Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (rorγ) and pharmaceutical uses thereof

Abstract

The present invention relates to benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (RORy) and their pharmaceutical uses, in particular to benzimidazole derivatives of formula (I) as inhibitors of the retinoid-related orphan receptor gamma (RORy) protein, pharmaceutical compositions comprising the compounds, processes for their preparation, and the use of the compounds as therapeutic agents for the treatment of RORy-mediated diseases or conditions.

Description

[0001] This application is a divisional application of Chinese PCT patent application No. 2019800279561, entitled "A benzimidazole derivative as a modulator of retinoic acid-associated orphan receptor γ (RORγ) and its pharmaceutical use thereof", filed on May 3, 2019.

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Provisional Patent Application No. 62 / 666,312, filed May 3, 2018, pursuant to 35 U.S. SC §119(e), the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0004] This invention relates to modulators of retinoic acid-associated orphan receptor γ (RORγ) and their use as therapeutic agents for treating RORγ-mediated diseases or conditions, including various inflammatory and autoimmune diseases and cancer. Background Technology

[0005] Nuclear receptors are ligand-regulated transcription factors that regulate development, immunity, and cellular metabolism, and are among the major drug targets for human diseases. Retinoid-related orphan receptor gamma (RORγ) protein is a member of the NR1 subfamily of nuclear receptors. It exhibits a typical nuclear receptor domain structure, consisting of a DNA-binding domain, a ligand-binding domain, a hinge domain, and an activation function domain (Benoit G et al., Pharmacological Reviews, 58(4):798–836, 2006; Zhang, Y. et al., Acta Pharmacogica Sinica, 36:71-87, 2015). Unlike most other nuclear receptors that bind as dimers, RORγ recognizes and binds as a monomer. It binds to a specific DNA sequence, typically composed of TAAA / TNTAGGTCA, known as the ROR response element (RORE).

[0006] RORγ has two isoforms, RORγ1 and RORγ2, which are likely produced from the same RORC gene through alternative promoter selection (Villey I et al., Eur. J. Immunol., 29(12):4072-80, 1999). RORγ2 (also known as RORγt) is produced from the same mRNA as RORγ1, except that one alternative exon is replaced by two 5'-most exons, resulting in a truncated form of RORγ1. These two isoforms exhibit different tissue-specific expression patterns. RORγt is preferentially expressed in a variety of different cell types in the thymus and immune system, while RORγ1 is expressed in many tissues, including the thymus, lung, kidney, muscle, and liver.

[0007] RORγt is a major regulator of the development of helper T cell 17 (Th17 cells) (Ruan, Q. et al., J. Exp. Med., 208(11):2321-2333, 2011; Ivanov, II et al., Cell, 126:1121-1133, 2006). Th17 cells produce a variety of cytokines, including interleukin-17 (IL-17), which are known to enhance inflammatory processes. In addition, RORγt shows a key role in non-Th17 lymphoid cells expressing Thy1, SCA-1, and IL-23R proteins (Buonocore, S. et al., Nature, 464:1371-1375, 2010). RORγt plays an important role in secondary lymphoid tissue development, thymogenesis, and lymphocyte development (Jetten, AM, 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).

[0008] RORγ has been identified as a key mediator in the pathogenesis of various diseases, such as rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, Sjögren's syndrome, and asthma (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). Other diseases (such as chronic dry eye, Kawasaki disease, mucosal leishmaniasis, and Hashimoto's thyroiditis) are characterized by elevated Th17 proportions 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, VS 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 above examples, inhibition can be enhanced by simultaneously inhibiting 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.

[0009] This invention describes a series of novel compounds that exhibit effective inhibition of RORγ, thus providing potential therapeutic methods for RORγ-mediated diseases or conditions. Summary of the Invention

[0010] In one aspect, the present invention relates to compounds of formula (I):

[0011]

[0012] Or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0013] in:

[0014] Selected from single and double bonds, when When it is a double bond, then For a single bond, R a It does not exist and R b For hydrogen; when When it is a double bond, then For a single bond, R a It is hydrogen and R b It does not exist;

[0015] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0016] R1, R2, and R3 may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0017] Each R4 group may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR8, -C(O)OR8, -COR9, -NR 10 COR9, -S(O)2R9, -NR 10 S(O)2R9、-CONR 11 R 12 -NR 11 R 12 and -S(O)2NR 11 R 12 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups.

[0018] R 5a and R 5b They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cyano, amino, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR8, -NR 10 COR9, -NR 10 COCH2OR8、-(CH2) x C(O)OR8、-(CH2) x CONR 11 R 12 and -(CH2) x NR 11 R 12The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally selected from halogen, alkyl, alkenyl, alkoxy, cyano, amino, nitro, hydroxyl, and -CONR groups. 11 R 12 -NR 10 COR9, substituted with one or more groups of cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0019] Or R 5a and R 5b Together

[0020] R6 is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and NR. 11 R 12 The alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0021] Each R7 may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR8, -C(O)OR8, -COR9, -NR 10 COR9, -S(O)2R9, -NR 10 S(O)2R9、-CONR 11 R 12 -NR 11 R 12 and -S(O)2NR 11 R 12 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups.

[0022] R8 is selected from hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclic groups, wherein the alkyl, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen and alkoxy groups;

[0023] R9 is selected from hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0024] R10 Selected from hydrogen, alkyl, haloalkyl, cycloalkyl, and heterocyclic groups;

[0025] R 11 and R 12 The same or different, and each independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, -COR 13 aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0026] Or R 11 and R 12 Together with the nitrogen atoms to which they are attached, they form heterocyclic groups, wherein the heterocyclic groups have one or more heteroatoms selected from O, N and S, and are optionally substituted by one or more groups selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0027] R 13 The group is selected from hydrogen, alkyl, hydroxy, alkoxy, cycloalkyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0028] n is 0, 1, 2, 3 or 4;

[0029] s is 0, 1, 2, 3, or 4; and

[0030] x is 0, 1, 2, 3 or 4.

[0031] In another aspect, the present invention relates to compounds of formula (IA),

[0032]

[0033] Or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, which are intermediates used in the synthesis of compounds of formula (I),

[0034] in:

[0035] R a R b R1~R3, R 5a R 5bR6, R7 and n are as defined in equation (I).

[0036] In another aspect, the present invention relates to compounds of formula (IC) or formula (ID) as intermediates for the synthesis of compounds of formula (I), or tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0037]

[0038] in:

[0039] R a and R b It is hydrogen;

[0040] Ring A, R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (I).

[0041] In another aspect, the present invention relates to various methods for preparing compounds of formula (I).

[0042] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0043] In another aspect, the present invention relates to a method of using a therapeutically effective amount of a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, to inhibit retinoic acid-associated orphan receptor γ (RORγ) or treat retinoic acid-associated orphan receptor γ (RORγ) protein-mediated disease or condition in a subject.

[0044] Other aspects and advantages of the invention will be better understood through the following detailed description and the accompanying claims. Detailed Implementation

[0045] In one aspect, the present invention relates to compounds of formula (I):

[0046]

[0047] Or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0048] in:

[0049] Selected from single and double bonds, when When it is a double bond, then For a single bond, R a It does not exist and R b For hydrogen; when When it is a double bond, then For a single bond, R a It is hydrogen and R b It does not exist;

[0050] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0051] R1, R2, and R3 may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0052] Each R4 group may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR8, -C(O)OR8, -COR9, -NR 10 COR9, -S(O)2R9, -NR 10 S(O)2R9、-CONR 11 R 12 -NR 11 R 12 and -S(O)2NR 11 R 12 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups.

[0053] R 5a and R 5b They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cyano, amino, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR8, -NR 10 COR9, -NR 10 COCH2OR8、-(CH2) x C(O)OR8、-(CH2) x CONR 11 R 12 and -(CH2) x NR 11 R 12The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally selected from halogen, alkyl, alkenyl, alkoxy, cyano, amino, nitro, hydroxyl, and -CONR groups. 11 R 12 -NR 10 COR9, substituted with one or more groups of cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0054] Or R 5a and R 5b Together

[0055] R6 is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and NR. 11 R 12 The alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0056] Each R7 may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR8, -C(O)OR8, -COR9, -NR 10 COR9, -S(O)2R9, -NR 10 S(O)2R9、-CONR 11 R 12 -NR 11 R 12 and -S(O)2NR 11 R 12 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups.

[0057] R8 is selected from hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclic groups, wherein the alkyl, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen and alkoxy groups;

[0058] R9 is selected from hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0059] R10 Selected from hydrogen, alkyl, haloalkyl, cycloalkyl, and heterocyclic groups;

[0060] R 11 and R 12 The same or different, and each independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, -COR 13 aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0061] Or R 11 and R 12 Together with the nitrogen atoms to which they are attached, they form heterocyclic groups, wherein the heterocyclic groups have one or more heteroatoms selected from O, N and S, and are optionally substituted by one or more groups selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0062] R 13 The group is selected from hydrogen, alkyl, hydroxy, alkoxy, cycloalkyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each optionally substituted by one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0063] n is 0, 1, 2, 3 or 4;

[0064] s is 0, 1, 2, 3, or 4; and

[0065] x is 0, 1, 2, 3 or 4.

[0066] In some embodiments of the present invention, the compound of formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates or prodrugs, are compounds of formula (Ia) or (Ib):

[0067]

[0068] in:

[0069] R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (I).

[0070] In some embodiments of the present invention, in a compound of formula (I) or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring A is selected from phenyl, C 3-6 Cycloalkyl and 5- or 6-membered heteroaryl groups, preferably piperidinyl, phenyl, thienyl, furanyl and pyridinyl.

[0071] In some embodiments of the present invention, a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is a compound of formula (II):

[0072]

[0073] in:

[0074] R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (I).

[0075] In some embodiments of the present invention, the compound of formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically acceptable salts, solvates, or prodrugs, are compounds of formula (IIa):

[0076]

[0077] in:

[0078] R a R b R1~R4, R 5a R 5b R6, R7 and n are as defined in equation (I).

[0079] In some embodiments of the present invention, the compound of formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates or prodrugs, are compounds of formula (III):

[0080]

[0081] in:

[0082] R a R b R1~R4, R 5a R5b R6, R7, n and s are as defined in equation (I).

[0083] In some embodiments of the present invention, the compound of formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, are compounds of formula (IIIa):

[0084]

[0085] in:

[0086] R 4a and R 4b They may be the same or different, and each is independently selected from halogens, hydrogen, alkyl groups and haloalkyl groups;

[0087] R a R b R1~R3, R 5a R 5b R6, R7 and n are as defined in equation (I).

[0088] In some embodiments of the invention, in compounds of formula (I) or their tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or their pharmaceutically acceptable salts, solvates or prodrugs, each R4 may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -OR8 and -NR. 11 R 12 ;

[0089] R8, R 11 and R 12 As defined in equation (I).

[0090] In some embodiments of the invention, R1, R2 and R3 are the same or different in the compound of formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, and are each independently selected from hydrogen, halogens and alkyl groups.

[0091] In some embodiments of the invention, R is present in a compound of formula (I) or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 5a and R 5b They may be the same or different, and each is independently selected from hydrogen, hydroxyl, hydroxyalkyl, -OR8, -NR. 10 COR9, -NR 10COCH2OR8、-(CH2) x C(O)OR8、-(CH2) x CONR 11 R 12 and -(CH2) x NR 11 R 12 ;

[0092] Or R 5a and R 5b Together R8 to R 12 x is as defined in equation (I).

[0093] In some embodiments of the invention, in a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R6 is selected from alkyl, haloalkyl, cycloalkyl, heterocyclic, and -NR groups. 11 R 12 The alkyl group is optionally substituted with one or more groups selected from alkoxy and cycloalkyl groups.

[0094] In some embodiments of the present invention, R7 is selected from hydrogen, halogens and alkyl groups in the compound of formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof.

[0095] Typical compounds of the present invention include, but are not limited to, those mentioned above.

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] In another aspect, the present invention relates to compounds of formula (IA),

[0129]

[0130] Or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, which are intermediates used in the synthesis of compounds of formula (I),

[0131] in:

[0132] R a R b R1~R3, R 5a R 5b R6, R7 and n are as defined in equation (I).

[0133] In another aspect, the present invention relates to compounds of formula (IC) or formula (ID) or their tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof.

[0134]

[0135] in:

[0136] R a and R b It is hydrogen;

[0137] Ring A, R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (I).

[0138] In some embodiments of the present invention, in a compound of formula (IC) or formula (ID) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ring A is selected from phenyl, C 3-6 Cycloalkyl and 5- or 6-membered heteroaryl groups, preferably piperidinyl, phenyl, thienyl, furanyl and pyridinyl.

[0139] Typical intermediate compounds of the present invention include, but are not limited to, the compounds listed in the table below.

[0140]

[0141]

[0142]

[0143]

[0144] In another aspect, the present invention relates to a method for preparing a compound of formula (I), comprising the step of coupling a compound of formula (IA) with a compound of formula (IB) under alkaline conditions in the presence of a catalyst to obtain a compound of formula (I):

[0145]

[0146] in:

[0147] G is a leaving group, preferably a borate group or a borate ester group, more preferably...

[0148] Ring A, R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (I).

[0149] In another aspect, the present invention relates to a method for preparing a compound of formula (I), comprising the step of cyclizing a compound of formula (IC) or formula (ID) to obtain a compound of formula (I):

[0150]

[0151] in:

[0152] Ring A, R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (I).

[0153] In another aspect, the present invention relates to a method 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):

[0154]

[0155] in:

[0156] R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (II).

[0157] In another aspect, the present invention relates to a method for preparing a compound of formula (III), comprising the step of cyclizing a compound of formula (IIIC) or a compound of formula (IIID) to obtain a compound of formula (III):

[0158]

[0159] in:

[0160] R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (III).

[0161] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0162] In another aspect, the present invention relates to a method for inhibiting retinoic acid-associated orphan receptor γ (RORγ) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0163] In another aspect, the present invention relates to a method for treating a disease or condition mediated by retinoic acid-associated orphan receptor γ (RORγ) protein in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0164] In another aspect, the present invention relates to the use of a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for inhibiting RORγ.

[0165] In another aspect, the present invention relates to the use of a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for treating RORγ protein-mediated diseases or conditions.

[0166] In another aspect, the invention further relates to a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, used as a medicament.

[0167] In another aspect, the invention further relates to a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, used as a RORγ inhibitor.

[0168] In another aspect, the present invention further relates to a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, used as a medicament for treating RORγ protein-mediated diseases or conditions.

[0169] RORγ protein-mediated diseases or conditions include, but are not limited to, inflammation, autoimmune diseases, and cancer. Inflammatory and autoimmune diseases include, but are not limited to, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoarthritis, regional colitis, ulcerative colitis, ankylosing spondylitis, autoimmune diabetes, type I diabetes, autoimmune eye disease, autoimmune thyroid disease, type I autoimmune polyendocrine syndrome, type II autoimmune polyendocrine syndrome, multiple sclerosis, inflammatory bowel disease, inflammatory 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), lung diseases, glomerulonephritis, myocarditis, and thyroiditis. Adenitis, dry eye syndrome, uveitis, Behcet's disease, asthma, atopic dermatitis, contact dermatitis, allogeneic transplant rejection, polymyocitis, graft-versus-host disease, acne, ulcerative colitis, systemic lupus erythematosus, scleroderma, bronchitis, dermatomyositis, and allergic rhinitis; among which 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 tumors, ovarian tumors, peritoneal tumors, melanoma, solid tumors, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumors, head and neck tumors, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

[0170] definition

[0171] Unless otherwise stated, the terms used herein have the following meanings.

