ (11 g; 0.08 mol) and (bromomethyl )cyclopropane (8.1 g; 0.06 mol). The reaction mixture was stirred at RT. After 2.5 hours, the starting material was completely consumed. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic phase was washed with water (30 ml) and brine (20 ml), dried over sodium sulfate, filtered and concentrated to give the desired product (%), MS (+) ES: 277 (M+H) ⁺ .

Stage 2. Obtaining cyclopropylmethyl-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetate

To a 250 ml round bottom flask was added cyclopropylmethyl-2-(4-((cyclopropylmethyl)thio)phenyl)acetate (6.76 g; 0.0245 mol) and dichloromethane (82.5 ml). The reaction mixture was cooled to 0°C. To the same flask was added m-chloroperbenzoic acid (12.6 g; 0.073 mol) at 0°C. The reaction mixture was stirred at room temperature for 12 hours. The resulting suspension was filtered through a pad of celite. The filtrate was washed with water. The organic layer was separated, washed three times with saturated sodium bicarbonate solution, then with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography using hexane/ethyl acetate to give the title compound as an oil, MS (+) ES: 309 (M+H) ⁺ .

Stage 3. Obtaining 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid

Cyclopropylmethyl-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetate (3.08 g; 0.01 mol) and ethanol (18 ml) were added to a 50 ml round bottom flask. To the same flask was added a solution of sodium hydroxide in water (1.42 g; 0.0355 mol; in 18 ml of water). The reaction mixture was stirred at room temperature for 12 hours. The volatiles were evaporated under reduced pressure. The residue was acidified to pH 5.0 using 1 N. HCl solution and extracted with ethyl acetate (15 ml ×3). The organic layer was separated and combined, washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a colorless oil which solidified on standing (85%). MS (+) ES: 255 (M+H) ⁺ .

Step 4: Preparation of N-(2-amino-5-bromo-4-chlorophenyl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetamide

1-Ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride (2.0 g; 0.01 mol) and hydroxybenzotriazol-1-ol (1.35 g; 0.01 mol) in portions over 30 minutes was added to a chilled (in an ice water bath) solution of 4-bromo-5-chlorobenzene-1,2-diamine (2.21 g; 0.01 mol) and 2-(4-((cyclopropylmethyl)sulfonyl)-phenyl) acetic acid (from step 3; 2.54 g; 0.01 mol) in DMF (10 ml). After the addition was complete, the mixture was stirred for 60 minutes and allowed to warm to room temperature, stirred overnight. The mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic phase was separated and dried over MgSO ₄ , filtered. The solvent was evaporated under reduced pressure to give an off-white solid which was purified by flash chromatography using hexane/ethyl acetate to give the product as an off-white solid (75%), MS (+) ES: 457 (M+H) ⁺ .

Step 5. Preparation of 5-bromo-6-chloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-1H-benzo[d]imidazole

N-(2-Amino-5-bromo-4-chlorophenyl)-2-(4-((cyclopropylmethyl)sulfonyl)-phenyl)acetamide (step 4) (3.42 g; 7.5 mmol) was mixed with acetic acid (25 ml) and the mixture was heated to 80°C for 4 hours, cooled. The solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution, dried over MgSO ₄ . This product was purified by flash chromatography using hexane/ethyl acetate to give the product as a white solid (2.6 g; 80%) MS (+) ES: 439 (M+H) ⁺ .

Step 6. Preparation of 6-chloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazole

A mixture of 5-bromo-6-chloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-1H-benzo[d]imidazole (step 5) (439 mg; 1 mmol), (2-isopropoxyphenyl)boronic acid ( 495 mg; 3 mmol), tris-(dibenzylideneacetone)dipalladium(0) (60 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (60 mg) and sodium carbonate (2 ml; 2 M solution) in 1,4-dioxane (8 ml) was degassed, sealed and heated to 100°C under microwave irradiation for 60 minutes. Volatile solvents were removed under reduced pressure. The residue was taken up directly in DCM, loaded onto a solid cartridge from ISCO and eluted rapidly with hexane/ethyl acetate to give a white solid (355 mg; 72% yield), MS (+) ES: 495 (M+H) ⁺ .

Step 7. Preparation of 2-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(cyclopropylmethyl)sulfonyl)phenyl)ethanol

6-Chloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazole (49.5 mg; 0.1 mmol) was dissolved in 1 ml anhydrous DMSO , paraformaldehyde (6 mg; 0.2 mmol) was added with stirring, then sodium ethoxide powder (12 mg; 0.2 mmol) was added. The mixture was stirred at room temperature for 60 minutes (checking completion of the reaction by LCMS). The mixture was then treated with EtOAc (10 ml) and washed with saturated NH ₄ Cl solution, then water. The organic phase was dried using MgSO ₄ . The product was purified by flash chromatography using hexane/EtOAc (with 10% 2N NH ₃ in MeOH) to give a white solid (37 mg; 70% yield of Example 124). MS (+) ES: 525 (M+H) ⁺ .

Examples 124-1 and 124-2

Preparation of (S)-2-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanol (Example 124 -1) and (R)-2-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanol (example 124-2)

The compounds of example 124 were separated on a chiral sorbent (separation conditions: Dasail, 20*200 mm, 5 μm; mobile phase: ethanol/hexane = 1:4 (v/v); flow rate: 30 ml/min). Appropriate fractions were collected and concentrated under reduced pressure to give the title compounds (400 mg; 400 mg).

Connection with individual configuration (lower retention time)

MS (+) ES: 525 (M+H) ⁺ ;

chiral HPLC analysis: retention time 6.296 minutes, chiral purity: 100% (chromatographic column: OZ Phenomenex Lux Cellulose-2, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 3:2 (v/v .));

¹ H NMR (400 MHz, DMSO-d ₆ ): 12.53 (s, 1H), 7.87 (d, 8.0 Hz, 2H), 7.71 (s, 0.6H) (due to benzoimidazole tautomerization), 7.67 (d, 12.0 Hz, 2H), 7.57 (s, 0.4H), 7.43 (s, 0.48H), 7.34 (t, 8.0 Hz, 1H), 7.31 (s, 0.44H), 7.16-7.11 ( m, 1H), 7.08 (d, 8.0 Hz, 1H), 6.98 (t, 8.0 Hz, 1H), 5.16 (t, 4.0 Hz, 1H), 4.59-4.43 (m, 2H), 4.29-4.15 (m, 1H), 4.06-3.95 (m, 1H), 3.23 (d, 8.0 Hz, 2H), 1.12 (d, 4.0 Hz, 6H), 0.89-0.75 (m, 1H) , 0.49–0.39 (m, 2Н), 0.18–0.09 (m, 2Н).

Connection with individual configuration (longer retention time)

MS (+) ES: 525 (M+H) ⁺ ;

chiral HPLC analysis: retention time 11.837 minutes, chiral purity: 98.875% (chromatographic column: OZ Phenomenex Lux Cellulose-2, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane=3:2 (v/v .);

¹ H NMR (400 MHz, DMSO-d ₆ ): 12.53 (s, 1H), 7.87 (d, 8.0 Hz, 2H), 7.71 (s, 0.6H) (due to benzoimidazole tautomerization), 7.67 (d, 12.0 Hz, 2H), 7.57 (s, 0.4H), 7.43 (s, 0.48H), 7.34 (t, 8.0 Hz, 1H), 7.31 (s, 0.44H), 7.16-7.11 ( m, 1H), 7.08 (d, 8.0 Hz, 1H), 6.98 (t, 8.0 Hz, 1H), 5.16 (t, 4.0 Hz, 1H), 4.59-4.43 (m, 2H), 4.29-4.15 (m, 1H), 4.06-3.95 (m, 1H), 3.23 (d, 8.0 Hz, 2H), 1.12 (d, 4.0 Hz, 6H), 0.89-0.75 (m, 1H) , 0.49–0.39 (m, 2Н), 0.18–0.09 (m, 2Н).

Example 125

Preparation of 4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-2-(4-(ethylsulfonyl)benzyl)-1H-benzo[d]imidazole

Stage 1. Obtaining 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitroaniline

A mixture of 2,3,4-trichloro-6-nitroaniline (241 mg; 1 mmol), 4,4-difluoropiperidine (190 mg; 1.2 mmol) and DIEA (390 mg; 3 mmol) in 8 ml of DMSO was heated in an airtight closed vessel to 108°C overnight. After cooling, the reaction mixture was partitioned between water (30 ml) and ethyl acetate (10 ml). The organic phase was separated and dried over MgSO ₄ . The solid was filtered off and the solvent was evaporated, the residue was directly eluted quickly using hexane/ethyl acetate to give a yellow solid (280 mg; 85% yield), MS (+) ES: 326 (M+H) ⁺ .

Stage 2. Obtaining 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine

A mixture of 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitroaniline (200 mg; 0.68 mmol) and Pd/C (20 mg) in 15 ml methanol was hydrogenated using a nitrogen for 2 h. The catalyst was filtered off and the solvent was evaporated to give a tan residue which was eluted immediately with hexane/ethyl acetate to give an oily product (120 mg; 66% yield), (MS (+) ES: 296 ( M+H) ⁺ .

Stage 3. Preparation of 4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-2-(4-(ethylsulfonyl)benzyl)-1H-benzo[d]imidazole

1-Ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride (20 mg; 0.1 mmol) and hydroxybenzotriazol-1-ol (13.5 mg; 0.1 mmol) were added to the chilled (in bath with ice water) solution of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (29.6 mg; 0.1 mmol) and 2-(4-(ethylsulfonyl) phenyl)acetic acid (22.8 mg; 0.01 mmol) in DMF (1 ml). After the addition was complete, the mixture was stirred and allowed to warm to room temperature, stirred overnight. The mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic phase was separated and dried over MgSO ₄ , filtered. The solvent was evaporated under reduced pressure to give an off-white solid which was mixed with acetic acid (1 ml). The mixture was heated to 80°C for 2 hours, cooled. The solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution, dried over MgSO ₄ . This product was purified by flash chromatography using hexane/ethyl acetate to give the product as a white solid (26 mg; 60%), MS (+) ES: 488 (M+H) ⁺ .

Example 126

Preparation of 2-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

Stage 1. Obtaining 2,3,4-trichloro-6-nitrobenzamine

A suspension of 4,5-dichloro-2-nitrobenzamine (30 g; 145 mmol) and N-chlorosuccinimide (24.2 g; 181.2 mmol) in 250 ml DMF was stirred at 100° C. for 2 hours. It was cooled to room temperature and poured into ice-cold water (1 ml). The precipitate formed was collected by filtration. It was dissolved in dichloromethane and washed with water. The organic layer was concentrated to give 2,3,4-trichloro-6-nitrobenzamine (34.2 g; 97.5% yield) as a bright yellow solid.

Stage 2. Obtaining 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitrobenzamine

A solution of 2,3,4-trichloro-6-nitrobenzamine (5 g; 20.7 mmol), N,N-diisopropylethylamine (11.8 ml; 62.1 mmol) and 4,4-difluoropiperidine (3.8 g; 31.06 mmol) in 20 ml DMF was stirred at 105° C. over the weekend. The reaction solution was absorbed onto 20 g of silica gel, loaded onto a silica gel column, and eluted with 30% ethyl acetate in hexanes to give 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitrobenzamine (4, 72 g, 70.0% yield as a bright yellow solid, MS (+) ES: 326 (M+H) ⁺ .

Stage 3. Obtaining 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine

Zinc dust (7 g) and concentrated hydrochloric acid (2 ml). The reaction mixture was stirred at room temperature overnight. She was filtered. The filtrate was concentrated and purified on a silica gel column eluting with ethyl acetate to give 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (1.85 g, 57.8% yield). ) as a pale solid, MS (+) ES: 296 (M+H) ⁺ .