[0172] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably C1-C2. 12 Alkyl groups, more preferably C1-C6 alkyl groups, and sometimes more preferably C1-C4 alkyl groups. 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-methylpropyl, 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 group having 1 to 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-methylpropyl, 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, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic thio, oxo, carboxyl, and carboxylic acid ester groups.

[0173] "Alkylene" refers to an alkyl group in which one hydrogen atom is further substituted. Examples include methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-).

[0174] "Alkenyl" refers to an alkyl group as defined above, having at least two carbon atoms, preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms, and sometimes more preferably 2-4 carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. Alkenyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, and heterocyclic alkylthio.

[0175] "Cycloalkyl" refers to a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc. Polycyclic cycloalkyl groups include cycloalkyl groups having spirocyclic, fused, or bridged rings.

[0176] "Spirocycloalkyl" refers to a 5- to 20-membered polycyclic group in which rings are linked by a 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. It is preferably a 6- to 14-membered spirocycloalkyl, more preferably a 7- to 10-membered spirocycloalkyl. Depending on the number of common spiro atoms, spirocycloalkyl can be classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include, but are not limited to:

[0177]

[0178] "Fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, and one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably a 6- to 14-membered fused cycloalkyl, more preferably a 7- to 10-membered fused cycloalkyl. Depending on the number of constituent rings, fused cycloalkyl can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic fused cycloalkyl, more preferably bicyclic or tricyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl include, but are not limited to:

[0179]

[0180] "Bridged cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group, wherein each pair of rings in the system shares two atoms that are not directly connected. The rings may have one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably a 6- to 14-membered bridged cycloalkyl, more preferably a 7- to 10-membered bridged cycloalkyl. Depending on the number of constituent rings, bridged cycloalkyl can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic bridged cycloalkyl, more preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl include, but are not limited to:

[0181]

[0182] The cycloalkyl group comprises the aforementioned cycloalkyl group fused to an aryl, heteroaryl, or heterocyclic group, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups.

[0183] "Heterocyclic group" refers to a 3- to 20-membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, which has one or more ring atoms selected from N, O, and S(O). mThe heterocyclic group comprises heteroatoms (where m is an integer selected from 0 to 2), but does not contain -OO-, -OS-, and -SS- in the ring, and the remaining ring atoms are carbon atoms. Preferably, the heterocyclic group has 3 to 12 atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 6 atoms. Non-limiting examples of monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include heterocyclic groups having spirocyclic, fused, or bridged rings.

[0184] "Spirocycloheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which the rings are linked by a common carbon atom (called a spiro atom), wherein the rings have one or more ring atoms selected from N, O, and S(O). m The heteroatom is a carbon atom, and the remaining ring atoms are carbon atoms. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably a 6- to 14-membered spiroheterocyclic group, more preferably a 7- to 10-membered spiroheterocyclic group. Depending on the number of common spiro atoms, spiroheterocyclic groups can be classified as monospiroheterocyclic, bispiroheterocyclic, or multispiroheterocyclic groups, preferably monospiroheterocyclic or bispiroheterocyclic, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclic groups. Non-limiting examples of spiroheterocyclic groups include, but are not limited to:

[0185]

[0186] "Fused heterocyclic groups" refer to 5 to 20-membered polycyclic heterocyclic groups, in which each ring in the system shares an adjacent pair of atoms with another ring, and one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system, wherein the rings have one or more atoms selected from N, O, and S(O) as ring atoms. m The heteroatoms are selected from 0 to 2 (where m is an integer selected from 0 to 2), and the remaining ring atoms are carbon atoms; preferably, it is a 6- to 14-membered fused heterocyclic group, more preferably a 7- to 10-membered fused heterocyclic group. Depending on the number of constituent rings, fused heterocyclic groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include, but are not limited to:

[0187]

[0188] "Bridged heterocyclic groups" refer to 5- to 14-membered polycyclic heterocyclic groups in which each pair of rings shares two atoms that are not directly connected. The rings may have one or more double bonds, but none of the rings have a fully conjugated π-electron system. The rings have one or more atoms selected from N, O, and S(O) as ring atoms. m The heteroatom is selected from 0 to 2 (where m is an integer selected from 0 to 2), and the remaining ring atoms are carbon atoms; it is preferably a 6- to 14-membered bridged heterocyclic group, more preferably a 7- to 10-membered bridged heterocyclic group. Depending on the number of constituent rings, bridged heterocyclic groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclic groups include, but are not limited to:

[0189]

[0190] The heterocyclic group includes the aforementioned heterocyclic group fused to an aryl, heteroaryl, or cycloalkyl group, wherein the ring attached to the parent structure is a heterocyclic group. Non-limiting examples include, but are not limited to:

[0191] wait.

[0192] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups.

[0193] "Aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic group (i.e., each ring in the system shares a pair of adjacent carbon atoms with another ring in the system) having a fully conjugated π-electron system; it is preferably a 6- to 10-membered aryl group, more preferably phenyl and naphthyl, and most preferably phenyl. Aryl groups include those fused to heteroaryl, heterocyclic, or cycloalkyl groups, wherein the ring attached to the parent structure is an aryl group. Non-limiting examples include, but are not limited to:

[0194] Preferred

[0195] The aryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, and carboxylic acid ester groups.

[0196] "Heteroaryl" refers to a 5- to 14-membered aryl group having 1 to 4 heteroatoms selected from O, S, and N as ring atoms, with the remaining ring atoms being carbon atoms; preferably a 5- to 10-membered heteroaryl group, more preferably a 5- or 6-membered heteroaryl group, such as imidazolyl, furanyl, thiophene, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, pyrazinyl, etc., preferably imidazolyl, pyrazolyl, pyrimidinyl, or thiadiazolyl, more preferably pyrazolyl. Heteroaryl groups include the aforementioned heteroaryl groups fused to an aryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is a heteroaryl group. Non-limiting examples include, but are not limited to:

[0197] Preferred

[0198] The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, and carboxylic acid ester groups.

[0199] "Alkoxy" refers to an -O- (alkyl) or -O- (unsubstituted cycloalkyl) group, wherein the alkyl group is as defined above. Non-limiting examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc. Alkoxy groups may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, and carboxylic acid ester groups.

[0200] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0201] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, where the alkoxy group is as defined above.

[0202] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0203] "Hydroxy group" refers to the -OH group.

[0204] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0205] "Amino" refers to the -NH2 group.

[0206] "Cyano" refers to the -CN group.

[0207] "Nitro" refers to the -NO2 group.

[0208] "Oxytochemical" means =O.

[0209] "Carboxyl group" refers to the -C(O)OH group.

[0210] "Carboxylic acid ester group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0211] "Optional" or "optionally" means that the event or environment described below may but not necessarily occur, and the description includes the possibility that the event or environment may or may not occur. For example, "optionally alkyl-substituted heterocyclic group" means that an alkyl group may but not necessarily be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0212] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions. Those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond (such as an alkene).

[0213] For any substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and carboxylic acid ester groups mentioned throughout the application, any alkyl group is preferably C1-C6 alkyl, sometimes more preferably C1-C4 alkyl; any alkenyl group is preferably C2-C6 alkenyl, sometimes more preferably C1-C4 alkenyl; any alkynyl group is preferably C2-C6 alkynyl, sometimes more preferably C1-C4 alkynyl; any cycloalkyl group is preferably C3-C6 cycloalkyl; any heterocyclic group is preferably 5 to 10-membered heterocyclic, sometimes more preferably 5 or 6-membered heterocyclic; any aryl group is preferably C6-C6 alkyl. 10 Aryl, more preferably phenyl; any heteroaryl is a 5- to 10-membered heteroaryl, sometimes more preferably a 5- or 6-membered heteroaryl; any carboxylic acid ester group is preferably a C1-C4 alkyl ester group, sometimes more preferably a methyl ester group or an ethyl ester group.

[0214] "Pharmaceutical composition" refers to a mixture of one or more compounds according to the invention, or their physiologically / pharmaceuticalally acceptable salts or prodrugs, and other chemical components (such as physiologically / pharmaceuticalally acceptable carriers and excipients). The purpose of a pharmaceutical composition is to facilitate the administration of the compound to an organism and the absorption of the active ingredient, thereby enabling it to exert its biological activity.

[0215] The compounds disclosed herein can exist as pharmaceutically acceptable salts or solvates. Pharmaceutically acceptable salts can be any acid addition salt formed from a compound of Formula I and a pharmaceutically acceptable acid (such as phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, etc.).

[0216] "Solvate" refers to the physical bond between the compound of the present invention and one or more, preferably one to three solvent molecules (whether organic or inorganic). This physical bond includes hydrogen bonds. In some cases, the solvate can be separated, for example, when one or more, preferably one to three solvent molecules are incorporated into the crystal lattice of a crystalline solid. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are well known in the art.

[0217] "Therapeutic effective amount" refers to the total amount of each active ingredient sufficient to demonstrate a meaningful patient benefit (e.g., a sustained reduction in viral load). When applied to a single active ingredient administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to the combined amount of active ingredients (whether combined, administered sequentially, or administered simultaneously) that produce a therapeutic effect.

[0218] "Pharmaceutical acceptable" means that compounds, materials, compositions, and / or dosage forms are suitable for contact with a patient's tissues within reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications with a reasonable benefit / risk ratio, and are effective for their intended use.

[0219] "Patients" or "subjects" include humans and other mammals, including but not limited to cats, dogs, cows, horses, etc.

[0220] "Treatment" or "treatment" means: (i) suppressing a disease, symptom, or condition, i.e., preventing its development; and (ii) alleviating a disease, symptom, or condition, i.e. causing the remission of the disease, symptom, and / or condition. In some embodiments, the invention also includes using a compound according to any of the disclosed embodiments for the prevention of the occurrence of a disease, symptom, or condition in a patient who may be susceptible to the disease, symptom, and / or condition but has not yet been diagnosed with the disease, symptom, and / or condition.

[0221] Unless otherwise defined, any terminology in this application shall have the ordinary meaning as understood by one of ordinary skill in the art. All references cited herein are incorporated herein by reference in their entirety.

[0222] Synthesis method of the present invention

[0223] To achieve the objectives of this invention, the following synthetic technique is employed:

[0224] A method for preparing the compound of formula (I) of the present invention or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0225] Option 1

[0226]

[0227] Step 1: Compound (I-1) is subjected to a condensation reaction with compound (I-2) under alkaline conditions to obtain compound (I-3) or compound (I-3').

[0228] Step 2: The compound of formula (I-3) or the compound of formula (I-3') undergoes an intramolecular reaction in the presence of an acid to obtain the compound of formula (IA).

[0229] Step 3: Compound (IA) is coupled with compound (IB) under alkaline conditions in the presence of a catalyst to obtain compound (I).

[0230] in:

[0231] X is a halogen, preferably bromine;

[0232] G is a leaving group, preferably a borate group or a borate ester group, more preferably...

[0233] Ring A, R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (I).

[0234] The alkaline reagents include organic bases and inorganic bases, wherein the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and wherein the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, or cesium carbonate.

[0235] Phosphine palladium-based 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]palladium dichloride, triphenylphosphine, and tetra(triphenylphosphine)palladium.

[0236] The above reaction is preferably carried out in a solvent. The solvents used include, but are 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.

[0237] A method for preparing the compound of formula (I) of the present invention or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0238] Option 2

[0239]

[0240] Compound of formula (IC) or compound of formula (ID) is subjected to an intramolecular reaction in the presence of an acid to obtain compound of formula (I);

[0241] in:

[0242] Ring A, R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (I).

[0243] Reagents that provide acidic conditions 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.

[0244] The above reaction is preferably carried out in a solvent. The solvents used include, but are 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.

[0245] A method for preparing compounds of formula (II) of the present invention, or tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0246] Option 3

[0247]

[0248] Compound of formula (IIC) or compound of formula (IID) is subjected to an intramolecular reaction in the presence of an acid to obtain compound of formula (II);

[0249] in:

[0250] R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (II).

[0251] Reagents that provide acidic conditions 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.

[0252] The above reaction is preferably carried out in a solvent. The solvents used include, but are 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.

[0253] A method for preparing compounds of formula (III) of the present invention, or tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0254]

[0255] Compound (IIIC) or compound (IIID) is subjected to an intramolecular reaction in the presence of an acid to obtain compound (III).

[0256] in:

[0257] R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in equation (III).

[0258] Reagents that provide acidic conditions 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.

[0259] The above reaction is preferably carried out in a solvent. The solvents used include, but are 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.

[0260] The invention will be further described through the following embodiments, but these embodiments should not be considered as limiting the scope of the invention.

[0261] Example

[0262] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR was determined using a Bruker AVANCE-400 or AVANCE III 500. Solvents included deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as an internal standard. NMR chemical shifts (δ) were expressed as 10⁻⁶. -6 (ppm) is given.

[0263] High performance liquid chromatography (HPLC) was performed on an Agilent 1200DAD high performance liquid chromatograph (Sunfire C18 150×4.6mm column) and a Waters 2695-2996 high performance liquid chromatograph (Gimini C18 150×4.6mm column).

[0264] Chiral high-performance liquid chromatography (HPLC) was performed on an LC-10A vp (Shimadzu) or an SFC-analytical (Berger Instruments Inc.).

[0265] MS was determined by a SHIMADZU (ESI) liquid chromatography-mass spectrometry system (manufacturer: Shimadzu, model: LC-20AD, LCMS-2020).

[0266] The known raw materials of this invention are prepared by conventional synthetic methods in the art, or purchased from Aldrich Chemical Company, Fisher Scientific, or Combi-Blocks, etc.

[0267] Unless otherwise specified, the reaction shall be carried out under a nitrogen or argon atmosphere.

[0268] The terms "nitrogen atmosphere" or "argon atmosphere" refer to a reaction flask containing 1L of nitrogen or argon gas.

[0269] The term "hydrogen atmosphere" refers to a reaction vessel containing a 1L hydrogen balloon.

[0270] Unless otherwise stated, the reaction temperature refers to room temperature and ranges from 20°C to 30°C.

[0271] The reaction process was monitored by thin-layer chromatography (TLC). The developing solvent system consisted of: A: dichloromethane and methanol, and B: hexane and ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compound. The elution system used for purifying the compound by column chromatography, TLC, and the CombiFlash rapid preparation system consisted of: A: dichloromethane and methanol, and B: hexane and ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compound, and sometimes a small amount of a basic reagent such as ammonia or an acidic reagent such as acetic acid was added.

[0272] The final compound was purified by elution using either an aqueous solution of 0.075% TFA and a MeOH solution of 0.075% TFA or a CH3CN solution of 0.075% TFA, via a Shimadzu (LC-20AD, SPD20A) preparative HPLC (Phenomenex Gemini-NX 5uM C18 21.2×100mm column).

[0273] Use the following abbreviations:

[0274] TEA is triethylamine.

[0275] DIPEA is N,N-diisopropylethylamine.

[0276] EDCI is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride.

[0277] HOBt is 1-hydroxybenzotriazole hydrate.

[0278] DCM stands for dichloromethane.

[0279] HBTU is O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0280] DMF is N,N-dimethylformamide.

[0281] NMR stands for proton nuclear magnetic resonance, and

[0282] MS stands for mass spectrometry, where (+) indicates positive mode. It usually provides the absorption of M+1 (or M+H), where M = molecular weight.

[0283] Prep HPLC is a preparative high-performance liquid chromatography.