Step 4. Preparation of N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide and N-(2- amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

To a solution of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (350 mg; 1.18 mmol) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (225 mg; 0.99 mmol) in dichloromethane (10 ml) were added EDCI (285 mg; 1.49 mmol) and HBTU (565 mg; 1.49 mmol). The reaction solution was stirred at room temperature for 2 hours. It was absorbed onto 5 g of silica gel and loaded onto a silica gel column. The column was eluted with 45% ethyl acetate in hexanes to give N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl )acetamide and N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide (410 mg; yield 81, 8%) as a white solid, MS (+) ES: 506 (M+H) ⁺ .

Step 5. Preparation of 2-(4-(ethylsulfonyl)benzyl)-4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole

Mixture of N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide and N-(6-amino-2 ,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide (410 mg) obtained in the previous step was treated with 15 ml of glacial acetic acid at 80 °C for 2 hours. This was concentrated and purified on a silica gel column eluting with 60% ethyl acetate in hexanes to give 2-(4-(ethylsulfonyl)benzyl)-4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)- 1H-benzo[d]imidazole (375 mg; 94.8% yield) as a pale solid, MS (+) ES: 488 (M+H) ⁺ .

Step 6 Preparation of 2-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl) ethanol

To a solution of the resulting 2-(4-(ethylsulfonyl)benzyl)-4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole (20 mg; 0.04 mmol) and paraformaldehyde (6.3 mg; 0.21 mmol) in 3 ml DMSO was added sodium ethoxide (8.2 mg; 0.12 mmol). The reaction solution was stirred at room temperature for 2 hours. It was then directly loaded onto a reverse phase chromatography column using System D for elution and purified to give 2-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d] imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol (9 mg; 42.5% yield) as a white solid; MS (+) ES: 518 (M+H) ⁺ .

Examples 126-1 and 126-2

Preparation of (R)-2-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl )ethanol (Example 126-1) and (S)-2-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-2 -(4-(ethylsulfonyl)phenyl)ethanol (Example 126-2)

The compounds of example 126 were separated on a chiral sorbent (separation conditions: Cellulose-1, 20*250 mm, 5 μm; mobile phase: ethanol/hexane = 1:4 (v/v); flow rate: 20 ml/min). Appropriate fractions were collected and concentrated under reduced pressure to give the title compounds (420 mg; 410 mg).

Connection with individual configuration (lower retention time)

MS (+) ES: 518 (M+H) ⁺ ;

chiral HPLC analysis: retention time 7.275 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 15:85 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.90 (d, 8.0 Hz, 2H), 7.67 (d, 8.0 Hz, 2H), 7.62 (s, 0.5H), 7.49 (s, 0 .5H), 4.59 (t, 8.0 Hz, 1H), 4.38 (dd, 8.0; 11.0 Hz, 1H), 4.27-4.11 (m, 1H), 3.44-3.28 (m, 4H), 3.20 (q, 8.0 Hz, 2H), 2.24-2.01 (m, 4H), 1.21 (t, 8.0 Hz, 3H).

Connection with individual configuration (longer retention time)

MS (+) ES: 518 (M+H) ⁺ ;

chiral HPLC analysis: retention time 9.290 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 15:85 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.90 (d, 8.0 Hz, 2H), 7.67 (d, 8.0 Hz, 2H), 7.62 (s, 0.5H), 7.49 (s, 0 .5H), 4.59 (t, 8.0 Hz, 1H), 4.38 (dd, 8.0; 11.0 Hz, 1H), 4.27-4.11 (m, 1H), 3.44-3.28 (m, 4H), 3.20 (q, 8.0 Hz, 2H), 2.24-2.01 (m, 4H), 1.21 (t, 8.0 Hz, 3H).

Example 127

Preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole

Stage 1. Obtaining cyclopropylmethyl-2-(4-(cyclopropylmethylthio)-phenyl)acetate

To a solution of 2-(4-mercaptophenyl)acetic acid (5 g, 29.7 mmol) in DMF (50 ml) were added cesium carbonate (29.3 g, 89.1 mmol) and cyclopropylmethyl bromide (10 g, 74.21 mmol ). The reaction mixture was stirred at room temperature overnight. It was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified on a silica gel column eluting with 25% ethyl acetate in hexanes to give cyclopropylmethyl 2-(4-(cyclopropylmethylthio)phenyl)acetate (7.7 g; 93.7% yield) as a colorless oil. MS (+) ES: 277 (M+H) ⁺ .

Stage 2. Obtaining cyclopropylmethyl-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetate

To a solution of cyclopropylmethyl-2-(4-(cyclopropylmethylthio)phenyl)acetate (4.07 g; 14.7 mmol) in dichloromethane (20 ml) was added MCPBA (7.61 g; 44.3 mmol) at room temperature. After the addition, the reaction mixture was stirred at ambient temperature for 14 hours. It was partitioned between dichloromethane and saturated sodium thiosulfate solution. The organic layer was washed with 2N. aqueous sodium hydroxide solution and brine. This was concentrated and purified on a silica gel column eluting with 60% ethyl acetate in hexanes to give cyclopropylmethyl 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetate (4.23 g, 93.0% yield) as a white solid. MS (+) ES: 309(M+H) ⁺ .

Stage 3. Obtaining 2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetic acid

To a solution of cyclopropylmethyl-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetate (2.50 g; 8.1 mmol) in dioxane (10 ml) was added lithium hydroxide monohydrate (4.1 g; 40.6 mmol) and water ( 10 ml). The reaction mixture was stirred at ambient temperature overnight. It was acidified with hydrochloric acid to pH 5 and concentrated to dryness. The collected solid was dissolved in 15% methanol in dichloromethane, filtered through a pad of silica gel eluting with 15% methanol in dichloromethane, and concentrated to give 2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetic acid (2.1 g; 97% yield as a white solid. MS (+) ES: 255 (M+H) ⁺ .

Step 4. Preparation of N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetamide and N-(2- amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetamide

To a solution of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (175 mg; 0.193 mmol) and 2-(4-(cyclopentylmethylsulfonyl)phenyl)acetic acid (181 mg; 0.711 mmol) in dichloromethane (5 ml) were added EDCI (171 mg; 0.89 mmol) and HBTU (334 mg; 0.89 mmol). The reaction solution was stirred at room temperature for 2 hours. It was absorbed onto 5 g of silica gel and loaded onto a silica gel column. The column was eluted with 45% ethyl acetate in hexanes to give a mixture of N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethylsulfonyl)phenyl )acetamide and N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetamide (230 mg; yield 73, 2%) as a white solid. MS (+) ES: 532 (M+H) ⁺ .

Step 5. Preparation of 2-(4-(cyclopropylmethylsulfonyl)benzyl)-4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole

Mixture of N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetamide and N-(6-amino-2 ,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetamide (230 mg) obtained in the previous step was treated with 15 ml of glacial acetic acid at 80 °C for 2 hours. This was concentrated and purified on a reverse phase column eluting with 60% acetone in water to give 2-(4-(cyclopropylmethylsulfonyl)benzyl)-4,6-dichloro-5-(4,4-difluoropiperidine-1- yl)-1H-benzo[d]imidazole (375 mg; 94.8% yield) as a pale solid; MS (+) ES: 514(M+H) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ): 7.85 (d, 5.00 Hz, 2H), 7.66 (s, 0.5H), 7.50 (d, 5.00 Hz, 2H), 7.30 (s, 0, 5Н), 4.45 (m, 2Н), 3.30 (m, 4Н), 3.00 (m, 2Н), 2.12 (m, 5Н), 0.51 (m, 2Н), 0.35 (m, 2Н).

Example 128

Preparation of 2-(7-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanamine

Stage 1. Obtaining benzyl-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetate

A mixture _of benzyl alcohol (648 mg, 6.0 mmol), _2- (4- ((cyclopropylmethyl)sulfonyl)phenyl)acetic acid (1.5 g; 6.0 mmol) and tri-n-butylamine (2.66 g; 14.4 mmol) in CH ₂ Cl ₂ (8 ml) and the resulting mixture boiled under reflux for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography and the benzyl-containing product was isolated as a white solid (1.8 g, 90% yield). MS (+) ES: 344 (M+H) ⁺ .

Step 2. Preparation of benzyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(1,3-dioxoisoindolin-2-yl)propanoate

To a chilled mixture of hexamethyldisilazane (HMDS) (608 mg; 4.56 mmol) in THF (20 ml) was added dropwise over 20 min with stirring a solution of n-butyllithium in THF (1.8 ml; 2.5 M; 4. 5 mmol). The mixture was stirred for 30 min, after which benzyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetate (1.3 g; 3.8 mmol) in THF (5 ml). Stirred for another 30 min at -78°C, after which 2-(bromomethyl)isoindoline-1,3-dione (912 mg; 3.8 mmol) in THF (5 ml) was added over 10 min using a syringe. The mixture was stirred at -78°C and left to warm to room temperature overnight. The mixture was carefully treated with methanol and the solvents were evaporated. The product was purified by flash chromatography to give the product as a white solid (1.4 g, 74% yield). MS (+) ES: 504 (M+H) ⁺ .

Stage 3. Obtaining 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(1,3-dioxoisoindolin-2-yl)propanoic acid

Benzyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(1,3-dioxoisoindolin-2-yl)propanoate from step 2 (1.4 g; 2.8 mmol) was dissolved in ethyl acetate (20 ml ), Pd(OH) ₂ (140 mg) was added and the mixture was hydrogenated using a hydrogen balloon for 8 hours. The catalyst was filtered off and the solvent was evaporated to give the product as a white solid (900 mg; 78% yield). MS (+) ES: 414 (M+H) ⁺ .

Stage 4. Obtaining 6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3,4-diamine

4-Bromo-5-chlorobenzene-1,2-diamine mixture (1.5 g; 6.78 mmol), 2-(2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3 ,2-dioxaborolane (2.2 g; 8.15 mmol), tris-(dibenzylideneacetone)dipalladium(0) (620 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (393 mg) and sodium carbonate (1.7 g ; 13.7 mmol) in 1,4-dioxane (50 ml) and water (10 ml) was degassed, heated to 90° C. for 3 h. Volatile solvents were removed under reduced pressure. The residue was loaded directly onto a solid cartridge from ISCO and eluted rapidly with hexane/ethyl acetate to give the product (1.0 g; 51.9% yield), MS (+) ES: 285 (M+H) ⁺ .

Step 5. Preparation of 2-(2-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl )ethyl)-isoindoline-1,3-dione

To a mixture of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(1,3-dioxoisoindolin-2-yl)propanoic acid (from step 3; 400 mg; 0.97 mmol) and 6-chloro-2 '-(difluoromethoxy)-[1,1'-biphenyl]-3,4-diamine (from step 4; 275 mg; 0.98 mmol) in DMF (8 ml) was added N-(3-dimethylaminopropyl)-N' -ethylcarbodiimide hydrochloride (224 mg; 1.2 mmol) and 1-hydroxybenzotriazole (162 mg; 1.2 mmol). The mixture was stirred at room temperature overnight, partitioned between ethyl acetate (10 ml) and water (15 ml). The organic phase was separated and dried over MgSO ₄ . After filtration and evaporation of the solvent, the residue was treated with acetic acid (5 ml) and heated to 80°C for two hours. The mixture was cooled and the acetic acid was evaporated to dryness, the residue was dissolved in ethyl acetate (10 ml) and washed with saturated sodium bicarbonate solution and brine. The organic phase was separated and dried over MgSO ₄ . The product was purified by flash chromatography to give a white solid (454 mg; 70% yield). MS (+) ES: 662 (M+H) ⁺ .

Step 6. Preparation of 2-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanamine

2-(2-(5-Chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethyl)isoindoline -1,3-dione (from step 4; 454 mg; 0.68 mmol) was dissolved in ethanol (5 ml). Hydrazine hydrate (0.1 ml) was added and the mixture was stirred overnight. The solid precipitate was filtered off and the volatile solvents were evaporated to dryness. The product was purified by flash chromatography to give the product as a white solid (280 mg; 76% yield). MS (+) ES: 532 (M+H) ⁺ .

Example 129

Preparation of N-(2-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethyl) acetamide

To a solution of 2-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanamine (Example 128 ) (5.3 mg; 0.01 mmol) and triethylamine (3 mg; 0.03 mmol) in DCM (0.4 ml) were added acetic anhydride (1.2 mg; 0.012 mmol). The mixture was stirred for 4 hours. The solvent was evaporated under reduced pressure and the product was purified by preparative HPLC to give the product as a white solid (3.5 mg; 66% yield). MS (+) ES: 574 (M+H) ⁺ .

Example 130

Preparation of 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propanoic acid

Step 1. Preparation of 4-ethoxy-2-(4-(ethylsulfonyl)phenyl)-4-oxobutanoic acid

To 2-(4-(ethylsulfonyl)phenyl)acetic acid (250 mg; 1.1 mmol) in THF (8 ml) at -78°C was added lithium hexamethyldisilazide (LiHMDS) (1 M solution in THF; 2.31 ml ). After 50 minutes, ethyl 2-bromoacetate (147 µl, 1.32 mmol) was added. The reaction mixture was stirred at -78°C for 3.5 hours. To bring the pH to approximately 4 was added 0.1 N. HCl solution. Extracted three times with EtOAc, dried over Na ₂ SO ₄ , filtered, concentrated. The residue was purified on a silica gel column using System A as eluent to give a yellow oil (29 mg). MS (ESI): 315 (M+H) ⁺ .

Stage 2. Preparation of ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4 -oxobutanoate

To a solution of 4-ethoxy-2-(4-(ethylsulfonyl)phenyl)-4-oxobutanoic acid (27 mg) in DCM (1 ml) was added 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl )benzene-1,2-diamine (65 mg), HATU (150 mg), DIEA (0.1 ml). The mixture was stirred at room temperature for 18 hours. Saturated NaHCO ₃ solution was added, extracted three times with EtOAc, dried over Na ₂ SO ₄ , filtered, concentrated. The residue was purified on a silica gel column using System A as eluent to give the title compound (40 mg). MS (ESI): 593 (M+H) ⁺ .

Stage 3. Preparation of ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl) phenyl) propanoate

A solution of ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutanoate ( 39 mg) in AcOH (2 ml) was heated to 80° C. for 3 hours. The mixture was purified on a silica gel column using system C to elute to give the title compound (18 mg). MS (ESI): 574 (M+H) ⁺ .

Step 4 Preparation of 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl) propanoic acid

Ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propanoate ( 18 mg) in THF (1.5 ml)/MeOH (0.5 ml) was treated with LiOH (1M solution; 0.2 ml). The mixture was stirred at room temperature for 3 hours until ethyl-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d] was depleted by LCMS. imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)-propanoate. To bring the pH to a value less than 5 was added 1 M HCl solution. The solvent was evaporated under reduced pressure and the product was purified by reverse phase preparative HPLC (elution system: 0.075% TFA in water and 0.075% TFA in MeOH) to give the title compound as a white solid (11 mg). MS (ESI): m/z=546 (M+H) ⁺ .

Example 131

Preparation of 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propanamide

To a solution of the compound of example 172 (9 mg) in DMF (1 ml) was added NH ₄ Cl (30 mg), HATU (17 mg), DIEA (60 μl). The mixture was stirred at room temperature for 20 hours. The solid was filtered off. The filtrate was purified by reverse phase preparative HPLC (elution system: 0.075% TFA in water and 0.075% TFA in MeOH) to give the title compound as a white solid (3 mg). MS (ESI): m/z=545 (M+H) ⁺ .

Example 132

Preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-6-(2-isopropoxyphenyl)-1H-benzo[d]imidazole

This compound was obtained in a manner essentially similar to that of example 124, obtaining the product as a white solid, MS (+) ES: 529 (M+H) ⁺ .

Example 133

Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(5,7-dichloro-6-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)methanol

This compound was prepared in a manner substantially similar to that of Example 2 and 124 to give the product as a white solid, MS (+) ES: 545 (M+H) ⁺ .

Example 134

Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(5,7-dichloro-6-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in a manner essentially similar to that of example 124, obtaining the product as a white solid, MS (+) ES: 559 (M+H) ⁺ .

Example 135

Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(5,7-dichloro-6-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in a manner essentially similar to that of example 124, obtaining the product as a white solid, MS (+) ES: 531 (M+H) ⁺ .

Example 136

Preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-6-(2-ethoxyphenyl)-1H-benzo[d]imidazole

This compound was obtained in a manner essentially similar to that of example 124, obtaining the product as a white solid, MS (+) ES: 515 (M+H) ⁺ .

Example 137

Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(5,7-dichloro-6-(2-ethoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethanol

This compound was obtained in a manner essentially similar to that of example 124, obtaining the product as a white solid, MS (+) ES: 545 (M+H) ⁺ .

Example 138

Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(5,7-dichloro-6-(2-ethoxyphenyl)-1H-benzo[d]imidazol-2-yl)methanol

This compound was prepared in a manner substantially similar to that of Example 2 and 124 to give the product as a white solid, MS (+) ES: 531 (M+H) ⁺ .

Examples 139 and 140

Preparation of (S)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl )propan-1-ol and (R)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-( 4-(ethylsulfonyl)phenyl)propan-1-ol

Stage 1. Obtaining ethyl 2- (4- (ethylthio) phenyl) acetate

To a solution of (4-mercaptophenyl)acetic acid (5.0 g; 29.7 mmol) in N,N-dimethylformamide (DMF) (100 ml) was added K ₂ CO ₃ (16.4 g; 118.8 mmol) and iodoethane (9.7 g; 62.2 mmol). The reaction mixture was stirred at RT. After 12 hours, the starting material was completely consumed. The reaction mixture was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic phase was washed with water (30 ml) and brine (20 ml), dried over sodium sulfate, filtered and concentrated to give the desired product ethyl 2-(4-(ethylthio)phenyl)acetate (6.0 g; 90%) in as a pale yellow solid, MS (+) ES: 225 (M+H) ⁺ .

Stage 2. Preparation of ethyl 2-(4-(ethylsulfonyl)phenyl)acetate

Ethyl 2-(4-(ethylthio)phenyl)acetate (6.0 g; 26.7 mmol) and dichloromethane (300 ml) were added to a 250 ml round bottom flask. The reaction mixture was cooled to 0°C. To the same flask was added m-chloroperbenzoic acid (13.8 g; 80.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12 hours. The resulting suspension was filtered through a pad of celite. The filtrate was washed with water. The organic layer was separated, washed with saturated sodium bicarbonate solution, then with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography using hexane/ethyl acetate to give the title compound as an oil which solidified on standing (6.0 g; 87.5%), MS (+) ES: 257 (M+H ) ⁺ .

Stage 3. Obtaining 2-(4-(ethylsulfonyl)phenyl)acetic acid

Ethyl 2-(4-(ethylsulfonyl)phenyl)acetate (6.8 g; 26.5 mmol) and methanol (80 ml) were added to a 250 ml round bottom flask. To the same flask was added a solution of sodium hydroxide in water (2.1 g; 52.5 mmol; in 20 ml of water). The reaction mixture was heated to reflux for 12 hours. The volatiles were evaporated under reduced pressure. The residue was acidified to pH 5.0 using 1 N. HCl solution and extracted with ethyl acetate (50 ml x 3). The organic layer was separated and combined, washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a white solid (3.3 g; 54.5%), MS (+) ES: 229 (M+H) ⁺ .

Stage 4. Obtaining 4-ethoxy-2-(4-(ethylsulfonyl)phenyl)-4-oxobutanoic acid

To 2-(4-(ethylsulfonyl)phenyl)acetic acid (1.0 g; 4.4 mmol) in THF (20 ml) at -78°C was added LiHMDS (1 M solution in THF; 9.0 ml). Ethyl 2-bromoacetate (1.1 g, 6.58 mmol) was added after 15 min. The reaction mixture was stirred at -78°C for 3.5 hours. To bring the pH to approximately 4 was added 0.1 N. HCl solution. Extracted three times with EtOAc, dried over Na ₂ SO ₄ , filtered, concentrated. The residue was purified on a silica gel column using System A as eluent to give a yellow oil (0.45 g). MS (ESI): 315 (M+H) ⁺ .

Stage 5. Obtaining 2,3,4-trichloro-6-nitrobenzamine

A suspension of 4,5-dichloro-2-nitrobenzamine (10 g; 48.3 mmol) and N-chlorosuccinimide (7.7 g; 57.6 mmol) in 100 ml of DMF was stirred at 100° C. for 2 hours. It was cooled to room temperature and poured into ice-cold water (500 ml). The precipitate formed was collected by filtration. It was dissolved in dichloromethane and washed with water. The organic layer was concentrated to give 2,3,4-trichloro-6-nitrobenzamine (11.0 g; 94.3% yield) as a light yellow solid.

Stage 6. Obtaining 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitrobenzamine

A solution of 2,3,4-trichloro-6-nitrobenzamine (5 g; 20.7 mmol), N,N-diisopropylethylamine (8.0 g; 61.9 mmol) and 4,4-difluoropiperidine (10.0 g; 157.6 mmol) in 50 ml DMF was stirred at 105° C. for 2 days. The reaction solution was absorbed onto 40 g of silica gel, loaded onto a silica gel column, and eluted with 30% ethyl acetate in hexanes to give 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitrobenzamine (2, 0 g, 29.6% yield as a light yellow solid. MS (ESI): 326 (M+H) ⁺ .

Stage 7. Obtaining 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine

Fe powder (1, 0 g; 18.0 mmol) and NH ₄ Cl (1.0 g; 18.5 mmol). The reaction mixture was stirred at 80° C. overnight. She was filtered. The filtrate was concentrated and purified on a silica gel column eluting with ethyl acetate to give 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (0.6 g, 33.0% yield). ) as a pale solid (LCMS (M+1): 296).

Step 8 Preparation of ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4 -oxobutanoate and ethyl 4-((6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4- oxobutanoate

To a solution of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (450 mg; 1.43 mmol) and 4-ethoxy-2-(4-(ethylsulfonyl) phenyl)-4-oxobutanoic acid (424 mg; 1.43 mmol) in DMF (10 ml) was added EDCI (410 mg; 2.15 mmol), HOBT (327 mg; 2.15 mmol) and DIPEA (554 mg; 4.30 mmol). The reaction solution was stirred at room temperature for 2 hours. It was absorbed onto 5 g of silica gel and loaded onto a silica gel column. The column was eluted with 45% ethyl acetate in hexanes to give ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4 -(ethylsulfonyl)phenyl)-4-oxobutanoate and ethyl-4-((6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4- (ethylsulfonyl)phenyl)-4-oxobutanoate (385 mg; 45.4% yield) as a white solid. MS (ESI): m/z=592 (M+H) ⁺ .

Step 9 Preparation of ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl) phenyl) propanoate

A mixture of ethyl 4-((6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutanoate and ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutanoate (385 mg) obtained in the previous step was treated with 15 ml of glacial acetic acid at 80° C. for 2 hours. This was concentrated and purified on a silica gel column eluting with 60% ethyl acetate in hexanes to give ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d] imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propanoate (230 mg; 61.6% yield) as a pale solid. MS (ESI): 574 (M+H) ⁺

Step 10: Preparation of (S)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-( ethylsulfonyl)phenyl)propan-1-ol and (R)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)- 3-(4-(ethylsulfonyl)phenyl)propan-1-ol

To a solution of ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl) propanoate (300 mg; 0.52 mmol) in THF (20 ml) was added LiAlH ₄ (20 mg; 0.52 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. 5.0 ml of water was added, the mixture was filtered. The filtrate was concentrated, the crude product was purified by flash column chromatography using hexane/ethyl acetate to give 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2 -yl)-3-(4-(ethylsulfonyl)phenyl)propan-1-ol (200 mg).

It was separated on a chiral sorbent (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), 0.46 cm inner diameter (ID) × 15 cm long (L); mobile phase: hexane/EtOH/DEA = 70/ 30/0.1 (v/v/v), flow rate: 1.0 ml/min). Appropriate fractions were collected and concentrated under reduced pressure to give the title compounds (85 mg; 89 mg).