[0284] Example 1

[0285] Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-phenyl-1H-benzimidazole

[0286]

[0287] Step 1: Preparation of ethyl 2-(4-(ethylthio)phenyl)acetate

[0288]

[0289] To a solution of 2-(4-mercaptophenyl)acetic acid (3.4 g, 0.02 mol) in N,N-dimethylformamide (DMF) (20 mL), K₂CO₃ (11 g, 0.04 mol) and iodoethane (6.4 g, 0.06 mol) were added. The reaction mixture was stirred at room temperature (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 obtain the desired product, ethyl [4-(ethylthio)phenyl]acetate (3.6 g, 80%), as a pale yellow solid. MS(+)ES: 225 (M+H) + .

[0290] Step 2: Preparation of ethyl 2-(4-(ethylsulfonyl)phenyl)acetate

[0291]

[0292] Add ethyl 2-(4-(ethylthio)phenyl)acetate (5.5 g, 0.0245 mol) and dichloromethane (82.5 mL) to a 250 mL round-bottom flask. Cool the reaction mixture to 0 °C. At 0 °C, add m-chloroperoxybenzoic acid (12.6 g, 0.073 mol) to the same flask. Stir the reaction mixture at room temperature for 12 hours. Filter the resulting suspension through a diatomaceous earth mat. Wash the filtrate with water. Separate the organic layer, wash successively with saturated sodium bicarbonate solution and brine, and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure to obtain the crude product. Purify the crude product by rapid column chromatography with hexane / ethyl acetate to obtain the title compound in an oily form, which solidifies upon standing (4.7 g, 75%), MS(+)ES: 257 (M+H). + .

[0293] Step 3: Preparation of 2-(4-(ethylsulfonyl)phenyl)acetic acid

[0294]

[0295] Add ethyl 2-(4-(ethylsulfonyl)phenyl)acetate (2.56 g, 0.01 mol) and ethanol (18 mL) to a 50 mL round-bottom flask. Add an aqueous solution of sodium hydroxide (1.42 g, 0.0355 mol in 18 mL of water) to the same flask. Stir the reaction mixture at room temperature for 12 hours. Evaporate the volatiles under reduced pressure. Acidify the residue to pH 5.0 with 1 N HCl and extract with ethyl acetate (15 mL × 3). Separate and combine the organic layers, wash with brine and dry with sodium sulfate. Evaporate the solvent under reduced pressure to obtain the title compound as a colorless oil that solidifies upon standing (2.0 g, 85%), MS(+)ES: 229 (M+H). + .

[0296] Step 4: Preparation of 2-bromo-1,3-dichloro-4,5-dinitrobenzene

[0297]

[0298] Under stirring, 2-bromo-1,3-dichloro-5-nitrobenzene (2.7 g, 0.01 mol) was carefully added to a pre-prepared solution of fuming nitric acid (10 ml) and concentrated sulfuric acid (10 ml). After the addition was complete, the mixture was heated in a water bath to 50 °C for two hours until the reaction was complete (LCMS monitoring). The mixture was then cooled and poured onto ice. The yellow precipitate was collected by filtration, thoroughly washed with water, and dried to obtain a yellow solid product (3 g, 95%), MS(+)ES: 314 (M+H). + .

[0299] Step 5: Preparation of 4-bromo-3,5-dichlorophenyl-1,2-diamine

[0300]

[0301] 2-Bromo-1,3-dichloro-4,5-dinitrobenzene (3.1 g, 0.01 mol) and iron powder (4.4 g, 0.08 mol) were suspended in a mixture of AcOH (50 mL) and EtOH (100 mL) under stirring. The reaction mixture was slowly heated to mild reflux and stirred for 1 hour. The reaction mixture was then cooled to room temperature, and diethyl ether (50 mL) and water (50 mL) were added. 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 NaHCO3 (2 x 30 mL), H2O (2 x 30 mL), and brine (1 x 30 mL), then dried over MgSO4, filtered, and concentrated under vacuum to dryness to obtain the title compound (2.0 g, 78%) as a grayish-white solid. MS(+)ES: 255 (M+H) +.

[0302] Step 6: Preparation of N-(6-amino-3-bromo-2,4-dichlorophenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0303]

[0304] 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 in portions over 30 minutes to a cold DMF (10 mL) solution (ice-water bath) of 4-bromo-3,5-dichlorophenyl-1,2-diamine (2.55 g, 0.01 mol) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (step 3, 2.28 g, 0.01 mol). After the addition was complete, the mixture was stirred for 60 minutes, then heated to room temperature and stirred overnight. The mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic phase was separated, dried over MgSO4, and filtered. The solvent was evaporated under reduced pressure to obtain a grayish-white solid, which was purified by rapid chromatography with hexane / ethyl acetate to obtain a grayish-white solid product (3.5 g, 75%), MS(+)ES: 466 (M+H). + .

[0305] Step 7: Preparation of 5-bromo-4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-1H-benzimidazole

[0306]

[0307] N-(6-amino-3-bromo-2,4-dichlorophenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide (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, followed by cooling. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate, and dried over MgSO4. The product was purified by rapid chromatography with hexane / ethyl acetate to obtain a white solid (2.7 g, 80%), MS(+)ES: 448 (M+H). + .

[0308] Step 8: Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-phenyl-1H-benzimidazole

[0309]

[0310] A mixture of 5-bromo-4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-1H-benzi[d]imidazole (step 7) (448 mg, 1 mmol), phenylboronic acid (363 mg, 3 mmol), tris(dibenzylacetone)dipalladium(O) (60 mg), tri-tert-butylphosphine tetrafluoroborate (60 mg), and sodium carbonate (2 M solution) in 1,4-dioxane (3 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 directly loaded onto an ISCO solid column and subjected to rapid chromatography with hexane / ethyl acetate to obtain a white solid product of 320 mg (72% yield), MS(+)ES: 445 (M+H). + .

[0311] Example 2

[0312] Preparation of (4,6-dichloro-5-phenyl-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0313]

[0314] Step 1: Preparation of (4,6-dichloro-5-phenyl-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyl ketone

[0315]

[0316] 4,6-Dichloro-2-(4-(ethylsulfonyl)benzyl)-5-phenyl-1H-benzi[d]imidazole (Example 1) (4.5 mg, 0.01 mmol) was dissolved in 1,4-dioxane (0.5 mL), and MnO2 (5 mg, 0.058 mmol) was added at room temperature. The mixture was stirred and heated to 60 °C for 60 minutes until the reaction was complete (LCMS monitoring). After cooling, the solid was filtered off, and the product was purified by rapid chromatography with hexane / ethyl acetate to obtain a white solid (4 mg, 87%), MS(+)ES: 459 (M+H). + .

[0317] Step 2: Preparation of (4,6-dichloro-5-phenyl-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0318]

[0319] (4,6-Dichloro-5-phenyl-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyl ketone (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 until complete. The product was purified by preparative HPLC using elution system C to obtain a white solid (3.3 mg, 82%), MS(+)ES: 461(M+H). + .

[0320] Example 3

[0321] Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-(trifluoromethyl)phenyl)-1H-benzimidazole

[0322]

[0323] According to the synthetic route of Example 1, the starting material phenylboronic acid in step 8 was replaced with 2-trifluoromethylphenylboronic acid to obtain the title compound as a white solid, MS(+)ES: 513(M+H). + .

[0324] Example 4

[0325] Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0326]

[0327] 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 of anhydrous DMSO. Paraformaldehyde (0.6 mg, 0.02 mmol) was added with stirring, followed by powdered sodium ethoxide (1.2 mg, 0.02 mmol). The mixture was stirred at room temperature for 60 minutes. The mixture was treated with a small amount of dilute hydrochloric acid and purified directly by preparative HPLC using elution system C to obtain a white solid product (3.8 mg, 70% yield), MS(+)ES: 559 (M+H). + .

[0328] Example 5

[0329] Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0330]

[0331] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 545 (M+H). + .

[0332] Example 6

[0333] Preparation of 2-(4,6-dichloro-5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0334]

[0335]

[0336] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 505(M+H). + .

[0337] Example 7

[0338] Preparation of (4,6-dichloro-5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0339]

[0340] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 491(M+H). + .

[0341] Example 8

[0342] Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-isopropoxyphenyl)-1H-benzimidazole

[0343]

[0344] Except that 2-isopropoxyphenylboronic acid was used instead of phenylboronic acid in step 8, the compound was prepared using essentially the same range as in Example 1 to obtain a white solid product, MS(+)ES: 503(M+H). + .

[0345] Example 9

[0346] Preparation of 2-(4,6-dichloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0347]

[0348] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 533(M+H). + .

[0349] Example 10

[0350] Preparation of (4,6-dichloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0351]

[0352] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 519(M+H). + .

[0353] Example 11

[0354] Preparation of 2-(4,6-dichloro-5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0355]

[0356] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 493 (M+H). + .

[0357] Example 12

[0358] Preparation of (4,6-dichloro-5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0359]

[0360] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 479 (M+H). + .

[0361] Example 13

[0362] Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-(methoxymethoxy)phenyl)-1H-benzimidazole

[0363]

[0364] Except that 2-methoxymethoxyphenylboronic acid was used instead of phenylboronic acid in step 8, the compound was prepared using essentially the same range as in Example 1 to obtain a white solid product, MS(+)ES: 505(M+H). + .

[0365] Example 14

[0366] Preparation of 2-(4,6-dichloro-5-(2-methoxymethoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0367]

[0368] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 535(M+H). + .

[0369] Example 15

[0370] Preparation of (4,6-dichloro-5-(2,5-dichlorophenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0371]

[0372] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 534 (M+H). + .

[0373] Example 16

[0374] Preparation of 4,6-dichloro-5-(2-ethoxyphenyl)-2-(4-(ethylsulfonyl)benzyl)-1H-benzimidazole

[0375]

[0376] Except that 2-ethoxyphenylboronic acid was used instead of phenylboronic acid in step 8, the compound was prepared using essentially the same range as in Example 1 to obtain a white solid product, MS(+)ES: 489(M+H). + .

[0377] Example 17

[0378] Preparation of 2-(4,6-dichloro-5-(2-ethoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0379]

[0380] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 519(M+H). + .

[0381] Example 18

[0382] Preparation of (4,6-dichloro-5-(2-ethoxyphenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0383]

[0384] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 505(M+H). + .

[0385] Example 19

[0386] Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-(2-methoxyethoxy)phenyl)-1H-benzimidazole

[0387]

[0388] Except that (2-(2-methoxyethoxy)phenyl)boronic acid was used instead of phenylboronic acid in step 8, the compound was prepared using essentially the same range as in Example 1 to obtain a white solid product, MS(+)ES: 519(M+H). + .

[0389] Example 20

[0390] Preparation of 2-(4,6-dichloro-5-(2-(2-methoxyethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0391]

[0392] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 549(M+H). + .

[0393] Example 21

[0394] Preparation of (4,6-dichloro-5-(2-(2-methoxyethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0395]

[0396] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 535 (M+H). + .

[0397] Example 22

[0398] Preparation of 2-(4,6-dichloro-2-(1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-1H-benzo[d]imidazol-5-yl)benzyl nitrile

[0399]

[0400] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 500 (M+H). + .

[0401] Example 23

[0402] Preparation of 2-(4,6-dichloro-2-((4-(ethylsulfonyl)phenyl)(hydroxy)methyl)-1H-benzo[d]imidazol-5-yl)benzyl nitrile

[0403]

[0404] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 486 (M+H). + .

[0405] Example 24

[0406] Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(thiophen-3-yl)-1H-benzimidazole

[0407]

[0408] Except that 3-thiopheneboronic acid was used instead of phenylboronic acid in step 8, the compound was prepared using essentially the same range as in Example 1 to obtain a white solid product, MS(+)ES: 451(M+H). + .

[0409] Example 25

[0410] Preparation of 2-(4,6-dichloro-5-(thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0411]

[0412] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 481(M+H). + .

[0413] Example 26

[0414] Preparation of (4,6-dichloro-5-(thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0415]

[0416] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 467(M+H). + .

[0417] Example 27

[0418] Preparation of 2-(4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-1H-benzo[d]imidazol-5-yl)-N,N-dimethylaniline

[0419]

[0420] Except that (2-(dimethylamino)phenyl)boronic acid was used instead of phenylboronic acid in step 8, the compound was prepared using essentially the same range as in Example 1 to obtain a white solid product, MS(+)ES: 488(M+H). + .

[0421] Example 28

[0422] Preparation of 4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-2-(4-(ethylsulfonyl)benzyl)-1H-benzimidazole

[0423]

[0424] Except that 2-difluoromethoxyphenylboronic acid pinacol ester was used instead of phenylboronic acid in step 8, the compound was prepared using essentially the same range as in Example 1 to obtain a white solid product, MS(+)ES: 511(M+H). + .

[0425] Example 29

[0426] Preparation of 2-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0427]

[0428] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 541(M+H). + .

[0429] Example 30

[0430] Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0431]

[0432] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 527(M+H). + .

[0433] Example 31

[0434] Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-(2,2,2-trifluoroethoxy)phenyl)-1H-benzimidazole

[0435]

[0436] Except that 4,4,5,5-tetramethyl-2-(2-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborane was used instead of phenylboronic acid in step 8, the compound was prepared using essentially the same range as in Example 1 to obtain a white solid product, MS(+)ES: 543(M+H). + .

[0437] Example 32

[0438] Preparation of 2-(4,6-dichloro-5-(2-(2,2,2-trifluoroethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0439]

[0440] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 573 (M+H). + .

[0441] Example 33

[0442] Preparation of (4,6-dichloro-5-(2-(2,2,2-trifluoroethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0443]

[0444] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 559 (M+H). + .

[0445] Example 34

[0446] Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-(3,3,3-trifluoropropyl)phenyl)-1H-benzimidazole

[0447]

[0448] Except that 4,4,5,5-tetramethyl-2-(2-(3,3,3-trifluoropropyl)phenyl)-1,3,2-dioxaborane was used instead of phenylboronic acid in step 8, the compound was prepared using essentially the same range as in Example 1 to obtain a white solid product, MS(+)ES: 541(M+H). + .

[0449] Example 35

[0450] Preparation of (4,6-dichloro-5-(2-(3,3,3-trifluoropropyl)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0451]

[0452] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 557(M+H). + .

[0453] Example 36

[0454] Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzyl)-5-(2-isopropylphenyl)-1H-benzimidazole

[0455]

[0456] Except that 2-isopropylphenylboronic acid was used instead of phenylboronic acid in step 8, the compound was prepared using essentially the same range as in Example 1 to obtain a white solid product, MS(+)ES: 487(M+H). + .

[0457] Example 37

[0458] Preparation of 2-(4,6-dichloro-5-(2-isopropylphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0459]

[0460] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 517(M+H). + .

[0461] Example 38

[0462] Preparation of (E,Z)-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyl ketone oxime

[0463]

[0464] A mixture of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl) methyl ketone (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 to dryness under reduced pressure. The product was purified by rapid chromatography with hexane / ethyl acetate to obtain a white solid (42 mg, 78%), MS(+)ES: 540 (M+H). + .

[0465] Example 39

[0466] Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methylamine

[0467]

[0468]

[0469] A mixture of (E,Z)-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyl ketone oxime (42 mg, 0.078 mmol) was dissolved in anhydrous THF (2 mL). A 1 M borane THF solution (4 mL) was added to this solution, and the mixture was stirred overnight at room temperature. The volatile solvent was evaporated under reduced pressure, and the residue was purified directly by preparative HPLC using elution system C to obtain a white solid (18 mg, 45%), MS(+)ES: 526 (M+H). + .

[0470] Example 40

[0471] Preparation of N-((4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyl)acetamide

[0472]

[0473] Acetyl chloride solution (in DCM) (1 eq) was added to a cold solution of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methylamine (Example 39) (4 mg, 0.0076 mmol) and triethylamine (1 eq) in dichloromethane (0.5 mL) (ice-water bath). The mixture was stirred for 30 minutes, and then the dichloromethane was evaporated. The residue was separated directly by preparative HPLC using elution system C to obtain a white solid (2.6 mg, 42%), MS(+)ES: 568 (M+H). + .

[0474] Example 41

[0475] Preparation of N-((4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyl)-2-methoxyacetamide

[0476]

[0477]

[0478] A white solid product was obtained by applying a method similar to that used in Example 40, MS(+)ES: 598 (M+H). + .

[0479] Example 42

[0480] 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

[0481]

[0482] A white solid product was obtained by applying a method similar to that used in Example 40, MS(+)ES: 649 (M+H). + .

[0483] Example 43

[0484] Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methylamine

[0485]

[0486] A white solid product was obtained by applying a method similar to that used in Example 39, MS(+)ES: 544 (M+H). + .

[0487] Example 44

[0488] Preparation of N-((4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyl)acetamide

[0489]

[0490] A white solid product was obtained by applying a method similar to that used in Example 40, MS(+)ES: 586 (M+H). + .

[0491] Example 45

[0492] Preparation of 4,6-dichloro-2-(4-(methylsulfonyl)benzyl)-5-(2-(trifluoromethyl)phenyl)-1H-benzimidazole

[0493]

[0494] The compound was prepared using essentially the same methods as in Example 1 to obtain a white solid product, MS(+)ES: 499 (M+H). + .

[0495] Example 46

[0496] Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(methylsulfonyl)phenyl)ethanol

[0497]

[0498] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 529(M+H). + .

[0499] Example 47

[0500] Preparation of 4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-2-(4-(methylsulfonyl)benzyl)-1H-benzimidazole

[0501]

[0502] The compound was prepared using essentially the same methods as in Example 28 to obtain a white solid product, MS(+)ES: 497 (M+H). + .

[0503] Example 48

[0504] Preparation of 2-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(methylsulfonyl)phenyl)ethanol

[0505]

[0506] The compound was prepared by essentially the same method as in Example 29 to obtain a white solid product, MS(+)ES: 527(M+H). + .

[0507] Example 49

[0508] Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(methylsulfonyl)phenyl)methanol

[0509]

[0510] The product was prepared using essentially the same method as in Example 30 to obtain a white solid product, MS(+)ES: 513(M+H). + .

[0511] Example 50

[0512] Preparation of 4,6-dichloro-2-(4-(propylsulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

[0513]

[0514] The compound was prepared using essentially the same methods as in Example 1 to obtain a white solid product, MS(+)ES: 543 (M+H). + .

[0515] Example 51

[0516] Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(propylsulfonyl)phenyl)ethanol

[0517]

[0518] The compound was prepared by essentially the same method as in Example 6 to obtain a white solid product, MS(+)ES: 573 (M+H). + .

[0519] Example 52

[0520] Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(propylsulfonyl)phenyl)methanol

[0521]

[0522] The product was prepared using essentially the same method as in Example 7 to obtain a white solid product, MS(+)ES: 559 (M+H). + .

[0523] Example 53

[0524] Preparation of 4,6-dichloro-2-(4-((2-methoxyethyl)sulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

[0525]

[0526] The compound was prepared using substantially the same methods as in Example 1 to obtain a white solid product, MS(+)ES: 559 (M+H). + .

[0527] Example 54

[0528] Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((2-methoxyethyl)sulfonyl)phenyl)ethanol

[0529]

[0530] The compound was prepared by essentially the same method as in Example 6 to obtain a white solid product, MS(+)ES: 589(M+H). + .

[0531] Example 55

[0532] Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-((2-methoxyethyl)sulfonyl)phenyl)methanol

[0533]

[0534] The product was prepared using essentially the same method as in Example 7 to obtain a white solid product, MS(+)ES: 575 (M+H). + .

[0535] Example 56

[0536] Preparation of 4,6-dichloro-2-(4-(methylsulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzimidazole

[0537]

[0538] The compound was prepared using essentially the same methods as in Example 1 to obtain a white solid product, MS(+)ES: 515(M+H). + .

[0539] Example 57

[0540] Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(methylsulfonyl)phenyl)ethanol

[0541]

[0542] The compound was prepared by essentially the same method as in Example 6 to obtain a white solid product, MS(+)ES: 545(M+H). + .

[0543] Example 58

[0544] Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(methylsulfonyl)phenyl)methanol

[0545]

[0546] The product was prepared using essentially the same method as in Example 7 to obtain a white solid product, MS(+)ES: 531(M+H). + .

[0547] Example 59

[0548] Preparation of 4,6-dichloro-2-(4-((2,2,2-trifluoroethyl)sulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzimidazole

[0549]

[0550] The compound was prepared using essentially the same methods as in Example 1 to obtain a white solid product, MS(+)ES: 583 (M+H). + .

[0551] Example 60

[0552] 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

[0553]

[0554] The compound was prepared by essentially the same method as in Example 6 to obtain a white solid product, MS(+)ES: 613(M+H). + .

[0555] Example 61

[0556] Preparation of 4,6-dichloro-2-(4-((2-fluoroethyl)sulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

[0557]

[0558] The compound was prepared using substantially the same methods as in Example 1 to obtain a white solid product, MS(+)ES: 547 (M+H). + .

[0559] Example 62

[0560] Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((2-fluoroethyl)sulfonyl)phenyl)ethanol

[0561]

[0562] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 577(M+H). + .

[0563] Example 63

[0564] Preparation of 4,6-dichloro-2-(4-((2-fluoroethyl)sulfonyl)benzyl)-5-(2-(trifluoromethyl)phenyl)-1H-benzimidazole

[0565]

[0566] The compound was prepared using essentially the same methods as in Example 1 to obtain a white solid product, MS(+)ES: 531(M+H). + .

[0567] Example 64

[0568] Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((2-fluoroethyl)sulfonyl)phenyl)ethanol

[0569]

[0570] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 561(M+H). + .

[0571] Example 65

[0572] Preparation of 4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-2-(4-((trifluoromethyl)sulfonyl)benzyl)-1H-benzimidazole

[0573]

[0574] The compound was prepared using essentially the same methods as in Example 1 to obtain a white solid product, MS(+)ES: 553 (M+H). + .

[0575] Example 66

[0576] Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzimidazole

[0577]

[0578] The compound was prepared using essentially the same methods as in Example 1 to obtain a white solid product, MS(+)ES: 555 (M+H). + .

[0579] Example 67

[0580] Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[0581]

[0582] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 585 (M+H). + .

[0583] Example 68

[0584] Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

[0585]

[0586] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 571(M+H). + .

[0587] Example 69

[0588] Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-(trifluoromethyl)phenyl)-1H-benzimidazole

[0589]

[0590] The compound was prepared using essentially the same methods as in Example 1 to obtain a white solid product, MS(+)ES: 539 (M+H). + .

[0591] Example 70

[0592] Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[0593]

[0594] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 569 (M+H). + .

[0595] Example 71

[0596] Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

[0597]

[0598] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 555 (M+H). + .

[0599] Example 72

[0600] Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-(difluoromethoxy)phenyl)-1H-benzimidazole

[0601]

[0602] The compound was prepared using essentially the same methods as in Example 1 to obtain a white solid product, MS(+)ES: 537 (M+H). + .

[0603] Example 73

[0604] Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[0605]

[0606] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 567(M+H). + .

[0607] Example 74

[0608] Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[0609]

[0610] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 519(M+H). + .

[0611] Example 75

[0612] Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)methanol

[0613]

[0614] The product was prepared using essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 505(M+H). + .

[0615] Example 76

[0616] Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

[0617]

[0618]

[0619] Step 1: Preparation of methyl 2-(2-fluoro-4-nitrophenyl)acetate

[0620]

[0621] Concentrated sulfuric acid (1 ml) was added to a methanol (20 ml) solution of 4.0 g (0.02 mol) 2-(2-fluoro-4-nitrophenyl)acetic acid. The solution was heated to reflux overnight. After cooling, the mixture was concentrated to a minimum and partitioned between diethyl ether (30 ml) and water. The ether phase was separated and washed with a saturated sodium bicarbonate solution (30 ml). The organic phase was then separated again, washed with water, and dried over MgSO4. The solid was filtered off and the solvent was evaporated to obtain a product (3.8 g, 88%) of sufficient purity for the next step, MS(+)ES:214(M+H). + .

[0622] Step 2: Preparation of methyl 2-(4-amino-2-fluorophenyl)acetate

[0623]

[0624] To a 50 mL round-bottom flask, add methyl 2-(2-fluoro-4-nitrophenyl)acetate (3.8 g, 0.018 mol) and ethyl acetate (30 mL). Add 10% palladium / activated carbon (0.5 g) to the same flask. Stir the reaction mixture under a hydrogen atmosphere (using a gasket) for 5 hours. Filter the reaction mixture through a diatomaceous earth pad. Evaporate the filtrate under reduced pressure to obtain the title compound (2.8 g, 86%), MS(+)ES: 184 (M+H). + .

[0625] Step 3: Preparation of 2-(2-fluoro-4-mercaptophenyl)acetic acid

[0626]

[0627] At 0°C, a solution of sodium nitrite (1.06 g, 0.015 mol) in 16 ml of water was added dropwise to a 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, while stirring. After the addition was complete, the reaction mixture was stirred at the same temperature for another 60 minutes. Then, at room temperature, this cold diazonium salt solution was added dropwise to a mixture of potassium O-ethyl dithiocarbonate (2.8 g), 50 ml of water, and 16 ml of 2 M sodium carbonate solution, and heated to 45°C until gas expulsion ceased. The mixture was cooled to room temperature, and the pH was adjusted to 1 with concentrated hydrochloric acid. The oily xanthate ester was extracted with diethyl ether. The solvent was evaporated to obtain a deep red liquid (methyl 2-(4-(ethoxythiocarbonyl)thio)-2-fluorophenyl)acetate (3.5 g), MS(+)ES: 288(M+H). + .

[0628] The oily product was dissolved in ethanol (10 ml), and a solution of KOH (1.8 g) in water (10 ml) was added. The mixture was heated to reflux overnight. The mixture was concentrated to a minimum and acidified with concentrated HCl. The product was extracted with ethyl acetate (10 ml x 3). The combined organic phases were dried over MgSO4, and the solid was filtered off. The solvent was evaporated to obtain the crude product (2.5 g, 89%), MS(+)ES: 187 (M+H). + .

[0629] Step 4: Preparation of ethyl 2-(4-(ethylthio)-2-fluorophenyl)

[0630]

[0631] 2-(2-fluoro-4-mercaptophenyl)acetic acid (2.5 g, 0.013 mol) was dissolved in DMF (25 mL), and then cesium carbonate (13.0 g, 0.039 mol) was added. The mixture was stirred for 10 minutes, then iodoethane (6 g, 0.039 mol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (30 mL). The organic phase was separated and dried over MgSO4. The solid was filtered off, and the solvent was evaporated to dryness. The product was purified by rapid chromatography with hexane / ethyl acetate to obtain an oil (2.8 g, 86%), MS(+)ES: 243(M+H). + .

[0632] Step 5: Preparation of ethyl 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetate

[0633]

[0634] 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 in an ice bath. MCPBA (6.0 g) was added in portions. The reaction mixture was stirred overnight at room temperature, and then filtered to remove solids. The filtrate was washed with saturated sodium carbonate solution (30 mL × 2), water (30 mL), and brine (30 mL), dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography with hexane / ethyl acetate to obtain the target compound ethyl 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetate (2.0 g, 64%), MS(+)ES: 275 (M+H). + .

[0635] Step 6: Preparation of 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetic acid

[0636]

[0637] A solution of 1.0 g of NaOH in 10 mL of water was added to a solution of 2.0 g of ethyl acetate (2.0 g, 7.3 mmol) in ethanol (30 mL). The reaction mixture was stirred overnight at room temperature. The ethanol was removed under reduced pressure, and 20 mL of water was added. The aqueous phase was acidified to pH 1 with 6 M HCl and then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried over magnesium sulfate, and concentrated to obtain an oil that solidified upon standing (1.6 g, 90%). MS(+)ES: 247 (M+H) + .

[0638] Step 7: Preparation of N-(6-amino-3-bromo-2,4-dichlorophenyl)-2-(4-(ethylsulfonyl)-2-fluorophenyl)acetamide

[0639]

[0640] 1-Ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride (1.0 g, 5 mmol) and benzotriazol-1-ol (0.7 g, 5 mmol) were added fractionally to a cold solution of 4-bromo-3,5-dichlorophenyl-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 10 mL of DMF (ice-water bath). After the addition was complete, the mixture was stirred for 60 minutes, then heated to room temperature and stirred overnight. The mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic phase was separated, dried over MgSO4, and filtered. The solvent was evaporated under reduced pressure to obtain a grayish-white solid, which was purified by rapid chromatography with hexane / ethyl acetate to obtain a solid product (1.7 g, 70%), MS(+)ES: 484 (M+H). + .

[0641] Step 8: Preparation of 5-bromo-4,6-dichloro-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-1H-benzimidazole

[0642]

[0643] 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), and the mixture was heated to 100 °C for 4 hours, followed by cooling. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate, and dried over MgSO4. The product was purified by rapid chromatography with hexane / ethyl acetate to obtain a white solid (1.2 g, 73%), MS(+)ES: 466 (M+H). + .

[0644] Step 9: Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzimidazole

[0645]

[0646] A mixture of 5-bromo-4,6-dichloro-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-1H-benzi[d]imidazole (step 8) (47 mg, 0.1 mmol), 2-trifluoromethoxyphenylboronic acid (62 mg, 0.3 mmol), tris(dibenzylacetone)dipalladium(0) (6 mg), tri-tert-butylphosphine tetrafluoroborate (6 mg), and sodium carbonate (2 M solution) in 1,4-dioxane (0.6 mL) was degassed and heated to 100 °C for 1 hour under microwave irradiation. Volatile solvents were removed under reduced pressure. The residue was directly loaded onto an ISCO solid column and subjected to rapid chromatography with hexane / ethyl acetate to obtain a white solid product (38 mg, 70% yield), MS(+)ES: 547 (M+H). + .

[0647] Example 77

[0648] Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)-2-fluorophenyl)ethanol

[0649]

[0650] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 577(M+H). + .

[0651] Example 78

[0652] Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)-2-fluorophenyl)methanol

[0653]

[0654] The compound was prepared by essentially the same method as in Example 2 to obtain a white solid product, MS(+)ES: 563 (M+H). + .

[0655] Example 79

[0656] Preparation of (4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)-2-fluorophenyl)methanol

[0657]

[0658] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 547(M+H). + .

[0659] Example 80

[0660] Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)-2-fluorobenzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzimidazole

[0661]

[0662] The compound was prepared by a method substantially similar to that used in Example 76 to obtain a white solid product, MS(+)ES: 573 (M+H). + .

[0663] Example 81

[0664] Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)-2-fluorophenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[0665]

[0666] The compound was prepared by a method substantially similar to that used in Example 77 to obtain a white solid product, MS(+)ES: 603(M+H). + .

[0667] Example 82

[0668] Preparation of (4-((cyclopropylmethyl)sulfonyl)-2-fluorophenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

[0669]

[0670] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 589 (M+H). + .