Connection with individual configuration (lower retention time)

MS (+) ES: 532 (M+H) ⁺ ;

chiral HPLC analysis: retention time 7.640 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 15:85 (v/v .);

¹ H NMR (400 MHz, CD ₃ Cl): 7.90 (d, 8.0 Hz, 2H), 7.72 (s, 1H), 7.68 (d, 8.0 Hz, 2H), 4.68 (t, 8.0 Hz, 1H), 3.76 (t, 8.0 Hz, 2H), 3.71 (m, 4H), 3.14-3.12 (m, 2H), 2.65-2.60 (m, 1H), 2.38-2.35 (m, 1H) , 2.10-2.10 (m, 4H), 1.23-1.19 (t, 8.0 Hz, 3H).

Connection with individual configuration (longer retention time)

MS (+) ES: 532 (M+H) ⁺ ;

chiral HPLC analysis: retention time 9.398 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 15:85 (v/v );

¹ H NMR (400 MHz, CD ₃ OD): 7.90 (d, 8.0 Hz, 2H), 7.72 (s, 1H), 7.68 (d, 8.0 Hz, 2H), 4.68 (t, 8.0 Hz, 1H), 3.76 (t, 8.0 Hz, 2H), 3.71 (m, 4H), 3.14-3.12 (m, 2H), 2.65-2.60 (m, 1H), 2.38-2.35 (m, 1H) , 2.10-2.10 (m, 4H), 1.23-1.19 (t, 8.0 Hz, 3H).

Example 141

Preparation of 3-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide

This compound was prepared in the same manner as the racemic mixture of Examples 152 and 153. MS (+) ES: 560 (M+H) ⁺ .

Example 142

Preparation of 3-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-1-ol

This compound was prepared in the same manner as the racemic mixture of Examples 155 and 156. MS (+) ES: 547 (M+H) ⁺ .

Example 143

Preparation of 3-(5-chloro-6-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide

This compound was prepared in the same manner as the racemic mixture of Examples 148 and 149. MS (+) ES: 552 (M+H) ⁺ .

Example 144

Preparation of 3-(5-chloro-6-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-1-ol

This compound was prepared in the same manner as the racemic mixture of Examples 150 and 151. MS (+) ES: 539 (M+H) ⁺ .

Example 145

Preparation of 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propan-1 -ola

This compound was prepared in the same manner as the racemic mixture of Examples 139 and 140. MS (+) ES: 532 (M+H) ⁺ .

Examples 146 and 147

Preparation of (S)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl )propanamide and (R)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl )phenyl)propanamide

To a solution of ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl) propanoate (310 mg; 0.54 mmol) in methanol (20 ml) was added NH ₃ (7.7 ml; 7N solution in methanol; 53.9 mmol). The reaction mixture was stirred at 60° C. for 12 hours. The mixture was concentrated, the crude product was purified by flash column chromatography using hexane/ethyl acetate to give 3-(4,6-dichloro-5-(4,4-difluoropiperidine-1 -yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propanamide (300 mg).

It was separated on a chiral sorbent (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), i.d. 0.46 cm × L 15 cm; mobile phase: 100% methanol; flow rate: 1.0 ml/min ). Appropriate fractions were collected and concentrated under reduced pressure to give the title compounds (140 mg; 135 mg).

Connection with individual configuration (lower retention time)

MS (+) ES: 545 (M+H) ⁺ ;

chiral HPLC analysis: retention time 9.537 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 15:85 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.84 (d, 8.0 Hz, 2H), 7.63 (d, 8.0 Hz, 2H), 7.57 (s, 1H), 6.44 (s, 1H), 5.71 (s, 1H), 5.14 (t, 8.0 Hz, 1H), 3.74-3.68 (dd, 8.0 Hz, 1H), 3.2-3.22 (m, 4H), 3.15-3.09 (q, 2H) , 3.09-3.03 (dd, 8.0 Hz, 1H), 2.18-2.10 (m, 4H), 1.31-1.27 (t, 8.0 Hz, 3H).

Connection with individual configuration (longer retention time)

MS (+) ES: 545 (M+H) ⁺ ;

chiral HPLC analysis: retention time 11.851 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 15:85 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.84 (d, 8.0 Hz, 2H), 7.63 (d, 8.0 Hz, 2H), 7.57 (s, 1H), 6.44 (s, 1H), 5.71 (s, 1H), 5.14 (t, 8.0 Hz, 1H), 3.74-3.68 (dd, 8.0 Hz, 1H), 3.2-3.22 (m, 4H), 3.15-3.09 (q, 2H) , 3.09-3.03 (dd, 8.0 Hz, 1H), 2.18-2.10 (m, 4H), 1.31-1.27 (t, 8.0 Hz, 3H).

Examples 148 and 149

Preparation of (S)-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide and (R )-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide

To a solution of ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate (340 mg; 0.59 mmol) in methanol (5 ml) was added NH ₃ (4.1 ml; 7N solution in methanol; 29.2 mmol). The reaction mixture was stirred at 60° C. for 12 hours. The mixture was concentrated, the crude product was purified by flash column chromatography using hexane/ethyl acetate to give the title compound (220 mg).

It was separated on a chiral sorbent (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), i.d. 0.46 cm × L 15 cm; mobile phase: 100% methanol; flow rate: 1.0 ml/min ). Appropriate fractions were collected and concentrated under reduced pressure to give 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl )propanamide (97 mg; 87 mg).

Connection with individual configuration (lower retention time)

MS (+) ES: 552 (M+H) ⁺ ;

chiral HPLC analysis: retention time 5.617 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 70:30 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.92 (d, 8.0 Hz, 2H), 7.65 (d, 8.0 Hz, 2H), 7.51-7.49 (s, 1H), 7.35-7.31 (t , 8.0 Hz, 1H), 7.28 (s, 1H), 7.16-7.14 (d, 8.0 Hz, 1H), 7.05-7.03 (d, 8.0 Hz, 1H), 7.00-6.96 (d, 8.0 Hz, 1H), 4.95-4.91 (t, 8.0 Hz, 1H), 4.51-4.46 (m, 1H), 3.39-3.34 (dd, 8.0 Hz, 1H), 3.13-3.11 (d , 8.0 Hz, 2Н), 3.12-3.06 (dd, 8.0 Hz, 1Н), 1.16-1.15 (d, 4.0 Hz, 6Н), 0.93-0.91 (m, 1Н), 0.51-0.49 ( d, 8.0 Hz, 2H), 0.13-0.11 (d, 8.0 Hz, 2H).

Connection with individual configuration (longer retention time)

MS (+) ES: 552 (M+H) ⁺ ;

chiral HPLC analysis: retention time 15.283 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 70:30 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.92 (d, 8.0 Hz, 2H), 7.65 (d, 8.0 Hz, 2H), 7.51-7.49 (s, 1H), 7.35-7.31 (t , 8.0 Hz, 1H), 7.28 (s, 1H), 7.16-7.14 (d, 8.0 Hz, 1H), 7.05-7.03 (d, 8.0 Hz, 1H), 7.00-6.96 (d, 8.0 Hz, 1H), 4.95-4.91 (t, 8.0 Hz, 1H), 4.51-4.46 (m, 1H), 3.39-3.34 (dd, 8.0 Hz, 1H), 3.13-3.11 (d , 8.0 Hz, 2Н), 3.12-3.06 (dd, 8.0 Hz, 1Н), 1.16-1.15 (d, 4.0 Hz, 6Н), 0.93-0.91 (m, 1Н), 0.51-0.49 ( d, 8.0 Hz, 2H), 0.13-0.11 (d, 8.0 Hz, 2H).

Examples 150 and 151

Preparation of (R)-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-1- ol and (S)-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-1 -ola

Stage 1. Obtaining cyclopropylmethyl-2-(4-(cyclopropylmethylthio)-phenyl)acetate

To a solution of 2-(4-mercaptophenyl)acetic acid (10 g, 59.4 mmol) in DMF (100 ml) was added potassium carbonate (25.0 g, 181.2 mmol) and cyclopropylmethyl bromide (20 g, 148.1 mmol ). The reaction mixture was stirred at 50° C. overnight. It was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified on a silica gel column eluting with 25% ethyl acetate in hexanes to give cyclopropylmethyl 2-(4-(cyclopropylmethylthio)phenyl)acetate (15.0 g; 91.3% yield) as a colorless oil.

Stage 2. Obtaining cyclopropylmethyl-2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetate

To a solution of cyclopropylmethyl-2-(4-(cyclopropylmethylthio)phenyl)acetate (15.0 g; 54.3 mmol) in dichloromethane (200 ml) was added MCPBA (23.4 g; 135.6 mmol) at 0°C. After the addition, the reaction mixture was stirred at ambient temperature for 14 hours. It was partitioned between dichloromethane and saturated sodium thiosulfate solution. The organic layer was washed with 2N. aqueous sodium hydroxide solution and brine. It was concentrated and purified on a silica gel column eluting with 60% ethyl acetate in hexanes to give cyclopropylmethyl 2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetate (12 g; 71.6% yield) as a white solid.

Stage 3. Obtaining 2-(4-(cyclopentylmethylsulfonyl)phenyl)acetic acid

To a 250 ml round bottom flask was added cyclopropylmethyl-2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetate (15.0 g; 48.6 mmol) and methanol (100 ml). A solution of sodium hydroxide in water (3.8 g; 95.0 mmol; in 100 ml water) was added. The reaction mixture was heated to reflux for 12 hours. The volatiles were evaporated under reduced pressure. The residue was acidified to pH 3.0 using 1N. HCl solution and extracted with ethyl acetate (100 ml x 3). The organic layer was separated and combined, washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a white solid (9.0 g; 72.7%), MS (+) ES: 255 (M+H) ⁺ .

Stage 4. Obtaining 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-ethoxy-4-oxobutanoic acid

To 2-(4-(cyclopentylmethyl)sulfonyl)phenyl)acetic acid (1.0 g; 3.9 mmol) in THF (30 ml) at -78°C was added LiHMDS (1 M solution in THF; 8.4 ml ). Ethyl 2-bromoacetate (1.0 g, 5.9 mmol) was added after 15 min. The reaction mixture was stirred at -78°C for 1.0 h, then 0.1 N sodium hydroxide was added. HCl solution to bring the pH to 3-4. Extracted three times with EtOAc, dried over Na ₂ SO ₄ , filtered, concentrated. The residue was purified on a silica gel column using System A to elute to give a yellow oil (0.8 g); MS (ESI): 341 (M+H) ⁺ .

Stage 5. Obtaining 4-bromo-5-chlorobenzene-1,2-diamine

Fe powder (6.0 g, 107.4 mmol) and NH ₄ Cl (5.7 g; 106.5 mmol). The reaction mixture was stirred at 80° C. overnight. She was filtered. The filtrate was concentrated and purified on a silica gel column eluting with ethyl acetate to give 4-bromo-5-chlorobenzene-1,2-diamine (6.0 g, 75.7% yield) as a yellow solid.

Stage 6. Obtaining 6-chloro-2'-isopropoxy-[1,1'-biphenyl]-3,4-diamine

Mixture of 4-bromo-5-chlorobenzene-1,2-diamine (1.1 g; 5.0 mmol), (2-isopropoxyphenyl)boronic acid (1.1 g; 6.1 mmol), tris-(dibenzylideneacetone) dipalladium(0) (454 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (288 mg) and sodium carbonate (1.8 g; 14.5 mmol) in 1,4-dioxane (100 ml) and water (10 ml ) was degassed, heated to 90°C for 3 hours. Volatile solvents were removed under reduced pressure. The residue was loaded directly onto an ISCO solid cartridge and eluted rapidly with hexane/ethyl acetate to give a white solid (1.1 g; 80% yield), MS (+) ES: 277 (M+H) ⁺ .