[0671] Example 83

[0672] Preparation of 4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-1H-benzimidazole

[0673]

[0674] The compound was prepared by replacing 2-trifluoromethoxyphenylboronic acid with 2-difluorophenylboronic acid in step 9, using essentially the same method as in Example 76, to obtain a white solid product, MS(+)ES: 529(M+H). + .

[0675] Example 84

[0676] Preparation of 2-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)-2-fluorophenyl)ethanol

[0677]

[0678] The compound was prepared by a method substantially similar to that used in Example 77 to obtain a white solid product, MS(+)ES: 559 (M+H). + .

[0679] Example 85

[0680] Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)-2-fluorophenyl)methanol

[0681]

[0682] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 545 (M+H). + .

[0683] Example 86

[0684] Preparation of 4,6-dichloro-2-(2-chloro-4-(ethylsulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

[0685]

[0686] The compound was prepared by a method substantially similar to that in Example 76 to obtain a white solid product, MS(+)ES: 563 (M+H). + .

[0687] Example 87

[0688] Preparation of 2-(2-chloro-4-(ethylsulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[0689]

[0690] The compound was prepared by a method substantially similar to that used in Example 77 to obtain a white solid product, MS(+)ES: 593 (M+H). + .

[0691] Example 88

[0692] Preparation of (2-chloro-4-(ethylsulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

[0693]

[0694] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 579 (M+H). + .

[0695] Example 89

[0696] Preparation of 4,6-dichloro-2-(2-chloro-4-(ethylsulfonyl)benzyl)-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazole

[0697]

[0698] The compound was prepared by a method substantially similar to that in Example 76 to obtain a white solid product, MS(+)ES: 545 (M+H). + .

[0699] Example 90

[0700] Preparation of 4,6-dichloro-2-(2-chloro-4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzimidazole

[0701]

[0702] The compound was prepared by a method substantially similar to that in Example 76 to obtain a white solid product, MS(+)ES: 589 (M+H). + .

[0703] Example 91

[0704] Preparation of 2-(2-chloro-4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[0705]

[0706] The compound was prepared by a method substantially similar to that used in Example 77 to obtain a white solid product, MS(+)ES: 619(M+H). + .

[0707] Example 92

[0708] Preparation of (2-chloro-4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

[0709]

[0710] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 605(M+H). + .

[0711] Example 93

[0712] Preparation of 4,6-dichloro-5-(2-chlorophenyl)-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-1H-benzimidazole

[0713]

[0714] The compound was prepared by a method substantially similar to that in Example 76 to obtain a white solid product, MS(+)ES: 505 (M+H). + .

[0715] Example 94

[0716] Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-chlorophenyl)-1H-benzo[d]imidazol-2-yl)methanol

[0717]

[0718] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 521(M+H). + .

[0719] Example 95

[0720] Preparation of 2-(4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-1H-benzo[d]imidazol-5-yl)benzyl nitrile

[0721]

[0722] The compound was prepared by a method substantially similar to that used in Example 76 to obtain a white solid product, MS(+)ES: 496 (M+H). + .

[0723] Example 96

[0724] Preparation of 2-(4,6-dichloro-2-(1-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-hydroxyethyl)-1H-benzo[d]imidazol-5-yl)benzyl nitrile

[0725]

[0726] The compound was prepared by a method substantially similar to that in Example 77 to obtain a white solid product, MS(+)ES: 526(M+H). + .

[0727] Example 97

[0728] Preparation of 2-(4,6-dichloro-2-((4-((cyclopropylmethyl)sulfonyl)phenyl)(hydroxy)methyl)-1H-benzo[d]imidazol-5-yl)benzyl nitrile

[0729]

[0730] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 512(M+H). + .

[0731] Example 98

[0732] Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)-2-fluorobenzyl)-5-(2-(difluoromethoxy)phenyl)-1H-benzimidazole

[0733]

[0734] The compound was prepared by a method substantially similar to that in Example 76 to obtain a white solid product, MS(+)ES: 555 (M+H). + .

[0735] Example 99

[0736] Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)-2-fluorophenyl)-2-(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[0737]

[0738] The compound was prepared by a method substantially similar to that in Example 77 to obtain a white solid product, MS(+)ES: 585 (M+H). + .

[0739] Example 100

[0740] Preparation of (4-((cyclopropylmethyl)sulfonyl)-2-fluorophenyl)(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

[0741]

[0742] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 571(M+H). + .

[0743] Example 101

[0744] Preparation of 4,6-dichloro-2-(2-chloro-4-(methylsulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzimidazole

[0745]

[0746] The compound was prepared by a method substantially similar to that in Example 76 to obtain a white solid product, MS(+)ES: 549 (M+H). + .

[0747] Example 102

[0748] Preparation of 2-(2-chloro-4-(methylsulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[0749]

[0750] The compound was prepared by a method substantially similar to that used in Example 77 to obtain a white solid product, MS(+)ES: 579 (M+H). + .

[0751] Example 103

[0752] Preparation of (2-chloro-4-(methylsulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

[0753]

[0754] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 565 (M+H). + .

[0755] Example 104

[0756] Preparation of 4,6-dichloro-2-(4-((isopropylsulfonyl)benzyl)-5-(2-(trifluoromethoxy)phenyl)-1H-benzimidazole

[0757]

[0758] The compound was prepared by a method substantially similar to that used in Example 76 to obtain a white solid product, MS(+)ES: 543 (M+H). + .

[0759] Example 105

[0760] Preparation of 2-(4-((isopropyl)sulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[0761]

[0762] The compound was prepared by a method substantially similar to that used in Example 77 to obtain a white solid product, MS(+)ES: 573 (M+H). + .

[0763] Example 106

[0764] Preparation of (4-((isopropyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

[0765]

[0766] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 559 (M+H). + .

[0767] Example 107

[0768] Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((isopropylsulfonyl)phenyl)ethanol

[0769]

[0770] The compound was prepared by essentially the same method as in Example 4 to obtain a white solid product, MS(+)ES: 557(M+H). + .

[0771] Example 108

[0772] Preparation of 2-(4-(ethylsulfonyl)benzyl)-4,6-difluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

[0773]

[0774] Step 1: Preparation of N-(4-bromo-3,5-difluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide

[0775]

[0776] KNO3 was added in a single step to a chilled (ice water) solution of 4-bromo-3,5-difluoroaniline (2 g, 0.01 mol) in 10 mL of trifluoroacetic anhydride. The reaction mixture was then heated to room temperature overnight with stirring. The solvent was evaporated to dryness, and the residue was treated with ethyl acetate, washed with saturated sodium bicarbonate solution and water, and dried over MgSO4. The solid was filtered off, and the solvent was evaporated. The product was purified by rapid chromatography with hexane / ethyl acetate to obtain a grayish-white solid (1.8 g, 51%), MS(+)ES: 349 (M+H). + .

[0777] Step 2: Preparation of 4-bromo-3,5-difluoro-2-nitroaniline

[0778]

[0779] A mixture of K₂CO₃ (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 hours. After cooling, water (50 mL) was added, and the precipitate was collected by filtration, thoroughly washed with water, and dried under vacuum to obtain a grayish-white solid product (1.4 g, 98%), which was used directly for the next step without purification. MS(+)ES: 253 (M+H) + .

[0780] Step 3: Preparation of 4-bromo-3,5-difluorophenyl-1,2-diamine

[0781]

[0782] 4-Bromo-3,5-difluoro-2-nitroaniline (2.5 g, 0.01 mol) and iron powder (4.4 g, 0.08 mol) were suspended in a mixture of AcOH (50 mL) and EtOH (100 mL) under stirring. The reaction was slowly heated to reflux and stirred for 1 hour. The reaction was cooled to room temperature, and 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 NaHCO3 (2 x 30 mL), H2O (2 x 30 mL), and brine (1 x 30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to dryness to obtain the title compound (1.6 g, 71%) as a white solid. MS(+)ES: 223(M+H) + .

[0783] Step 4: Preparation of N-(6-amino-3-bromo-2,4-difluorophenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide

[0784]

[0785] 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 in portions over 30 minutes to a cold DMF (10 ml) solution (ice-water bath) of 4-bromo-3,5-difluorophenyl-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). After the addition was complete, the mixture was stirred at 0–5 °C for 60 minutes, then heated to room temperature and stirred overnight. The mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic phase was separated, dried over MgSO4, and filtered. The solvent was evaporated under reduced pressure to obtain a grayish-white solid, which was purified by rapid chromatography with hexane / ethyl acetate to obtain a solid product (3.5 g, 80%), MS(+)ES: 433 (M+H). + .

[0786] Step 5: Preparation of 5-bromo-2-(4-(ethylsulfonyl)benzyl)-4,6-difluoro-1H-benzo[d]imidazole

[0787]

[0788] 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, followed by cooling. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate, and dried over MgSO4. The product was purified by rapid chromatography with hexane / ethyl acetate to obtain a white solid (2.8 g, 85%), MS(+)ES: 415 (M+H). + .

[0789] Step 6: Preparation of 2-(4-(ethylsulfonyl)benzyl)-4,6-difluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole

[0790]

[0791] A 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 mmol), tris(dibenzylacetone)dipalladium(0) (6 mg), tri-tert-butylphosphine tetrafluoroborate (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 directly loaded onto a rapid solid-state column and subjected to rapid chromatography with hexane / ethyl acetate to obtain a white solid product (34 mg, 68% yield), MS(+)ES: 497 (M+H). + .

[0792] Example 109

[0793] Preparation of 2-(4,6-difluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0794]

[0795] The compound was prepared by a method substantially similar to that used in Example 77 to obtain a white solid product, MS(+)ES: 527(M+H). + .

[0796] Example 110

[0797] Preparation of (4,6-difluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0798]

[0799] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 513(M+H). + .

[0800] Example 111

[0801] Preparation of 2-(4-(ethylsulfonyl)benzyl)-4,6-difluoro-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole

[0802]

[0803] Except that 2-trifluoromethylphenylboronic acid was used instead of 2-trifluoromethoxyphenylboronic acid in step 6, the compound was prepared by essentially the same method as in Example 91 to obtain a white solid product, MS(+)ES: 481(M+H). + .

[0804] Example 112

[0805] Preparation of 2-(4,6-difluoro-5-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0806]

[0807] The compound was prepared by a method substantially similar to that used in Example 92 to obtain a white solid product, MS(+)ES: 461(M+H). + .

[0808] Example 113

[0809] Preparation of (4,6-difluoro-5-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanol

[0810]

[0811] The compound was prepared by a method substantially similar to that in Example 93 to obtain a white solid product, MS(+)ES: 459 (M+H). + .

[0812] Example 114

[0813] Preparation of 2-(4,6-difluoro-5-phenyl-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0814]

[0815] The compound was prepared by a method substantially similar to that used in Example 92 to obtain a white solid product, MS(+)ES: 443(M+H). + .

[0816] Example 115

[0817] Preparation of 2-(4-(ethylsulfonyl)benzyl)-4,6-dimethyl-5-(2-(trifluoromethyl)phenyl)-1H-benzimidazole

[0818]

[0819] The compound was prepared by the same method described in Example 108 to obtain a white solid product, MS(+)ES: 473 (M+H). + .

[0820] Example 116

[0821] Preparation of 2-(4,6-dimethyl-5-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0822]

[0823] The compound was prepared by a method substantially similar to that in Example 77 to obtain a white solid product, MS(+)ES: 503(M+H). + .

[0824] Example 117

[0825] Preparation of 2-(4-(ethylsulfonyl)phenyl)-2-(5-(2-methoxyphenyl)-4,6-dimethyl-1H-benzo[d]imidazol-2-yl)ethanol

[0826]

[0827] The compound was prepared by a method substantially similar to that used in Example 77 to obtain a white solid product, MS(+)ES: 465 (M+H). + .

[0828] Example 118

[0829] Preparation of (4-(ethylsulfonyl)phenyl)(5-(2-methoxyphenyl)-4,6-dimethyl-1H-benzo[d]imidazol-2-yl)methanol

[0830]

[0831] The compound was prepared by a method substantially similar to that in Example 78 to obtain a white solid product, MS(+)ES: 451(M+H). + .

[0832] Example 119

[0833] Preparation of 2-(6-chloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0834]

[0835] The compound was prepared by a method substantially similar to that in Example 4 to obtain a white solid product, MS(+)ES: 525(M+H). + .

[0836] Example 120

[0837] Preparation of 2-(4-(ethylsulfonyl)phenyl)-2-(6-fluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[0838]

[0839] The compound was prepared by a method substantially similar to that in Example 4 to obtain a white solid product, MS(+)ES: 509(M+H). + .

[0840] Example 121

[0841] Preparation of (4-(ethylsulfonyl)phenyl)(6-fluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methanol

[0842]

[0843] The compound was prepared by a method substantially similar to that in Example 2 to obtain a white solid product, MS(+)ES: 495 (M+H). + .

[0844] Example 122

[0845] Preparation of N-cyclopropyl-4-((4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)benzenesulfonamide

[0846]

[0847] Step 1: Preparation of 2-(4-(chlorosulfonyl)phenyl)acetic acid

[0848]

[0849] 2-Phenylacetic acid (5 g, 36.724 mmol) was added dropwise to chlorosulfonic acid (35 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour, then stirred overnight at room temperature. After the reaction was complete, 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 MgSO4. The solid was filtered off, and the solvent was evaporated under reduced pressure to obtain a grayish-white solid of the target compound (6.8 g, 78%), MS(+)ES: 235 (M+H). + .

[0850] Step 2: Preparation of 2-(4-(N-cyclopropylaminosulfonyl)phenyl)acetic acid

[0851]

[0852] Cyclopropylamine (0.076 mL, 1.1 mmol) was added to a solution of 2-(4-(chlorosulfonyl)phenyl)acetic acid (234 mg, 1.0 mmol) and i-Pr2NEt (0.52 mL, 2.86 mmol) in CH2Cl2 (10 mL) under stirring. The mixture was stirred overnight at room temperature, diluted with EtOAc (80 mL), washed with 5% HCl aqueous solution (2 × 10 mL) and brine (10 mL), and dried over MgSO4. The solvent was removed, leaving a gelatinous solid product (180 mg, 70%). MS(+)ES: 256 (M+H) + .

[0853] Step 3: Preparation of N-(2-amino-4-bromo-3,5-dichlorophenyl)-2-(4-(N-cyclopropylaminosulfonyl)phenyl)acetamide

[0854]

[0855] To a DMF solution of 2-(4-(N-cyclopropylaminosulfonyl)phenyl)acetic acid (255 mg, 1 mmol), 4-bromo-3,5-dichlorophenyl-1,2-diamine (255 mg, 1 mmol), HOBt (135 mg, 1 mmol), and triethylamine (202 mg, 2 mmol) were added, followed by the addition of EDCI (191 mg, 1 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes, allowed to reach 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 MgSO4. The solvent was evaporated to obtain a brownish-yellow solid (490 mg, 99% yield), which was used directly for the next step without purification. MS(+)ES:492(M+H) + .

[0856] Step 4: Preparation of 4-((5-bromo-4,6-dichloro-1H-benzo[d]imidazol-2-yl)methyl)-N-ethylbenzenesulfinamide

[0857]

[0858] A solution of N-(2-amino-4-bromo-3,5-dichlorophenyl)-2-(4-(N-cyclopropylaminosulfonyl)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 (910 mL), washed with saturated sodium bicarbonate solution and brine, and dried over MgSO4. The ethyl acetate was evaporated, leaving a solid, which was purified by rapid chromatography using hexane / ethyl acetate (containing 10% MeOH) to obtain 288 mg of the product as a white solid (60% yield). MS(+)ES: 474 (M+H) + .