Step 7 Preparation of ethyl 4-((4-amino-6-chloro-2'-isopropoxy-[1,1'-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl) phenyl)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2'-isopropoxy-[1,1'-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl )sulfonyl)phenyl)-4-oxobutanoate

To a solution of 6-chloro-2'-isopropoxy-[1,1'-biphenyl]-3,4-diamine (600 mg; 1.76 mmol) and 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4 -ethoxy-4-oxobutanoic acid (585 mg; 2.11 mmol) in DMF (5 ml) was added EDCI (674 mg; 3.53 mmol), HOBT (537 mg; 3.53 mmol) and DIPEA (455 mg; 3.53 mmol). The reaction solution was stirred at room temperature for 2 hours. It was absorbed onto 5 g of silica gel and loaded onto a silica gel column. The column was eluted with 45% ethyl acetate in hexanes to give ethyl 4-((4-amino-6-chloro-2'-isopropoxy-[1,1'-biphenyl]-3-yl)amino)-3-( 4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2'-isopropoxy-[1,1'-biphenyl]-4-yl)amino)- 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate (750 mg; 71% yield) as a white solid. MS (ESI): 599 (M+H) ⁺ .

Step 8. Preparation of ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate

A mixture of ethyl-4-((4-amino-6-chloro-2'-isopropoxy-[1,1'-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)- 4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2'-isopropoxy-[1,1'-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl)-sulfonyl )phenyl)-4-oxobutanoate (800 mg) was treated with 15 ml of glacial acetic acid at 80° C. for 2 hours. This was concentrated and purified on a silica gel column eluting with 60% ethyl acetate in hexanes to give ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate (700 mg; 90% yield) as a pale solid. MS (ESI): 581 (M+H) ⁺ .

Step 9 Preparation of (R)-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propane -1-ol and (S)-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl) propan-1-ol

To a solution of ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate (440 mg; 0.76 mmol) in THF (20 ml) was added LiAlH ₄ (29 mg; 0.76 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. 5.0 ml of water was added, the mixture was filtered. The filtrate was concentrated, the crude product was purified by flash column chromatography using hexane/ethyl acetate to give 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4 -((cyclopropylmethyl)sulfonyl)phenyl)propan-1-ol (400 mg).

It was separated on a chiral sorbent (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), i.d. 0.46 cm × L 15 cm; mobile phase: ethanol/hexane=6:4 (v/v); flow rate: 1.0 ml/min). Appropriate fractions were collected and concentrated under reduced pressure to give the title compounds (183 mg; 165 mg).

Connection with individual configuration (lower retention time)

MS (+) ES: 539 (M+H) ⁺ ;

chiral HPLC analysis: retention time 6.938 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane=40:60 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.90 (d, 8.0 Hz, 2H), 7.67 (d, 8.0 Hz, 2H), 7.62 (s, 0.5H), 7.49 (s, 0 .5H), 4.59 (t, 8.0 Hz, 1H), 4.38 (dd, 8.0; 11.0 Hz, 1H), 4.27-4.11 (m, 1H), 3.44-3.28 (m, 4H), 3.20 (q, 8.0 Hz, 2H), 2.24-2.01 (m, 4H), 1.21 (t, 8.0 Hz, 3H).

Connection with individual configuration (longer retention time)

MS (+) ES: 539 (M+H) ⁺ ;

chiral HPLC analysis: retention time 11.098 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 40:60 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.90 (d, 8.0 Hz, 2H), 7.67 (d, 8.0 Hz, 2H), 7.62 (s, 0.5H), 7.49 (s, 0 .5H), 4.59 (t, 8.0 Hz, 1H), 4.38 (dd, 8.0; 11.0 Hz, 1H), 4.27-4.11 (m, 1H), 3.44-3.28 (m, 4H), 3.20 (q, 8.0 Hz, 2H), 2.24-2.01 (m, 4H), 1.21 (t, 8.0 Hz, 3H).

Examples 152 and 153

Preparation of (S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide and (R)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide

Stage 1. Obtaining 6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3,4-diamine

4-Bromo-5-chlorobenzene-1,2-diamine mixture (1.5 g; 6.78 mmol), 2-(2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3 ,2-dioxaborolane (2.2 g; 8.15 mmol), tris-(dibenzylideneacetone)dipalladium(0) (620 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (393 mg) and sodium carbonate (1.7 g ; 13.7 mmol) in 1,4-dioxane (50 ml) and water (10 ml) was degassed, heated to 90° C. for 3 h. Volatile solvents were removed under reduced pressure. The residue was loaded directly onto an ISCO solid cartridge and eluted rapidly with hexane/ethyl acetate to give a white solid (1.0 g; 51.9% yield), MS (+) ES: 285 (M+H) ⁺ .

Step 2 Preparation of ethyl 4-((4-amino-6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl) sulfonyl)phenyl)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)-3-(4 -((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate

To a solution of 6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3,4-diamine (543 mg; 1.9 mmol) and 2-(4-((cyclopropylmethyl)sulfonyl)phenyl) -4-ethoxy-4-oxobutanoic acid (500 mg; 1.47 mmol) in DMF (5 ml) was added EDCI (560 mg; 2.93 mmol), HOBT (447 mg; 2.93 mmol) and DIPEA (380 mg; 2.94 mmol). The reaction solution was stirred at room temperature for 2 hours. It was absorbed onto 5 g of silica gel and loaded onto a silica gel column. The column was eluted with 45% ethyl acetate in hexanes to give ethyl 4-((4-amino-6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-4-yl )amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate (600 mg; 62.3% yield) as a white solid. MS (ESI): 607 (M+H) ⁺ .

Step 3 Preparation of ethyl 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl) propanoate

Ethyl 4-((4-amino-6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl mixture )-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)-3-(4-(( cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate (800 mg) was treated with 15 ml of glacial acetic acid at 80° C. for 2 hours. This was concentrated and purified on a silica gel column eluting with 60% ethyl acetate in hexanes to give ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate (600 mg; 77.3% yield) as a pale solid. MS (ESI): 589 (M+H) ⁺ .

Step 4 Preparation of ethyl-(S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl) sulfonyl)phenyl)propanamide and (R)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl) sulfonyl)phenyl)propanamide

To a solution of ethyl 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate ( 400 mg; 0.68 mmol) in methanol (5 ml) was added NH ₃ (4.8 ml; 7N solution in methanol; 33.9 mmol). The reaction mixture was stirred at 60° C. for 12 hours. The mixture was concentrated, the crude product was purified by flash column chromatography using hexane/ethyl acetate to give 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H- benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide (177 mg).

It was separated on a chiral sorbent (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), i.d. 0.46 cm × L 15 cm; mobile phase: 100% methanol; flow rate: 1.0 ml/min ). Appropriate fractions were collected and concentrated under reduced pressure to give the title compounds (67 mg; 60 mg).

Connection with individual configuration (lower retention time)

MS (+) ES: 560 (M+H) ⁺ ;

chiral HPLC analysis: retention time 3.919 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 80:20 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.92 (d, 8.0 Hz, 2H), 7.51-7.49 (s, 1H), 7.65 (d, 8.0 Hz, 2H), 7.56-7.54 (m , 1H), 7.48-7.44 (m, 1H), 7.33-7.32 (m, 2H), 7.28-7.26 (d, 8.0 Hz, 1H), 6.86 (d, 8.0 Hz, 1H), 4.96- 4.92 (t, 8.0 Hz, 1H), 3.41-3.35 (dd, 8.0 Hz, 1H), 3.13-3.11 (d, 8.0 Hz, 2H), 3.12-3.06 (dd, 8.0 Hz , 1Н), 0.93-0.91 (m, 1Н), 0.52-0.50 (d, 8.0 Hz, 2Н), 0.13-0.11 (d, 8.0 Hz, 2Н).

Connection with individual configuration (longer retention time)

MS (+) ES: 560 (M+H) ⁺ ;

chiral HPLC analysis: retention time 8.942 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 80:20 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.92 (d, 8.0 Hz, 2H), 7.51-7.49 (s, 1H), 7.65 (d, 8.0 Hz, 2H), 7.56-7.54 (m , 1H), 7.48-7.44 (m, 1H), 7.33-7.32 (m, 2H), 7.28-7.26 (d, 8.0 Hz, 1H), 6.86 (d, 8.0 Hz, 1H), 4.96- 4.92 (t, 8.0 Hz, 1H), 3.41-3.35 (dd, 8.0 Hz, 1H), 3.13-3.11 (d, 8.0 Hz, 2H), 3.12-3.06 (dd, 8.0 Hz , 1Н), 0.93-0.91 (m, 1Н), 0.52-0.50 (d, 8.0 Hz, 2Н), 0.13-0.11 (d, 8.0 Hz, 2Н).

Example 154

Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl) propanamide

Step 1. Preparation of tert-butyl-4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole- 1-carboxylate

To a solution of 2-(4-(cyclopropylmethylsulfonyl)benzyl)-5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole (3.35 g; 6.51 mmol ) in DCM (25 ml) was added tert-butoxycarbonyl(Boc)-anhydride (1.25 g; 9.77 mmol), DIEA (1.7 ml; 9.77 mmol) and a catalytic amount of 4-dimethylaminopyridine (DMAP) at ambient temperature. After the addition, the reaction solution was stirred at ambient temperature overnight. He was concentrated. The residue was purified on a silica gel column eluting with 25% EtOAc in DCM to give a mixture of the two product isomers as a pale solid (10.7 g, 90% yield).

MS (+) ES: 614 (M+H) ⁺ .

Stage 2. Preparation of tert-butyl-4,6-dichloro-2-(1-(4-((cyclopropylmethyl)-sulfonyl)phenyl)-3-methoxy-3-oxopropyl)-5-(4,4-difluoropiperidine- 1-yl)-1H-benzo[d]imidazole-1-carboxylate

To a solution of tert-butyl 2-(4-(cyclopropylmethylsulfonyl)benzyl)-4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole-1-carboxylate (465 mg; 0.76 mmol) in anhydrous THF (10 ml) was added a solution of lithium hexamethyldisylamide (1 M solution, 1 ml; 1 mmol) at -78°C. After stirring at -78° C. for 30 minutes, methyl bromoethyl acetate (233 mg; 1.52 mmol) was added, the reaction solution was slowly warmed to ambient temperature and stirred overnight. It was treated with EtOAc and water. The organic layer was concentrated and purified on a silica gel column eluting with 25% EtOAc in DCM to give the desired product as a white solid (511 mg; 98% yield). MS (+) ES: 686 (M+H) ⁺ .

Step 3. Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole-2 -yl)propanamide

Solution of tert-butyl-4,6-dichloro-2-(1-(4-(cyclopropylmethyl)sulfonyl)-phenyl)-3-methoxy-3-oxopropyl)-5-(4,4-difluoropiperidin-1-yl) -1H-benzo[d]imidazole-1-carboxylate (1 g; 1.45 mmol) in 20 ml of methanol (containing approximately 7 N ammonia solution) in a sealed reaction flask was stirred at 80° C. for 10 hours. This was concentrated and purified on a silica gel column eluting with EtOAc to give the desired product as a white solid (0.65 g, 78% yield). MS (+) ES: 571 (M+H) ⁺ .

Examples 155 and 156

Preparation of (S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propane -1-ol and (R)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl )phenyl)propan-1-ol

To a solution of ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate (550 mg; 0.93 mmol) in THF (15 ml) was added LiAlH ₄ (35 mg; 0.93 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. 5.0 ml of water was added, the mixture was filtered. The filtrate was concentrated, the crude product was purified by flash column chromatography using hexane/ethyl acetate to give 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-1-ol (250 mg).

It was separated on a chiral sorbent (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), i.d. 0.46 cm × L 15 cm; mobile phase: 100% hexane/ethanol = 80/20 (vol./vol. ); flow rate: 1.0 ml/min). Appropriate fractions were collected and concentrated under reduced pressure to give the title compounds (110 mg; 100 mg).