[0859] Step 5: Preparation of N-cyclopropyl-4-((4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)benzenesulfonamide (Example 164)

[0860]

[0861] 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(dibenzylacetone)dipalladium(O) (24 mg), tri-tert-butylphosphine tetrafluoroborate (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 directly loaded onto an ISCO solid column and subjected to rapid chromatography with hexane / ethyl acetate to obtain a white solid product of 83 mg (30% yield), MS(+)ES: 556 (M+H). + .

[0862] Example 123

[0863] Preparation of N-cyclopropyl-4-(1-(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-hydroxyethyl)benzenesulfonamide

[0864]

[0865] Paraformaldehyde (0.6 mg, 0.02 mmol) was added to a solution of 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), 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 elution system C to obtain 3.8 mg of the product as a white solid (66% yield), MS(+)ES: 586 (M+H). + .

[0866] Example 124

[0867] Preparation of 2-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanol

[0868]

[0869] Step 1: Preparation of cyclopropyl methyl 2-(4-((cyclopropylmethyl)thio)phenyl)acetic acid

[0870]

[0871] To a solution of (4-mercaptophenyl)acetic acid (3.4 g, 0.02 mol) in N,N-dimethylformamide (DMF) (20 ml), K₂CO₃ (11 g, 0.08 mol) and (bromomethyl)cyclopropane (8.1 g, 0.06 mol) were added. The reaction mixture was stirred at room temperature. 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 obtain the desired product. MS(+)ES: 277 (M+H) + .

[0872] Step 2: Preparation of cyclopropyl methyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid

[0873]

[0874] To a 250 mL round-bottom flask, add 6.76 g (0.0245 mol) of cyclopropyl methyl acetate and 82.5 mL of dichloromethane. Cool the reaction mixture to 0 °C. At 0 °C, add 12.6 g (0.073 mol) of m-chloroperoxybenzoic acid to the same flask. Stir the reaction mixture at room temperature for 12 hours. Filter the resulting suspension through a diatomaceous earth mat. Wash the filtrate with water. Separate the organic layer, wash three times with saturated sodium bicarbonate solution, then wash with brine and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure to obtain the crude product. Purify the crude product by rapid column chromatography with hexane / ethyl acetate to obtain the title compound in oil form, MS(+)ES: 309(M+H). + .

[0875] Step 3: Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid

[0876]

[0877] To a 50 mL round-bottom flask, add 3.08 g (0.01 mol) of cyclopropyl methyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid and 18 mL of ethanol. To the same flask, add an aqueous solution of sodium hydroxide (1.42 g, 0.0355 mol in 18 mL of water). Stir the reaction mixture at room temperature for 12 hours. Evaporate the volatiles under reduced pressure. Acidify the residue to pH 5.0 with 1 NHCl and extract with ethyl acetate (15 mL × 3). Separate and combine the organic layers, wash with brine, and dry over sodium sulfate. Evaporate the solvent under reduced pressure to obtain a colorless, oily title compound that solidifies (85%) upon standing. MS(+)ES: 255 (M+H) + .

[0878] Step 4: Preparation of N-(2-amino-5-bromo-4-chlorophenyl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetamide

[0879]

[0880] 1-Ethyl-(3-(3-dimethylamino)propyl)carbodiimide hydrochloride (2.0 g, 0.01 mol) and hydroxybenzotriazol-1-ol (1.35 g, 0.01 mol) were added in portions over 30 minutes to a cold DMF (10 mL) solution (ice-water bath) of 4-bromo-5-chlorophenyl-1,2-diamine (2.21 g, 0.01 mol) and 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid (step 3, 2.54 g, 0.01 mol). After the addition was complete, the mixture was stirred for 60 minutes, then heated to room temperature and stirred overnight. The mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic phase was separated, dried over MgSO4, and filtered. The solvent was evaporated under reduced pressure to obtain a grayish-white solid, which was purified by rapid chromatography with hexane / ethyl acetate to obtain a grayish-white solid product (75%), MS(+)ES: 457 (M+H). + .

[0881] Step 5: Preparation of 5-bromo-6-chloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-1H-benzimidazole

[0882]

[0883] 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, then cooled. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc, washed with saturated sodium bicarbonate, and dried over MgSO4. The product was purified by rapid chromatography with hexane / ethyl acetate to obtain 2.6 g (80%) of a white solid, MS(+)ES: 439 (M+H). + .

[0884] Step 6: Preparation of 6-chloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-isopropoxyphenyl)-1H-benzimidazole

[0885]

[0886] A mixture of 5-bromo-6-chloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-1H-benzi[d]imidazole (step 5) (439 mg, 1 mmol), (2-isopropoxyphenyl)boronic acid (495 mg, 3 mmol), tris(dibenzylacetone)dipalladium(0) (60 mg), tri-tert-butylphosphine tetrafluoroborate (60 mg), and sodium carbonate (2 ml, 2 M solution) in 1,4-dioxane (8 ml) was degassed, sealed, and heated to 100 °C for 60 min under microwave irradiation. Volatile solvents were removed under reduced pressure. The residue was directly loaded into a DCM column, loaded onto an ISCO solids column, and subjected to rapid chromatography with hexane / ethyl acetate to obtain a white solid product of 355 mg (72% yield), MS(+)ES: 495 (M+H). + .

[0887] Step 7: Preparation of 2-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanol

[0888]

[0889] 6-Chloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-isopropoxyphenyl)-1H-benzimidazole (49.5 mg, 0.1 mmol) was dissolved in 1 mL of anhydrous DMSO. Paraformaldehyde (6 mg, 0.2 mmol) was added with stirring, followed by powdered sodium ethoxide (12 mg, 0.2 mmol). The mixture was stirred at room temperature for 60 minutes (monitored by LCMS). The mixture was then treated with EtOAc (10 mL) and washed successively with saturated NH4Cl solution and water. The organic phase was dried over MgSO4. The product was purified by rapid chromatography with hexane / EtOAc (10% 2N NH3 in MeOH) to give 37 mg of white solid (70% yield, Example 124). MS(+)ES: 525 (M+H) + .

[0890] Examples 124-1 and 124-2

[0891] 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)

[0892]

[0893] Chiral separation was performed as described in Example 124 (separation conditions: Dasail 20*200mm, 5μm; mobile phase: ethanol / hexane = 1:4 (v / v); flow rate: 30mL / min), the corresponding fractions were collected and concentrated under reduced pressure to obtain the title compound (400mg, 400mg).

[0894] Single-configuration compounds (shorter retention time)

[0895] MS(+)ES:525(M+H) +

[0896] Chiral HPLC analysis: retention time 6.296 min, chiral purity: 100% (column: OZ PhenomenexLux Cellulose-2 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 3:2 (v / v));

[0897] 1¹H NMR (400 mHz, DMSO-d6): 12.53 (s, 1H), 7.87 (d, 8.0 Hz, 2H), 7.71 (s, 0.6H) (due to tautomerization of benzimidazole), 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 ,8.0Hz,1H),6.98(t,8.0Hz,1H),5.16(t,4.0Hz,1H),4.59-4.43(m,2H),4.29-4.15(m,1H),4.06-3.95( m,1H),3.23(d,8.0Hz,2H),1.12(d,4.0Hz,6H),0.89-0.75(m,1H),0.49-0.39(m,2H),0.18-0.09(m,2H).

[0898] Single-configuration compounds (longer retention time)

[0899] MS(+)ES:525(M+H) +

[0900] Chiral HPLC analysis: retention time 11.837 min, chiral purity: 98.875% (column: OZ Phenomenex Lux Cellulose-2 150*4.6 mm, 5 μm; mobile phase: ethanol / hexane = 3:2 (v / v));

[0901] 1 ¹H NMR (400 mHz, DMSO-d6): 12.53 (s, 1H), 7.87 (d, 8.0 Hz, 2H), 7.71 (s, 0.6H) (due to tautomerization of benzimidazole), 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 ,8.0Hz,1H),6.98(t,8.0Hz,1H),5.16(t,4.0Hz,1H),4.59-4.43(m,2H),4.29-4.15(m,1H),4.06-3.95( m,1H),3.23(d,8.0Hz,2H),1.12(d,4.0Hz,6H),0.89-0.75(m,1H),0.49-0.39(m,2H),0.18-0.09(m,2H).

[0902] Example 125

[0903] Preparation of 4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-2-(4-(ethylsulfonyl)benzyl)-1H-benzimidazole

[0904]

[0905] Step 1: Preparation of 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitroaniline

[0906]

[0907] 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 to 108 °C overnight in a sealed container. After cooling, the reaction mixture was partitioned between water (30 mL) and ethyl acetate (10 mL). The organic phase was separated and dried over MgSO4. The solid was filtered off, the solvent was evaporated, and the residue was purified directly by rapid chromatography with hexane / ethyl acetate to obtain 280 mg of a yellow solid (85% yield), MS(+)ES: 326 (M+H). + .

[0908] Step 2: Preparation of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine

[0909]

[0910] 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 of methanol was hydrogenated with a nitrogen balloon for 2 hours. The catalyst was filtered off, and the solvent was evaporated to leave a brownish residue, which was then rapidly purified directly by hexane / ethyl acetate using chromatography to obtain 120 mg of oil (66% yield), MS(+)ES: 296 (M+H). + .

[0911] Step 3: Preparation of 4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-2-(4-(ethylsulfonyl)benzyl)-1H-benzimidazole

[0912]

[0913] 1-Ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride (20 mg, 0.1 mmol) and hydroxybenzotriazine-1-ol (13.5 mg, 0.1 mmol) were added to a chilled solution of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine (29.6 mg, 0.1 mmol) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (22.8 mg, 0.01 mmol) in 1 mL of DMF (ice-water bath). After the addition was complete, the mixture was stirred and allowed to warm to room temperature overnight. The mixture was then partitioned between water (50 mL) and ethyl acetate (50 mL). The organic phase was separated, dried over MgSO4, and filtered. The solvent was evaporated under reduced pressure to leave a grayish-white solid, which was mixed with acetic acid (1 mL). The mixture was heated to 80 °C for 2 hours and then cooled. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc, washed with saturated sodium bicarbonate, and dried over MgSO4. The product was purified by rapid chromatography with hexane / ethyl acetate to obtain 26 mg (60%) of a white solid. MS(+)ES: 488 (M+H) + .

[0914] Example 126

[0915] Preparation of 2-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0916]

[0917] Step 1: Preparation of 2,3,4-trichloro-6-nitroaniline

[0918]

[0919] A suspension of 4,5-dichloro-2-nitroaniline (30 g, 145 mmol) and N-chlorosuccinimide (24.2 g, 181.2 mmol) in 250 mL of DMF was stirred at 100 °C for 2 hours. The suspension was cooled to room temperature and poured into ice water (1 mL). The resulting precipitate was collected by filtration. It was dissolved in dichloromethane and washed with water. The organic layer was concentrated to obtain 2,3,4-trichloro-6-nitroaniline (34.2 g, 97.5% yield) as a bright yellow solid.

[0920] Step 2: Preparation of 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitroaniline

[0921]

[0922] A DMF (20 mL) solution of 2,3,4-trichloro-6-nitroaniline (5 g, 20.7 mmol), N,N-diisopropylethylamine (11.8 mL, 62.1 mmol), and 4,4-difluoropiperidine (3.8 g, 31.06 mmol) was stirred over a weekend at 105 °C. The reaction solution was aspirated onto 20 g of silica gel, loaded onto a silica gel column, and eluted with a hexane solution of 30% ethyl acetate to obtain a bright yellow solid of 2,4-dichloro-3-(4,4-difluoropiperidine-1-yl)-6-nitroaniline (4.72 g, 70.0% yield). MS(+)ES: 326(M+H) + .

[0923] Step 3: Preparation of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine

[0924]

[0925] To a solution of 3.5 g (10.8 mmol) of 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitroaniline in THF (30 mL), zinc powder (7 g) and concentrated hydrochloric acid (2 mL) were added. The reaction mixture was stirred overnight at room temperature. It was then filtered. The filtrate was concentrated and purified by elution with ethyl acetate on a silica gel column to obtain a grayish-white solid of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine (1.85 g, yield 57.8%), MS(+)ES: 296 (M+H). + .

[0926] 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

[0927]

[0928] To a solution of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine (350 mg, 1.18 mmol) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (225 mg, 0.99 mmol) in dichloromethane (10 mL), EDCI (285 mg, 1.49 mmol) and HBTU (565 mg, 1.49 mmol) were added. 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, eluted with a hexane solution of 45% ethyl acetate to obtain a 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 as a white solid (410 mg, yield 81.8%), MS(+)ES: 506 (M+H). + .

[0929] Step 5: Preparation of 2-(4-(ethylsulfonyl)benzyl)-4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzimidazole

[0930]

[0931] A mixture (410 mg) 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 obtained in the previous step was treated with 15 mL of glacial acetic acid at 80 °C for 2 hours. It was concentrated and purified by elution with hexane in 60% ethyl acetate on a silica gel column to obtain a grayish-white solid of 2-(4-(ethylsulfonyl)benzyl)-4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole (375 mg, yield 94.8%), MS(+)ES: 488(M+H). + .

[0932] Step 6: 2-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol

[0933]

[0934] Sodium ethoxide (8.2 mg, 0.12 mmol) was added to a DMSO (3 mL) solution of 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). The reaction solution was stirred at room temperature for 2 hours. It was then directly loaded onto a reverse-phase column and purified by elution system D to obtain a white solid of 2-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole-2-yl)-2-(4-(ethylsulfonyl)phenyl)ethanol (9 mg, 42.5% yield); MS(+)ES: 518(M+H). + .

[0935] Examples 126-1 and 126-2

[0936] 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)

[0937]

[0938] Chiral separation was performed in Example 126 (separation conditions: cellulose-120*250mm, 5μm; mobile phase: ethanol / hexane = 1:4 (v / v); flow rate: 20mL / min), the corresponding fractions were collected and concentrated under reduced pressure to obtain the title compound (420mg, 410mg).

[0939] Single-configuration compounds (shorter retention time)

[0940] MS(+)ES:518(M+H) + ;

[0941] Chiral HPLC analysis: retention time 7.275 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 15:85 (v / v));

[0942] 1H NMR(400mHz,CD3OD):7.90(d,8.0Hz,2H),7.67(d,8.0Hz,2H),7.62(s,0.5H),7.49(s,0.5H),4.59(t,8.0Hz,1H),4.38( dd,8.0,11.0Hz,1H),4.27-4.11(m,1H),3.44-3.28(m,4H),3.20(q,8.0Hz,2H),2.24-2.01(m,4H),1.21(t,8.0Hz,3H).

[0943] Single-configuration compounds (longer retention time)

[0944] MS(+)ES:518(M+H) + ;

[0945] Chiral HPLC analysis: retention time 9.290 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 15:85 (v / v));

[0946] 1 H NMR(400mHz,CD3OD):7.90(d,8.0Hz,2H),7.67(d,8.0Hz,2H),7.62(s,0.5H),7.49(s,0.5H),4.59(t,8.0Hz,1H),4.38( dd,8.0,11.0Hz,1H),4.27-4.11(m,1H),3.44-3.28(m,4H),3.20(q,8.0Hz,2H),2.24-2.01(m,4H),1.21(t,8.0Hz,3H).