Connection with individual configuration (lower retention time)

MS (+) ES: 547 (M+H) ⁺ ;

chiral HPLC analysis: retention time 6.374 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 20:80 (v/v);

¹ H NMR (400 MHz, CD ₃ OD): 7.94-7.92 (d, 8.0 Hz, 2H), 7.67-7.65 (d, 8.0 Hz, 2H), 7.48-7.44 (m, 2H), 7.32 -7.31 (m, 2H), 7.27-7.25 (m, 2H), 6.84-6.47 (t, 1H), 4.71-4.67 (t, 8.0 Hz, 1H), 3.64-3.53 (m, 1H), 3.13 -3.12 (d, 4.0 Hz, 2H), 2.68-2.57 (m, 1H), 2.40-2.31 (m, 1H), 1.32-1.30 (m, 2H), 0.99-0.89 (m, 1H), 0.53 -0.48 (q, 2H), 0.14-0.10 (q, 2H).

Connection with individual configuration (longer retention time)

MS (+) ES: 547 (M+H) ⁺ ;

chiral HPLC analysis: retention time 7.719 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 20:80 (v/v);

¹ H NMR (400 MHz, CD ₃ OD): 7.94-7.92 (d, 8.0 Hz, 2H), 7.67-7.65 (d, 8.0 Hz, 2H), 7.48-7.44 (m, 1H), 7.32 -7.31 (m, 2H), 7.27-7.25 (m, 2H), 6.84-6.47 (t, 1H), 4.71-4.67 (t, 8.0 Hz, 1H), 3.64-3.53 (m, 1H), 3.13 -3.12 (d, 4.0 Hz, 2H), 2.68-2.57 (m, 1H), 2.40-2.31 (m, 1H), 1.32-1.30 (m, 2H), 0.99-0.89 (m, 1H), 0.53 -0.48 (q, 2H), 0.14-0.10 (q, 2H).

Example 157

Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl) propan-1-ol

This compound was prepared in a manner analogous to that of the compounds of examples 139, 140 (racemic mixture) to give the title compound as a white solid. MS (+) ES: 558 (M+H) ⁺ .

Example 158

Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)propanamide

This compound was prepared in a manner analogous to that of the compounds of examples 148, 149 (racemic mixture) to give the title compound as a white solid. MS (+) ES: 594 (M+H) ⁺ .

Example 159

Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)propan-1 -ola

This compound was prepared in a manner analogous to that of Examples 150, 151 (racemic mixture) to give the title compound as a white solid. MS (+) ES: 581 (M+H) ⁺ .

Examples 160 and 161

Preparation of (S)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole- 2-yl)propan-1-ol and (R)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl) -1H-benzo[d]imidazol-2-yl)propan-1-ol

These two compounds were obtained from the compound of example 157 by separation on a chiral sorbent (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), i.d. 0.46 cm × L 15 cm; mobile phase: 100% hexane/ethanol = 70 /30 (v/v), flow rate: 1.0 ml/min). Appropriate fractions were collected and concentrated under reduced pressure to give the title compounds (350 mg; 350 mg).

Connection with individual configuration (lower retention time)

MS m/z (ESI): 557.9 [M+1];

chiral HPLC analysis: retention time 7.378 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 15:85 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.91 (d, 2H), 7.66 (d, 2H), 7.44-7.40 (m, 1H), 4.68-4.66 (m, 1H), 3.55-3.53 (m, 2Н), 3.13-3.11 (m, 2Н), 2.68-2.57 (m, 2Н), 2.40-2.31 (m, 2Н), 2.11-2.14 (m, 4Н), 1.32-1.30 (m, 1Н), 0.91- 0.89 (m, 2Н), 0.50 (q, 2Н), 0.12 (q, 2Н).

Connection with individual configuration (longer retention time)

MS m/z (ESI): 557.9 [M+1];

chiral HPLC analysis: retention time 8.738 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 15:85 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.91 (d, 2H), 7.66 (d, 2H), 7.44-7.40 (m, 1H), 4.68-4.66 (m, 1H), 3.55-3.53 (m, 2Н), 3.13-3.11 (m, 2Н), 2.68-2.57 (m, 2Н), 2.40-2.31 (m, 2Н), 2.11-2.14 (m, 4Н), 1.32-1.30 (m, 1Н), 0.91- 0.89 (m, 2Н), 0.50 (q, 2Н), 0.12 (q, 2Н).

Examples 162 and 163

Preparation of (S)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole- 2-yl)propanamide and (R)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo [d]imidazol-2-yl)propanamide

These two compounds were obtained from the compound of example 154 by separation on a chiral sorbent (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), i.d. 0.46 cm × L 15 cm; mobile phase: 100% hexane/ethanol = 45 /55 (vol./about.; flow rate: 1.0 ml/min). Appropriate fractions were collected and concentrated under reduced pressure to give the title compounds (250 mg; 250 mg).

Connection with individual configuration (lower retention time)

MS m/z (ESI): 571.0 [M+1];

chiral HPLC analysis: retention time 8.193 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 15:85 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.90 (d, 2H), 7.65-7.63 (m, 3H), 4.94-4.92 (m, 1H), 3.13-3.03 (m, 3H), 2.68-2.57 ( m, 1Н), 2.40-2.31 (m, 2Н), 2.11-2.14 (m, 4Н), 1.38-1.30 (m, 1Н), 0.94-0.91 (m, 2Н), 0.50 (q, 2Н), 0.11 ( q, 2H).

Connection with individual configuration (longer retention time)

MS m/z (ESI): 571.0 [M+1];

chiral HPLC analysis: retention time 10.536 minutes, chiral purity: 100% (chromatographic column: OD Phenomenex Lux Cellulose-1, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 15:85 (v/v .);

¹ H NMR (400 MHz, CD ₃ OD): 7.90 (d, 2H), 7.65-7.63 (m, 3H), 4.94-4.92 (m, 1H), 3.13-3.03 (m, 3H), 2.68-2.57 ( m, 1Н), 2.40-2.31 (m, 2Н), 2.11-2.14 (m, 4Н), 1.38-1.30 (m, 1Н), 0.94-0.91 (m, 2Н), 0.50 (q, 2Н), 0.11 ( q, 2H).

Examples 164 and 165

Preparation of (S)-4-(3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl) phenyl)propyl)morpholine and (R)-4-(3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-( (cyclopropylmethyl)sulfonyl)phenyl)propyl)morpholine

Step 1 Preparation of ethyl-(R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-(( cyclopropylmethyl)sulfonyl)phenyl)propanoate

These two compounds were obtained by separation on a chiral sorbent (separation conditions: CHIRALPAK IB-N (IBN5CD-VD005), i.d. 0.46 cm × L 15 cm; mobile phase: 100% hexane/ethanol = 80/20 (v/v ./vol.); flow rate: 1.0 ml/min). Appropriate fractions were collected and concentrated under reduced pressure to give the title compounds (690 mg; 490 mg).

Connection with custom configuration Int-164A (lower retention time)

MS m/z (ESI): 589.1 [M+1];

chiral HPLC analysis: retention time 11.508 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 20:80 (v/v).

Connection with custom configuration Int-164V (longer retention time)

MS m/z (ESI): 589.1 [M+1];

chiral HPLC analysis: retention time 17.164 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG, 150*4.6 mm, 5 µm; mobile phase: ethanol/hexane = 20:80 (v/v).

Stage 2(1). Preparation of (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl ) propanal

Ethyl-(R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl) phenyl)propanoate (shorter retention time) (from step 1) (45 mg; 0.076 mmol) was dissolved in DCM (3.0 ml), diisobutylaluminum hydride (0.16 ml; 0.16 mmol) was added and the mixture was stirred for 30 min to complete the reaction. The product was purified by flash chromatography using hexane/ethyl acetate to give a white solid (22 mg; 52%).

MS m/z (ESI): 543.0 [M-1].

Step 3(1). Preparation of (R or S)-4-(3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl) sulfonyl)phenyl)propyl)-morpholine

(R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl) propanal (from step 2(1)) (22 mg; 0.04 mmol) and morpholine (17 mg; 0.20 mmol) were dissolved in DCM (5.0 ml), acetic acid (14 mg; 0.24 mmol) was added ) and the mixture was stirred for 0.5 h, NaBH(OAc) ₃ (25 mg; 0.12 mmol) was added at room temperature. The mixture was stirred for 60 min to complete the reaction (monitoring using LC-MS). The mixture was treated with a little dilute HCl and purified directly by flash chromatography using hexane/ethyl acetate to give a white solid (7.3 mg; 29%).

MS m/z (ESI): 616.0 [M+1].

¹ H NMR (400 MHz, CDCl ₃ ): 7.99 (d, 2H), 7.72 (s, 1H), 7.50 (s, 1H), 7.46-7.44 (m, 1H), 7.43 (d, 2H), 7.36- 7.33 (m, 2H), 7.31-7.27 (m, 1H), 6.42 (d, 1H), 4.69 (t, 1H), 3.85-3.83 (m, 4H), 3.03-3.01 (m, 2H), 2.60- 2.58 (m, 4H), 2.50-2.45 (m, 4H), 2.39-2.35 (m, 1H), 1.03-0.98 (m, 1H), 0.60 (d, 2H), 0.19 (d, 2H).

Stage 2(2). Preparation of (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl ) propanal

Ethyl-(R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl) phenyl)propanoate (longer retention time) (example 164; step 1) (100 mg; 0.17 mmol) was dissolved in DCM (10.0 ml), diisobutylaluminum hydride (1.0 ml; 0.1 mmol) was added and the mixture stirred for 30 min to complete the reaction. The mixture was treated with a small amount of dilute HCl and purified directly by flash chromatography using hexane/ethyl acetate to give a white solid (50 mg; 54%).

MS m/z (ESI): 543.0 [M-1].

Stage 3(2). Preparation of (R or S)-4-(3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl) sulfonyl)phenyl)propyl)-morpholine

(R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl) propanal (from step 2(2)) (30 mg; 0.06 mmol) and morpholine (48 mg; 0.55 mmol) were dissolved in DCM (10.0 ml), acetic acid (33 mg; 0.55 mmol) was added ) and the mixture was stirred for 0.5 h, NaBH(OAc) ₃ (70 mg; 0.33 mmol) was added at room temperature. The mixture was stirred for 60 min to complete the reaction (monitoring using LC-MS). The mixture was treated with a small amount of dilute HCl and purified directly by flash chromatography using hexane/ethyl acetate to give a white solid (13.7 mg; 40%).

MS m/z (ESI): 616.0 [M+1].

¹ H NMR (400 MHz, CDCl ₃ ): 7.89 (d, 2H), 7.72 (s, 1H), 7.50 (s, 1H), 7.46-7.44 (m, 1H), 7.43 (d, 2H), 7.36 -7.33 (m, 2H), 7.31-7.27 (m, 1H), 6.42 (d, 1H), 4.69 (t, 1H), 3.85-3.83 (m, 4H), 3.03-3.01 (m, 2H), 2.60 -2.58 (m, 4H), 2.50-2.45 (m, 4H), 2.39-2.35 (m, 1H), 1.03-0.98 (m, 1H), 0.60 (d, 2H), 0.19 (d, 2H).

Examples 166, 167

Preparation of (S)-N-(3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl) phenyl)propyl)acetamide and (R)-N-(3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-( (cyclopropylmethyl)sulfonyl)phenyl)propyl)acetamide

Stage 1(1). Preparation of (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl ) propane-1-amine

(R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl) propanal (examples 164, 165, stage 2(1)) (45 mg; 0.08 mmol) was dissolved in MeOH (3.0 ml), acetic acid (50 mg; 0.83 mmol) was added and 7 N. a solution of NH ₃ in MeOH (1.2 ml; 8.4 mmol) and the mixture was stirred for 0.5 h, NaBH ₄ (31 mg; 0.84 mmol) was added at room temperature. The mixture was stirred for 60 min to complete the reaction (monitoring using LC-MS). The mixture was treated with a little dilute HCl and purified directly by flash chromatography using hexane/ethyl acetate to give a white solid (45 mg; 99%).