[0947] Example 127

[0948] Preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-6-(4,4-difluoropiperidin-1-yl)-1H-benzimidazole

[0949]

[0950] Step 1: Preparation of cyclopropyl methyl 2-(4-(cyclopropylmethylthio)phenyl)acetic acid ester

[0951]

[0952] Cesium carbonate (29.3 g, 89.1 mmol) and cyclopropylmethyl bromide (10 g, 74.21 mmol) were added to a DMF (50 mL) solution of 2-(4-mercaptophenyl)acetic acid (5 g, 29.7 mmol). The reaction mixture was stirred overnight at room temperature. It was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and purified by elution on a silica gel column with a hexane solution of 25% ethyl acetate to obtain a colorless oily cyclopropyl methyl 2-(4-(cyclopropylmethylthio)phenyl)acetic acid (7.7 g, 93.7% yield). MS(+)ES: 277(M+H) + .

[0953] Step 2: Preparation of cyclopropyl methyl 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetic acid

[0954]

[0955] At room temperature, MCPBA (7.61 g, 44.3 mmol) was added to a solution of cyclopropyl methyl 2-(4-(cyclopropylmethylthio)phenyl)acetate (4.07 g, 14.7 mmol) in 20 mL of dichloromethane. After addition, the reaction mixture was stirred at ambient temperature for 14 hours. It was partitioned between dichloromethane and saturated sodium thiosulfate. The organic layer was washed with 2N aqueous sodium hydroxide solution and brine. It was concentrated and purified by elution on a silica gel column with a solution of 60% ethyl acetate in hexane to obtain a white solid of cyclopropyl 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetate (4.23 g, 93.0% yield). MS(+)ES: 309(M+H) + .

[0956] Step 3: Preparation of 2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetic acid

[0957]

[0958] To a solution of cyclopropyl methyl 2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetic acid (2.50 g, 8.1 mmol) in dioxane (10 mL), lithium hydroxide monohydrate (4.1 g, 40.6 mmol) and water (10 mL) were added. The reaction mixture was stirred overnight at ambient temperature. It was acidified to pH 5 with hydrochloric acid and concentrated to dryness. The collected solid was dissolved in 15% methanol in dichloromethane, filtered through a silica gel pad, eluted with 15% methanol in dichloromethane, and concentrated to obtain a white solid of 2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetic acid (2.1 g, 97% yield). MS(+)ES: 255 (M+H) + .

[0959] Step 4: Preparation of N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethanesulfonyl)phenyl)acetamide and N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethanesulfonyl)phenyl)acetamide

[0960]

[0961] To a solution of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine (175 mg, 0.193 mmol) and 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetic acid (181 mg, 0.711 mmol) in dichloromethane (5 mL), EDCI (171 mg, 0.89 mmol) and HBTU (334 mg, 0.89 mmol) were added. 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, eluted with a hexane solution of 45% ethyl acetate to obtain 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 as a white solid (230 mg, yield 73.2%). MS(+)ES: 532(M+H) + .

[0962] Step 5: Preparation of 2-(4-(cyclopropylmethylsulfonyl)benzyl)-4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzimidazole

[0963]

[0964] A mixture (230 mg) of N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethanesulfonyl)phenyl)acetamide and N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethanesulfonyl)phenyl)acetamide obtained in the previous step was treated with 15 mL of glacial acetic acid at 80 °C for 2 hours. It was concentrated and purified by elution with an aqueous solution of 60% acetonitrile on a reverse-phase column to obtain a grayish-white solid of 2-(4-(cyclopropylmethanesulfonyl)benzyl)-4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzi[d]imidazole (375 mg, yield 94.8%); MS(+)ES: 514(M+H). + .

[0965] 1H NMR(500mHz, CDCl3):7.85(d,5.00Hz,2H),7.66(s,0.5H),7.50(d,5.00Hz,2H),7.30(s ,0.5H),4.45(m,2H),3.30(m,4H),3.00(m,2H),2.12(m,5H),0.51(m,2H),0.35(m,2H).

[0966] Example 128

[0967] Preparation of 2-(7-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethylamine

[0968]

[0969] Step 1: Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid benzyl ester

[0970]

[0971] 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 CH2Cl2 (8 mL) was added to a suspension of 2-bromo-1-methylpyridine iodide (2.16 g, 7.2 mmol) in CH2Cl2 (10 mL). The resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography to obtain 1.8 g of a white solid benzyl product (90% yield). MS(+)ES: 344(M+H) + .

[0972] Step 2: Preparation of benzyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(1,3-dioxoisoindoline-2-yl)propionate

[0973]

[0974] Under stirring, a THF solution of n-butyllithium (1.8 mL, 2.5 M, 4.5 mmol) was added dropwise over 20 minutes to a mixture of cold HMDS (608 mg, 4.56 mmol) in THF (20 mL). The mixture was stirred for 30 minutes, and then 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)benzyl acetate (1.3 g, 3.8 mmol) was added dropwise over 10 minutes via syringe to THF (5 mL). The mixture was stirred again at -78 °C for 30 minutes, and then 2-(bromomethyl)isoindoline-1,3-dione (912 mg, 3.8 mmol) was added over 10 minutes via syringe to THF (5 mL). The mixture was stirred at -78 °C and allowed to reach room temperature overnight. The mixture was carefully treated with methanol, and the solvent was evaporated. The product was purified by rapid chromatography to obtain 1.4 g of the product as a white solid (74% yield). MS(+)ES:504(M+H) + .

[0975] Step 3: Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(1,3-dioxoisoindoline-2-yl)propionic acid

[0976]

[0977] Benzyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(1,3-dioxoisoindoline-2-yl)propionate (1.4 g, 2.8 mmol) from step 2 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 obtain 900 mg of a white solid product (78% yield). MS(+)ES: 414(M+H) + .

[0978] Step 4: Preparation of 6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3,4-diamine

[0979]

[0980] A mixture of 4-bromo-5-chlorophenyl-1,2-diamine (1.5 g, 6.78 mmol), 2-(2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.2 g, 8.15 mmol), tris(dibenzylacetone)dipalladium(0) (620 mg), tri-tert-butylphosphine tetrafluoroborate (393 mg), and sodium carbonate (1.7 g, 13.7 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was degassed and heated to 90 °C for 3 hours. Volatile solvents were removed under reduced pressure. The residue was directly loaded onto an ISCO solid column and subjected to rapid chromatography with hexane / ethyl acetate to obtain 1.0 g of product (51.9% yield), MS(+)ES: 285 (M+H). + .

[0981] 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

[0982]

[0983] To a mixture of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(1,3-dioxoisoindoline-2-yl)propionic acid (step 3, 400 mg, 0.97 mmol) and 6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3,4-diamine (step 4, 275 mg, 0.98 mmol) in DMF (8 ml), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (224 mg, 1.2 mmol) and 1-hydroxybenzotriazole (162 mg, 1.2 mmol) were added. The mixture was stirred overnight at room temperature and partitioned between ethyl acetate (10 ml) and water (15 ml). The organic phase was separated and dried over MgSO4. After filtration and solvent evaporation, the residue was treated with acetic acid (5 ml) and heated to 80 °C for 2 hours. The mixture was cooled, and the acetic acid was evaporated to dryness and dissolved in ethyl acetate (10 ml). The solution was washed with saturated sodium bicarbonate and brine. The organic phase was separated and dried over MgSO4. The product was purified by rapid chromatography to give 454 mg of a white solid (70% yield). MS(+)ES: 662(M+H) + .

[0984] Step 6: Preparation of 2-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethylamine

[0985]

[0986] 2-(2-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethyl)isoindoline-1,3-dione (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 solvent was evaporated to dryness. The product was purified by rapid chromatography to obtain 280 mg of the product as a white solid (76% yield). MS(+)ES: 532(M+H) + .

[0987] Example 129

[0988] Preparation of N-(2-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethyl)acetamide

[0989]

[0990] Acetic anhydride (1.2 mg, 0.01 mmol) was added to a solution of 2-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethylamine (Example 128) (5.3 mg, 0.01 mmol) and triethylamine (3 mg, 0.03 mmol) in DCM (0.4 mL). The mixture was stirred for 4 hours. The solvent was evaporated under reduced pressure, and the product was purified by preparative HPLC to obtain 3.5 mg of a white solid (66% yield). MS(+)ES: 574 (M+H) + .

[0991] Example 130

[0992] Preparation of 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionic acid

[0993]

[0994] Step 1: Preparation of 4-ethoxy-2-(4-(ethylsulfonyl)phenyl)-4-oxobutyric acid

[0995]

[0996] At -78°C, LiHMDS (1M in THF, 2.31 mL) was added to a solution of 2-(4-(ethylsulfonyl)phenyl)acetic acid (250 mg, 1.1 mmol) in 8 mL of THF. 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. The pH was adjusted to approximately 4 by adding 0.1 N HCl solution. The mixture was extracted three times with EtOAc, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using elution system A to obtain 29 mg of a yellow oil. MS (ESI): 315 (M+H) + .

[0997] Step 2: Preparation of ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutyrate

[0998]

[0999] To a DCM solution (1 mL) of 27 mg of 4-ethoxy-2-(4-(ethylsulfonyl)phenyl)-4-oxobutyric acid, 65 mg of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine, 150 mg of HATU, and 0.1 mL of DIEA were added. The mixture was stirred at room temperature for 18 hours. A saturated NaHCO3 solution was added, and the mixture was extracted three times with EtOAc. After drying to Na2SO4, the extract was filtered and concentrated. The residue was purified by silica gel column chromatography using elution system A to obtain 40 mg of the title compound. MS (ESI): 593 (M+H) + .

[1000] Step 3: Preparation of ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionate

[1001]

[1002] Ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutyrate (39 mg) was heated to 80 °C for 3 hours in AcOH (2 mL). The mixture was purified by silica gel column chromatography using elution system C to obtain the title compound (18 mg). MS (ESI): 574 (M+H) + .

[1003] Step 4: Preparation of 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionic acid

[1004]

[1005] Ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionate (18 mg) was treated with LiOH (1 M, 0.2 mL) in THF (1.5 mL) / MeOH (0.5 mL). The mixture was stirred at room temperature for 3 hours until no ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionate remained as monitored by LCMS. 1 M HCl was added to adjust the pH to <5. The solvent was evaporated under reduced pressure, and the product was purified by reversed-phase preparative HPLC (elution system: 0.075% TFA aqueous solution and 0.075% TFA MeOH solution) to obtain the title compound (11 mg) as a white solid. MS(ESI): m / z = 546(M+H) + .

[1006] Example 131

[1007] Preparation of 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionamide

[1008]

[1009] To a DMF (1 mL) solution of 9 mg from Example 172, NH4Cl (30 mg), HATU (17 mg), and DIEA (60 μL) were added. The mixture was stirred at room temperature for 20 hours. The solid was filtered off. The filtrate was purified by reversed-phase preparative HPLC (elution system: 0.075% TFA aqueous solution and 0.075% TFA MeOH solution) to obtain the title compound (3 mg) as a white solid. MS (ESI): m / z = 545 (M+H) + .

[1010] Example 132

[1011] Preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-6-(2-isopropoxyphenyl)-1H-benzimidazole

[1012]

[1013] The compound was prepared by a method substantially similar to that in Example 124 to obtain a white solid product, MS(+)ES: 529(M+H). + .

[1014] Example 133

[1015] Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(5,7-dichloro-6-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)methanol

[1016]

[1017] The compound was prepared by a method substantially similar to that used in Examples 2 and 124 to obtain a white solid product, MS(+)ES: 545(M+H). + .

[1018] Example 134

[1019] Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(5,7-dichloro-6-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[1020]

[1021] The compound was prepared by a method substantially similar to that in Example 124 to obtain a white solid product, MS(+)ES: 559 (M+H). + .

[1022] Example 135

[1023] Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(5,7-dichloro-6-(2-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[1024]

[1025] The compound was prepared by a method substantially similar to that in Example 124 to obtain a white solid product, MS(+)ES: 531(M+H). + .

[1026] Example 136

[1027] Preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-6-(2-ethoxyphenyl)-1H-benzimidazole

[1028]

[1029] The compound was prepared by a method substantially similar to that in Example 124 to obtain a white solid product, MS(+)ES: 515(M+H). + .

[1030] Example 137

[1031] Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-2-(5,7-dichloro-6-(2-ethoxyphenyl)-1H-benzo[d]imidazol-2-yl)ethanol

[1032]

[1033] The compound was prepared by a method substantially similar to that in Example 124 to obtain a white solid product, MS(+)ES: 545 (M+H). + .

[1034] Example 138

[1035] Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(5,7-dichloro-6-(2-ethoxyphenyl)-1H-benzo[d]imidazol-2-yl)methanol

[1036]

[1037] The compound was prepared by a method substantially similar to that used in Examples 2 and 124 to obtain a white solid product, MS(+)ES: 531(M+H). + .

[1038] Examples 139 and 140

[1039] Preparation of (S)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)prop-1-ol and (R)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)prop-1-ol

[1040]

[1041]

[1042] Step 1: Preparation of ethyl 2-(4-(ethylthio)phenyl)acetate

[1043]

[1044] To a solution of 2-(4-mercaptophenyl)acetic acid (5.0 g, 29.7 mmol) in N,N-dimethylformamide (DMF) (100 mL), K₂CO₃ (16.4 g, 118.8 mmol) and iodoethane (9.7 g, 62.2 mmol) were added. The reaction mixture was stirred at room temperature. 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 obtain the desired product, ethyl 2-(4-(ethylthio)phenyl)acetate (6.0 g, 90%), as a pale yellow solid. MS(+)ES: 225 (M+H) + .

[1045] Step 2: Preparation of ethyl 2-(4-(ethylsulfonyl)phenyl)acetate

[1046]

[1047] Add ethyl 2-(4-(ethylthio)phenyl)acetate (6.0 g, 26.7 mmol) and dichloromethane (300 mL) to a 250 mL round-bottom flask. Cool the reaction mixture to 0 °C. At 0 °C, add m-chloroperoxybenzoic acid (13.8 g, 80.0 mmol) to the same flask. Stir the reaction mixture at room temperature for 12 hours. Filter the resulting suspension through a diatomaceous earth mat. Wash the filtrate with water. Separate the organic layer, wash successively with saturated sodium bicarbonate solution and brine, and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure to obtain the crude product. Purify the crude product by rapid column chromatography with hexane / ethyl acetate to obtain the title compound in an oily form, which solidifies upon standing (6.0 g, 87.5%), MS(+)ES: 257 (M+H). + .

[1048] Step 3: Preparation of 2-(4-(ethylsulfonyl)phenyl)acetic acid

[1049]

[1050] Add ethyl 2-(4-(ethylsulfonyl)phenyl)acetate (6.8 g, 26.5 mmol) and methanol (80 mL) to a 250 mL round-bottom flask. Add an aqueous solution of sodium hydroxide (2.1 g, 52.5 mmol in 20 mL of water) to the same flask. Heat the reaction mixture to reflux for 12 hours. Evaporate the volatiles under reduced pressure. Acidify the residue to pH 5.0 with 1 N HCl and extract with ethyl acetate (50 mL × 3). Separate and combine the organic layers, wash with brine and dry over sodium sulfate. Evaporate the solvent under reduced pressure to obtain the title compound (3.3 g, 54.5%) as a white solid, MS(+)ES: 229(M+H). + .