MS m/z (ESI): 546.1 [M+1].

Stage 2(1). Preparation of (R or S)-N-(3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl) sulfonyl)phenyl)propyl)-acetamide

(R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl) propane-1-amine (45 mg; 0.083 mmol) was dissolved in DCM (2.0 ml), acetyl chloride (8.0 mg; 0.1 mmol) was added, then Et ₃ N (9.0 mg; 0.1 mmol) and the mixture was stirred for 0.5 h. The mixture was treated with a small amount of dilute HCl and directly purified by preparative HPLC using System C to elute to give the product as a white solid (10.7 mg, 22%).

MS m/z (ESI): 587.9 [M+1].

¹ H NMR (400 MHz, CD ₃ OD): 7.93 (d, 2H), 7.74-7.72 (m, 1H), 7.67-7.65 (m, 2H), 7.57-7.53 (m, 1H), 7.48-7.44 ( m, 1Н), 7.32 (d, 2Н), 7.28-7.26 (m, 1Н), 6.66 (d, 1Н), 4.61 (s, 1Н), 4.51-4.47 (m, 1Н), 3.25-3.33 (m, 2Н), 3.13 (d, 2Н), 2.67-2.58 (m, 2Н), 2.41-2.31 (m, 2Н), 0.97-0.91 (m, 1Н), 0.50 (q, 2Н), 0.11 (q, 2Н ).

Stage 1(2). Preparation of (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl ) propane-1-amine

(R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl) propanal (examples 164, 165, stage 2(2)) (50 mg; 0.09 mmol) was dissolved in MeOH (5.0 ml), acetic acid (55 mg; 0.92 mmol) was added and 7 N. a solution of NH ₃ in MeOH (1.3 ml; 9.2 mmol) and the mixture was stirred for 0.5 h, NaBH ₄ (21 mg; 0.55 mmol) was added at room temperature. The mixture was stirred for 60 min until the reaction was complete (monitoring using LC-MS). The mixture was treated with a small amount of dilute HCl and purified directly by flash chromatography using hexane/ethyl acetate to give a white solid (45 mg; 90%).

MS m/z (ESI): 546.1 [M+1].

Stage 2(2). Preparation of (R or S)-N-(3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl) sulfonyl)phenyl)propyl)-acetamide

(R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl) propane-1-amine (40 mg; 0.073 mmol) was dissolved in DCM (5.0 ml), acetyl chloride (7.0 mg; 0.09 mmol) was added, then Et ₃ N (15 mg; 0.15 mmol) was added and the mixture was stirred for 0.5 h. The mixture was treated with a small amount of dilute HCl and directly purified by preparative HPLC using System C to elute to give the product as a white solid (20 mg; 46%).

MS m/z (ESI): 587.9 [M+1].

¹ H NMR (400 MHz, CD ₃ OD): 7.93 (d, 2H), 7.74-7.72 (m, 1H), 7.67-7.65 (m, 2H), 7.57-7.53 (m, 1H), 7.48-7.44 ( m, 1Н), 7.31 (d, 2Н), 7.28-7.26 (m, 1Н), 6.66 (d, 1Н), 4.61 (s, 1Н), 4.51-4.47 (m, 1Н), 3.25-3.33 (m, 2Н), 3.13 (d, 2Н), 2.67-2.58 (m, 2Н), 2.41-2.31 (m, 2Н), 0.97-0.91 (m, 1Н), 0.50 (q, 2Н), 0.11 (q, 2Н) .

Example 168

Preparation of N-(3-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl) acetamide

This compound can be prepared in a manner analogous to that of Examples 166, 167 from the appropriate racemic starting material.

Example 169

Preparation of 4-(3-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl) morpholine

This compound can be prepared in a manner analogous to that of Examples 164, 165 from the appropriate racemic starting material.

Example 170

Preparation of 4-(3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole-2 -yl)propyl)morpholine

Stage 1. Obtaining cyclopropylmethyl-2-(4-((cyclopropylmethyl)thio)phenyl)acetate

To a solution of 2-(4-mercaptophenyl)acetic acid (20 g, 118.9 mmol) in DMF (200 ml) was added (bromomethyl)cyclopropane (40.1 g, 297.2 mmol) and cesium carbonate (117 g, 356 .7 mmol). After the addition, the reaction mixture was stirred at ambient temperature for 14 hours. The reaction mixture was concentrated to remove about half of the solvent. Then it was treated with EtOAc and water. The organic layer was concentrated and purified on a silica gel column eluting with 25% EtOAc in hexanes to give cyclopropylmethyl 2-(4-(cyclopropylmethylthio)phenyl)acetate (26.5 g; 81% yield) as a colorless oil.

Stage 2. Obtaining cyclopropylmethyl-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetate

To a solution of cyclopropylmethyl-2-(4-(cyclopropylmethylthio)phenyl)acetate (31 g; 112.3 mmol) in dichloromethane (200 ml) was added meta-chloroperbenzoic acid (58 g; 337 mmol). After the addition, the reaction mixture was stirred at ambient temperature for 10 hours. It was partitioned between DCM (1 L) and aqueous saturated Na ₂ S ₂ O ₃ solution (1 L). The organic layer was washed with 2N. sodium hydroxide solution (200 ml) and brine. It was concentrated and purified on a silica gel column eluting with 60% EtOAc in hexanes to give cyclopropylmethyl 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetate (33.5 g, 96.7% yield) as a white solid.

Stage 3. Obtaining 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid

Mixture of cyclopropylmethyl-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetate (32.6 g; 105.7 mmol) and lithium hydroxide monohydrate (17.8 g; 423 mmol) in 1,4-dioxane (200 ml) and water (60 ml) was stirred at ambient temperature for 10 hours. It was acidified to pH 5 using concentrated hydrochloric acid and extracted with EtOAc (3×300 ml). The combined organic layers were concentrated to give the desired product, 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetic acid (26.3 g, 98% yield), as a white solid.

Stage 4. Obtaining 2,3,4-trichloro-6-nitroaniline

A suspension of 4,5-dichloro-2-nitrobenzamine (30 g; 145 mmol) and N-chlorosuccinimide (NCS) (24.2 g; 181.2 mmol) in DMF (250 ml) was heated to 100°C for 2 hours . It was poured into ice water. The bright yellow precipitate, 2,3,4-trichloro-6-nitrobenzamine, was collected by filtration and dried under high vacuum overnight (34.2 g; 98% yield).

Stage 5. Obtaining 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitroaniline

To a solution of (2,3,4-trichloro-6-nitrobenzamine (5 g; 20.7 mmol) in 30 ml DMF was added 4,4-difluoropiperidine (3.8 g; 31.06 mmol) and DIEA (11.8 ml; 62.1 mmol) The reaction mixture was stirred at 105° C. for 2 days. TLC showed mainly product. Most of the DMF was removed in vacuo. It was then absorbed onto silica gel and purified on a silica gel column eluting with 30%- EtOAc in hexanes to give the desired product, 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitrobenzamine, as a light yellow solid (4.72 g; 70% yield) .

Stage 6. Obtaining 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine

Zinc dust (7 g, 108 mmol) and concentrated HCl (2 ml). The reaction mixture was stirred at room temperature for 14 hours. It was filtered, the filtrate was concentrated and purified on a silica gel column eluting with neat EtOAc to give 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine as a pale solid (1 .83 g, 57% yield.

Step 7: Preparation of N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetamide

To a solution of 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetic acid (1.71 g; 6.71 mmol) in dichloromethane (20 ml) was added EDC (1.61 g; 8.40 mmol), HBTU (3.15 g; 8.40 mmol), then 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (1.65 g; 5.59 mmol). After the addition, the reaction solution was stirred at ambient temperature for 2 hours. This was absorbed onto silica gel and eluted with 50% ethyl acetate in hexanes to give N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-( cyclopropylmethylsulfonyl)phenyl)acetamide (2.9 g; 97% yield) as an off-white solid.

Step 8. Preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole

N-(2-Amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetamide (2.9 g; 5.45 mmol ) was treated with acetic acid (20 ml) at 80°C for 2 hours. The acid was removed under high vacuum. The residue was neutralized using NaHCO ₃ and absorbed onto silica gel. This was purified using 40% ethyl acetate in dichloromethane as eluent to give 2-(4-(cyclopropylmethylsulfonyl)benzyl)-5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo [d]imidazole (2.3 g; 82% yield) as a bright white solid.

Step 9. Preparation of tert-butyl-5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole- 1-carboxylate

To a solution of 2-(4-(cyclopropylmethylsulfonyl)benzyl)-5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole (3.35 g; 6.51 mmol ) in dichloromethane (50 ml) was added di-t-butyl di-carbonate (1.25 g; 9.77 mmol), N,N-diisopropylethylamine (1.7 ml; 9.77 mmol) and a catalytic amount of DMAP. After the addition, the reaction solution was stirred at ambient temperature for 6 hours. This was concentrated and purified on a silica gel column eluting with 50% ethyl acetate in dichloromethane to give tert-butyl-2-(4-(cyclopropylmethylsulfonyl)benzyl)-5,7-dichloro-6-(4,4-difluoropiperidine-1 -yl)-1H-benzo[d]imidazole-1-carboxylate (3.62 g; 90% yield) as a white solid.

Step 10. Preparation of tert-butyl-5,7-dichloro-2-(1-(4-(cyclopropylmethylsulfonyl)phenyl)-3-methoxy-3-oxopropyl)-6-(4,4-difluoropiperidin-1-yl) -1H-benzo[d]imidazole-1-carboxylate

To a solution of tert-butyl 2-(4-(cyclopropylmethylsulfonyl)benzyl)-5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole-1-carboxylate (8 .2 g; 13.35 mmol) in THF (150 ml) was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 17.4 ml) at -78°C. After stirring at -78° C. for half an hour, methyl 2-bromoacetate (4.1 g; 26.70 mmol) was added and the reaction mixture was slowly warmed to ambient temperature and stirred for 12 hours. It was treated with ethyl acetate and water. The organic layer was concentrated and purified on a silica gel column eluting with 40% ethyl acetate in dichloromethane to give t-butyl-5,7-dichloro-2-(1-(4-(cyclopropylmethylsulfonyl)phenyl)-3-methoxy-3- oxopropyl)-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole-1-carboxylate (6.3 g; 68.7% yield) as a white solid.

Step 11 Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole-2 -yl)-1-morpholinopropan-1-one

To a solution of tert-butyl-5,7-dichloro-2-(1-(4-(cyclopropylmethylsulfonyl)-phenyl)-3-methoxy-3-oxopropyl)-6-(4,4-difluoropiperidin-1-yl)- 1H-benzo[d]imidazole-1-carboxylate (350 mg; 0.51 mmol) in methanol (3 ml) was added morpholine (1 ml). The reaction solution was stirred at 100° C. for 14 hours. This was absorbed onto silica gel and eluted with 60% ethyl acetate to give 3-(4-(cyclopropylmethylsulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo [d]imidazol-2-yl)-1-morpholinopropan-1-one (310 mg; 94% yield) as an off-white solid.

Step 12: Preparation of 4-(3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d] imidazol-2-yl) propyl) morpholine

To a solution of 3-(4-(cyclopropylmethylsulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1 -morpholinopropan-1-one (305 g; 0.48 mmol) in anhydrous THF (10 ml) was added lithium aluminum hydride (LAH) (1 M solution in THF, 10 ml) at 0°C. After the addition, the reaction solution was stirred at 0° C. for 14 hours. This was purified on a reverse phase column to give 5,7-dichloro-2-(1-(4-(cyclopropylmethylsulfonyl)phenyl)-3-morpholinopropyl)-6-(4,4-difluoropiperidin-1-yl)- 1H-benzo[d]imidazole (100 mg; 33% yield) as a white solid.

MS m/z (ESI): 627 [M+1].

¹ H NMR (400 MHz, CD ₃ OD): 7.92 (d, 10 Hz, 2H), 7.69 (d, 10 Hz, 2H), 7.55 (s, 1H), 3.67 (m, 6H), 3.58 (m, 1Н), 3.13 (m, 2Н), 2.62 (m, 1Н), 2.48-2.41 (m, 4Н), 2.38-2.31 (m, 2Н), 2.13 (m, 4Н), 1.61 (m, 1Н), 1.32 (m, 2Н), 0.95-0.91 (m, 2Н), 0.50 (m, 2Н), 0.11 (m, 2Н).

Example 171

Preparation of N-(3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole-2 -yl)propyl)acetamide

This compound was prepared in a manner analogous to that of Example 170.

BIOLOGICAL ANALYSIS

Hereinafter, the present invention will be described with reference to the following test examples, however, these examples should not be considered as limiting the scope of the present invention.

Test Example 1: LanthaScreen™ Coactivator Assay for Retinoid-Related Orphan Receptor Gamma (RORγ) Using Time-Resolved Fluorescence Resonant Energy Transfer (TR-FRET)

Materials and reagents

1. Ligand-binding domain RORγ labeled with glutathione-S-transferase (RORγ LBD-GST) (catalog number RORC-114H, Creative Biomart).

2. Fluorescein-D22 coactivator peptide (catalog number PV4386, Invitrogen).

3. Terbium (Tb) labeled anti-GST LanthaScreen™ antibody (catalog number PV3550, Invitrogen).

4. Coregulatory buffer D for TR-FRET (catalog number PV4420, Invitrogen).

5. DTT (dithiothreitol) (cat. no. P2325, Fisher).

6. 384-well plate used in the assay (p/n 6008280, Perkin Elmer).

7. Tablet reader Tecan Infinite M1000 (Tecan).

Experimental technique

Prepare complete TR-FRET coregulatory buffer D by adding 1 M DTT solution to TR-FRET coregulatory buffer D to a final DTT concentration of 5mM. Perform a dilution of the compounds in complete coregulatory buffer D for TR-FRET. The highest concentration is 3 μM, 7-fold dilution for a total of 7 concentrations. Add 10 µl to each well of a 384-well plate. To prepare negative and positive controls, add 10 µl of TR-FRET Complete Coregulatory Buffer D.

Prepare RORγ LBD using complete coregulatory buffer D for TR-FRET. The final concentration of RORγ LBD is 25 ng/reaction mixture. Add 5 µl of RORγ LBD to all wells of the 384-well assay plate, except for the negative control wells, to which 5 µl of complete coregulatory buffer D for TR-FRET was added.

Prepare a solution containing 0.6 μM fluorescein-D22 and 8 nM Tb-labeled anti-GST antibody using complete coregulatory buffer D for TR-FRET. Add 5 µl to all wells of the 384-well assay plate used.

Quickly and gently mix wells of a 384-well plate using a plate shaker and incubate at room temperature protected from light for 1 hour. To reduce evaporation, the plate can be hermetically sealed with a lid.

Perform plate measurement at 520 nm and 495 nm on the Tecan Infinite M1000. IC ₅₀ values (concentration causing 50% inhibition) were calculated using GraphPad Prism by plotting percentage inhibition versus logarithm of compound concentration. The IC ₅₀ values for the compounds of the examples are shown in Table I.

Test Example 2 IL-17 Production Assay Using Human PBMC

Materials and reagents

1. Human cell PBMC (catalog number 70025.1, Zenbio).

2. Lymphocyte medium (catalog number LYMPH-1, Zenbio).

3. TexMACS (part number 130-097-196, Miltenyi).

4. CytoStim for human cells (p/n 1130-092-173, Miltenyi).

5. Human IL-17 ELISA kit (catalog number D1700, R&D Systems).

6. Tablet reader Tecan Infinite M1000 (Tecan).

Experimental procedure for the analysis of the formation of IL-17

Cryo-frozen human peripheral blood mononuclear cells (PBMCs) were rapidly thawed in heated lymphocyte medium and the cell suspension was centrifuged at 1000 rpm for 10 minutes. The supernatant was removed and the centrifuged cell pellets were gently resuspended in TexMACS medium.

PBMC human cells in TexMACS medium were seeded in plates in the amount of 1×10 ⁵ per well in triplicate. Various concentrations of test compounds or diluent as control (DMSO, less than 0.5%) were added to the cell culture. Cells were stimulated using CytoStim (10 μl/ml) for 3 days in a humidified incubator, 5% CO ₂ at 37°C.

After incubation, the cell culture supernatant was collected and the particles were further removed by centrifugation. The content of human IL-17 in the supernatant was measured using a human IL-17 ELISA kit according to the manufacturer's protocol. IC ₅₀ values were determined using GraphPad Prism by plotting percent inhibition versus compound concentration. The IC ₅₀ values for the compounds of the examples are shown in Table I.

The above examples and description of the preferred embodiments should be considered as illustrations and not as limitations of the present invention, which is defined by the claims. Numerous variations and combinations of features given above can be used without deviating from the present invention, as indicated in the claims.

Claims (128)

1. Compound of formula (I)

or its tautomer, racemate, enantiomer, or a pharmaceutically acceptable salt thereof, where

is a single bond or a double bond; when

is a double bond, then

represents a single bond, R _a is absent and R _b represents a hydrogen atom; and when

is a double bond, then

represents a single bond, R _a represents a hydrogen atom and R _b is absent; ring A is selected from the group consisting of phenyl, piperidinyl and thienyl; R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of hydrogen, halogen and C _1-6 alkyl; R ₄ at each occurrence is independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano, and —NR ₁₁ R ₁₂ , with this specified C _1-6 alkoxy optionally substituted C _1-6 alkoxy groups in an amount of from one to three; R _5a is hydrogen; R _5b is selected from the group consisting of hydrogen, C _1-6 alkyl, hydroxy, C _1-6 hydroxyalkyl, -(CH ₂ ) _x NR ₁₀ COR ₉ , -NR ₁₀ COCH ₂ OR ₈ , -(CH ₂ ) _x C(O)OR ₈ , -(CH ₂ ) _x CONR ₁₁ R ₁₂ and -(CH ₂ ) _x NR ₁₁ R ₁₂ , said C _1-6 alkyl optionally substituted with one morpholinyl; or R _5a and R _5b together form

R ₆ is selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl and -NR ₁₁ R ₁₂ , wherein said C _1-6 alkyl is optionally substituted with one to three groups selected from the group consisting of C _1-6 alkoxy and 3-6 membered cycloalkyl; R ₇ in each occurrence independently represents a hydrogen or halogen atom; R ₈ is selected from the group consisting of hydrogen and C _1-6 alkyl; R ₉ is selected from the group consisting of C _1-6 alkyl and a 5-membered heteroaryl containing two heteroatoms representing N and O, said C _1-6 alkyl and 5-membered heteroaryl, each optionally substituted with C _{1- 6} alkyl groups in an amount of from one to three; R ₁₀ represents a hydrogen atom; R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, and 3-6 membered cycloalkyl; n is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and x is 0, 1, 2, 3, or 4. 2. The compound according to claim 1 or its tautomer, racemate, enantiomer or pharmaceutically acceptable salt thereof, having the structure of formula (Ia) or formula (Ib):

where R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in paragraph 1. 3. The compound of claim. 1 or its tautomer, racemate, enantiomer or its pharmaceutically acceptable salt having the structure of formula (II)

where

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in paragraph 1. 4. A compound according to claim 1 or 3, or a tautomer, racemate, enantiomer or pharmaceutically acceptable salt thereof, having the structure of formula (IIa)

where

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ and n are as defined in paragraph 1. 5. The compound according to p. 1 or its tautomer, racemate, enantiomer or its pharmaceutically acceptable salt having the structure of formula (III)

where

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in paragraph 1. 6. A compound according to claim 1 or 5, or a tautomer, racemate, enantiomer or pharmaceutically acceptable salt thereof, having the structure of formula (IIIa)

where R _4a and R _4b are each independently selected from the group consisting of a halogen atom, a hydrogen atom, C _1-6 alkyl and C _1-6 haloalkyl;

R _a , R _b , R ₁ - R ₃ , R _5a , R _5b , R ₆ , R ₇ and n are as defined in paragraph 1. 7. Connection according to any one of paragraphs. 1 and 2 or a tautomer, racemate, enantiomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

8. Compound of formula (IA)

or its tautomer, racemate, enantiomer, or a pharmaceutically acceptable salt thereof, wherein

is a single bond or a double bond; when

is a double bond, then

represents a single bond, R _a is absent and R _b represents a hydrogen atom; and when

is a double bond, then

represents a single bond, R _a represents a hydrogen atom and R _b is absent; R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of hydrogen, halogen and C _1-6 alkyl; R _5a and R _5b are hydrogen atoms; R ₆ is selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl and -NR ₁₁ R ₁₂ , said C _1-6 alkyl optionally being substituted with one 3-6 membered cycloalkyl; R ₇ at each occurrence is independently selected from the group consisting of hydrogen or halogen; R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, and 3-6 membered cycloalkyl; n is 0, 1, 2, 3, or 4. 9. The compound according to claim 8 or its tautomer, racemate, enantiomer or its pharmaceutically acceptable salt, where the compound is selected from the group consisting of:

10. A compound of formula (IC) or formula (ID) or a tautomer, racemate, enantiomer or a pharmaceutically acceptable salt thereof:

where R _a and R _b represents a hydrogen atom; ring A is phenyl or piperidinyl; R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of hydrogen, halogen and C _1-6 alkyl; R ₄ at each occurrence is independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy; R _5a is hydrogen; R _5b is selected from the group consisting of a hydrogen atom, C _1-6 hydroxyalkyl and -(CH ₂ ) _x C(O)OR ₈ ; R ₆ is C _1-6 alkyl or C _1-6 haloalkyl, said C _1-6 alkyl optionally being substituted with one 3-6 membered cycloalkyl; R ₇ at each occurrence is independently hydrogen or halogen; R ₈ represents a hydrogen atom or C _1-6 alkyl; n is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and x is 0, 1, 2, 3, or 4. 11. A compound according to claim 10 or a tautomer, racemate, enantiomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

12. A method for preparing a compound of formula (I), comprising the step of combining a compound of formula (IA) with a compound of formula (IB) under alkaline conditions in the presence of a catalyst:

where G is a leaving group, preferably boronic acid or borate; and ring A,

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in paragraph 1. 13. A process for preparing a compound of formula (I), comprising the step of cyclizing a compound of formula (IC) or formula (ID) by a nucleophilic substitution reaction under acidic conditions:

where is ring A,

R _a , R _b , R ₁ - R ₄ , R _5a , R _5b , R ₆ , R ₇ , n and s are as defined in paragraph 1. 14. Pharmaceutical composition having inhibitory activity against retinoid-associated orphan receptor gamma (RORγ) and containing as the main active ingredient the compound according to any one of paragraphs. 1-7, or a tautomer, racemate, enantiomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. 15. A method of inhibiting retinoid-associated orphan receptor gamma (RORγ), comprising contacting a biological sample containing RORγ with a compound according to any one of paragraphs. 1-7 or its tautomer, racemate, enantiomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14. 16. The use of a compound according to any one of paragraphs. 1-7 or its tautomer, racemate, enantiomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14 for the preparation of a medicament having RORγ inhibitory activity. 17. The use of a compound according to any one of paragraphs. 1-7 or its tautomer, racemate, enantiomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14 in the manufacture of a medicament for the treatment of RORγ-mediated diseases or conditions, where the disease or condition is selected from the group consisting of inflammatory and autoimmune diseases, with inflammatory and autoimmune diseases including arthritis, psoriasis, ankylosing spondylitis, autoimmune diabetes, multiple sclerosis, inflammatory bowel disease, Sjögren's syndrome, asthma, Kawasaki disease, Hashimoto's thyroiditis, pulmonary disease, glomerulonephritis, dry eye syndrome, asthma, atopic dermatitis, systemic lupus erythematosus and scleroderma. 18. The use of claim 17, wherein the arthritis is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, and juvenile idiopathic arthritis, and wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.