[1051] Step 4: Preparation of 4-ethoxy-2-(4-(ethylsulfonyl)phenyl)-4-oxobutyric acid

[1052]

[1053] At -78°C, LiHMDS (1M in THF, 9.0 mL) was added to a solution of 2-(4-(ethylsulfonyl)phenyl)acetic acid (1.0 g, 4.4 mmol) in 20 mL of THF. After 15 minutes, ethyl 2-bromoacetate (1.1 g, 6.58 mmol) was added. The reaction mixture was stirred at -78°C for 3.5 hours. The pH was adjusted to approximately 4 by adding 0.1 N HCl solution. The mixture was extracted three times with EtOAc, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using elution system A to obtain 0.45 g of a yellow oil. MS (ESI): 315 (M+H) + .

[1054] Step 5: Preparation of 2,3,4-trichloro-6-nitroaniline

[1055]

[1056] A suspension of 4,5-dichloro-2-nitroaniline (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. The suspension was cooled to room temperature and poured into ice water (500 mL). The resulting precipitate was collected by filtration. It was dissolved in dichloromethane and washed with water. The organic layer was concentrated to obtain 2,3,4-trichloro-6-nitroaniline (11.0 g, 94.3% yield) as a bright yellow solid.

[1057] Step 6: Preparation of 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitroaniline

[1058]

[1059] A DMF (50 mL) solution of 2,3,4-trichloro-6-nitroaniline (5 g, 20.7 mmol), N,N-diisopropylethylamine (8.0 g, 61.9 mmol), and 4,4-difluoropiperidine (10.0 g, 157.6 mmol) was stirred at 105 °C for two days. The reaction solution was aspirated onto 40 g of silica gel, loaded onto a silica gel column, and eluted with a hexane solution of 30% ethyl acetate to obtain a bright yellow solid of 2,4-dichloro-3-(4,4-difluoropiperidine-1-yl)-6-nitroaniline (2.0 g, yield 29.6%). MS (ESI): 326 (M+H) + .

[1060] Step 7: Preparation of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine

[1061]

[1062] Iron powder (1.0 g, 18.0 mmol) and NH4Cl (1.0 g, 18.5 mmol) were added to a methanol (120 mL) and water (30 mL) solution of 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitroaniline (2.0 g, 6.1 mmol). The reaction mixture was stirred overnight at 80 °C. It was filtered. The filtrate was concentrated and purified by elution with ethyl acetate on a silica gel column to obtain a grayish-white solid of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine (0.6 g, yield 33.0%) (LCMS(M+1):296).

[1063] Step 8: Preparation of ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutyrate and ethyl 4-((6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutyrate

[1064]

[1065] To a DMF (10 mL) solution of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine (450 mg, 1.43 mmol) and 4-ethoxy-2-(4-(ethylsulfonyl)phenyl)-4-oxobutyric acid (424 mg, 1.43 mmol), EDCI (410 mg, 2.15 mmol), HOBT (327 mg, 2.15 mmol), and DIPEA (554 mg, 4.30 mmol) were added. 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. Elution with a hexane solution of 45% ethyl acetate yielded a white solid mixture of ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutyrate and ethyl 4-((6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutyrate (385 mg, yield 45.4%). MS (ESI): m / z = 592 (M+H) + .

[1066] 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)propionate

[1067]

[1068] The mixture (385 mg) of ethyl 4-((6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutyrate and ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutyrate obtained in the previous step was treated with 15 mL of glacial acetic acid at 80 °C for 2 hours. The solution was concentrated and purified by elution with a hexane solution of 60% ethyl acetate on a silica gel column to obtain ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionate (230 mg, yield 61.6%) as a grayish-white solid. MS (ESI): 574 (M+H) + .

[1069] 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)prop-1-ol and (R)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)prop-1-ol

[1070]

[1071] At 0 °C, LiAlH4 (20 mg, 0.52 mmol) was added to a THF (20 mL) solution of ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionate (300 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 1 hour. 5.0 mL of water was added, and the mixture was filtered. The filtrate was concentrated, and the crude product was purified by rapid column chromatography with hexane / ethyl acetate to obtain 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)prop-1-ol (200 mg).

[1072] Chiral separation was performed (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), 0.46 cm ID × 15 cm L; mobile phase: hexane / EtOH / DEA = 70 / 30 / 0.1 (v / v / v); flow rate: 1.0 mL / min), the corresponding fractions were collected and concentrated under reduced pressure to obtain the title compound (85 mg, 89 mg).

[1073] Single-configuration compounds (shorter retention time)

[1074] MS(+)ES:532(M+H) + ;

[1075] Chiral HPLC analysis: retention time 7.640 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 15:85 (v / v));

[1076] 1H NMR(400mHz,CD3Cl):7.90(d,8.0Hz,2H),7.72(s,1H),7.68(d,8.0Hz,2H),4.68(t,8.0Hz,1H),3.76(t,8.0Hz,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,8.0Hz,3H).

[1077] Single-configuration compounds (longer retention time)

[1078] MS(+)ES:532(M+H) + ;

[1079] Chiral HPLC analysis: retention time 9.398 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 15:85 (v / v));

[1080] 1 H NMR(400mHz,CD3OD):7.90(d,8.0Hz,2H),7.72(s,1H),7.68(d,8.0Hz,2H),4.68(t,8.0Hz,1H),3.76(t,8.0Hz,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,8.0Hz,3H).

[1081] Example 141

[1082] Preparation of 3-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionamide

[1083]

[1084] This compound was prepared using the same method as the racemic mixtures of Examples 152 and 153. MS(+)ES: 560(M+H) + .

[1085] Example 142

[1086] Preparation of 3-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-ol

[1087]

[1088] This compound was prepared using the same method as the racemic mixtures of Examples 155 and 156. MS(+)ES: 547(M+H) + .

[1089] Example 143

[1090] Preparation of 3-(5-chloro-6-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionamide

[1091]

[1092] This compound was prepared using the same method as the racemic mixtures of Examples 148 and 149. MS(+)ES:552(M+H) + .

[1093] Example 144

[1094] Preparation of 3-(5-chloro-6-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-ol

[1095]

[1096] This compound was prepared by the same method as the racemic mixtures of Examples 150 and 151. MS(+)ES: 539(M+H) + .

[1097] Example 145

[1098] Preparation of 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)prop-1-ol

[1099]

[1100] This compound was prepared by the same method as the racemic mixtures of Examples 139 and 140. MS(+)ES:532(M+H) + .

[1101] Examples 146 and 147

[1102] Preparation of (S)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionamide and (R)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionamide

[1103]

[1104]

[1105] To a methanol (20 mL) solution of ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionate (310 mg, 0.54 mmol), NH3 (7.7 mL, 7N in methanol, 53.9 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The mixture was concentrated, and the crude product was purified by rapid column chromatography with hexane / ethyl acetate to obtain 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propionamide (300 mg).

[1106] Chiral separation was performed (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), 0.46 cm ID × 15 cm L; mobile phase: 100% methanol; flow rate: 1.0 mL / min), the corresponding fractions were collected and concentrated under reduced pressure to obtain the title compound (140 mg, 135 mg).

[1107] Single-configuration compounds (shorter retention time)

[1108] MS(+)ES:545(M+H) + ;

[1109] Chiral HPLC analysis: retention time 9.537 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 15:85 (v / v));

[1110] 1H NMR(400mHz,CD3OD):7.84(d,8.0Hz,2H),7.63(d,8.0Hz,2H),7.57(s,1H),6.44(s,1H),5.71(s,1H),5.14(t,8.0Hz,1H),3.74-3 .68(dd,8.0Hz,1H),3.2-3.22(m,4H),3.15-3.09(q,2H),3.09-3.03(dd,8.0Hz,1H),2.18-2.10(m,4H),1.31-1.27(t,8.0Hz,3H).

[1111] Single-configuration compounds (longer retention time)

[1112] MS(+)ES:545(M+H) + ;

[1113] Chiral HPLC analysis: retention time 11.851 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 15:85 (v / v));

[1114] 1 H NMR(400mHz,CD3OD):7.84(d,8.0Hz,2H),7.63(d,8.0Hz,2H),7.57(s,1H),6.44(s,1H),5.71(s,1H),5.14(t,8.0Hz,1H),3.74-3 .68(dd,8.0Hz,1H),3.2-3.22(m,4H),3.15-3.09(q,2H),3.09-3.03(dd,8.0Hz,1H),2.18-2.10(m,4H),1.31-1.27(t,8.0Hz,3H).

[1115] Examples 148 and 149

[1116] Preparation of (S)-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionamide and (R)-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionamide

[1117]

[1118] To a methanol (5 mL) solution of ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate (340 mg, 0.59 mmol), NH3 (4.1 mL, 7 N in methanol, 29.2 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The mixture was concentrated, and the crude product was purified by rapid column chromatography with hexane / ethyl acetate to obtain the title compound (220 mg).

[1119] Chiral separation was performed (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), 0.46 cm ID × 15 cm L; mobile phase: 100% methanol; flow rate: 1.0 mL / min), the corresponding fractions were collected and concentrated under reduced pressure to obtain 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionamide (97 mg, 87 mg).

[1120] Single-configuration compounds (shorter retention time)

[1121] MS(+)ES:552(M+H) + ;

[1122] Chiral HPLC analysis: retention time 5.617 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 70:30 (v / v));

[1123] 1 H NMR(400mHz,CD3OD):7.92(d,8.0Hz,2H),7.65(d,8.0Hz,2H),7.51-7.49(s,1H),7.35-7.31(t,8.0Hz,1H ),7.28(s,1H),7.16-7.14(d,8.0Hz,1H),7.05-7.03(d,8.0Hz,1H),7.00-6.96(d,8.0Hz,1H),4.95-4.91( t,8.0Hz,1H),4.51-4.46(m,1H),3.39-3.34(dd,8.0Hz,1H),3.13-3.11(d,8.0Hz,2H),3.12-3.06(dd,8.0 Hz,1H),1.16-1.15(d,4.0Hz,6H),0.93-0.91(m,1H),0.51-0.49(d,8.0Hz,2H),0.13-0.11(d,8.0Hz,2H).

[1124] Single-configuration compounds (longer retention time)

[1125] MS(+)ES:552(M+H) + ;

[1126] Chiral HPLC analysis: retention time 15.283 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 70:30 (v / v));

[1127] 1 H NMR(400mHz,CD3OD):7.92(d,8.0Hz,2H),7.65(d,8.0Hz,2H),7.51-7.49(s,1H),7.35-7.31(t,8.0Hz,1H ),7.28(s,1H),7.16-7.14(d,8.0Hz,1H),7.05-7.03(d,8.0Hz,1H),7.00-6.96(d,8.0Hz,1H),4.95-4.91( t,8.0Hz,1H),4.51-4.46(m,1H),3.39-3.34(dd,8.0Hz,1H),3.13-3.11(d,8.0Hz,2H),3.12-3.06(dd,8.0 Hz,1H),1.16-1.15(d,4.0Hz,6H),0.93-0.91(m,1H),0.51-0.49(d,8.0Hz,2H),0.13-0.11(d,8.0Hz,2H).

[1128] Examples 150 and 151

[1129] Preparation of (R)-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-ol and (S)-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-ol

[1130]

[1131]

[1132] Step 1: Preparation of cyclopropyl methyl 2-(4-(cyclopropylmethylthio)phenyl)acetic acid ester

[1133]

[1134] Potassium carbonate (25.0 g, 181.2 mmol) and cyclopropylmethyl bromide (20 g, 148.1 mmol) were added to a DMF (100 mL) solution of 2-(4-mercaptophenyl)acetic acid (10 g, 59.4 mmol). The reaction mixture was stirred overnight at 50 °C. It was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and purified by elution on a silica gel column with a hexane solution of 25% ethyl acetate to obtain a colorless oily cyclopropyl methyl 2-(4-(cyclopropylmethylthio)phenyl)acetic acid (15.0 g, 91.3% yield).

[1135] Step 2: Preparation of cyclopropyl methyl 2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetic acid

[1136]

[1137] At 0 °C, MCPBA (23.4 g, 135.6 mmol) was added to a solution of 2-(4-(cyclopropylmethylthio)phenyl)acetic acid cyclopropyl methyl ester (15.0 g, 54.3 mmol) in dichloromethane (200 mL). After addition, the reaction mixture was stirred at ambient temperature for 14 hours. It was partitioned between dichloromethane and saturated sodium thiosulfate. The organic layer was washed with 2N aqueous sodium hydroxide solution and brine. It was concentrated and purified by elution with 60% ethyl acetate in hexane on a silica gel column to obtain 2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetic acid cyclopropyl methyl ester (12 g, 71.6% yield) as a white solid.

[1138] Step 3: Preparation of 2-(4-(cyclopentylmethylsulfonyl)phenyl)acetic acid

[1139]

[1140] To a 250 mL round-bottom flask, add 15.0 g (48.6 mmol) of 2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetic acid cyclopropyl methyl ester and 100 mL of methanol. Add an aqueous solution of sodium hydroxide (3.8 g, 95.0 mmol in 100 mL of water). Heat the reaction mixture to reflux for 12 hours. Evaporate the volatiles under reduced pressure. Acidify the residue to pH 3.0 with 1 N HCl and extract with ethyl acetate (100 mL × 3). Separate and combine the organic layers, wash with brine and dry over sodium sulfate. Evaporate the solvent under reduced pressure to obtain the title compound (9.0 g, 72.7%) as a white solid, MS(+)ES: 255 (M+H). + .

[1141] Step 4: Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-ethoxy-4-oxobutyric acid

[1142]

[1143] At -78°C, LiHMDS (1M in THF, 8.4 mL) was added to a solution of 2-(4-(cyclopentylmethyl)sulfonyl)phenyl)acetic acid (1.0 g, 3.9 mmol) in 30 mL of THF. After 15 minutes, ethyl 2-bromoacetate (1.0 g, 5.9 mmol) was added. The reaction mixture was stirred at -78°C for 1.0 h, and then the pH was adjusted to 3–4 with 0.1 N HCl solution. The mixture was extracted three times with EtOAc, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography using elution system A to obtain 0.8 g of a yellow oil, MS (ESI): 341 (M+H). + .

[1144] Step 5: Preparation of 4-bromo-5-chlorophenyl-1,2-diamine

[1145]

[1146] Iron powder (6.0 g, 107.4 mmol) and NH4Cl (5.7 g, 106.5 mmol) were added to a solution of 5-bromo-4-chloro-2-nitroaniline (9.0 g, 35.8 mmol) in methanol (250 mL) and water (60 mL). The reaction mixture was stirred overnight at 80 °C. It was then filtered. The filtrate was concentrated and purified by elution with ethyl acetate on a silica gel column to obtain a yellow solid of 4-bromo-5-chlorophenyl-1,2-diamine (6.0 g, 75.7% yield).

[1147] Step 6: Preparation of 6-chloro-2'-isopropoxy-[1,1'-biphenyl]-3,4-diamine

[1148]

[1149] A mixture of 4-bromo-5-chlorophenyl-1,2-diamine (1.1 g, 5.0 mmol), (2-isopropoxyphenyl)boronic acid (1.1 g, 6.1 mmol), tris(dibenzylacetone)dipalladium(0) (454 mg), tri-tert-butylphosphine tetrafluoroborate (288 mg), and sodium carbonate (1.8 g, 14.5 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was degassed and heated to 90 °C for 3 hours. Volatile solvents were removed under reduced pressure. The residue was directly loaded onto an ISCO solid column and subjected to rapid chromatography with hexane / ethyl acetate to obtain 1.1 g of white solid product (80% yield), MS(+)ES: 277 (M+H). + .

[1150] Step 7: Preparation of ethyl 4-((4-amino-6-chloro-2'-isopropoxy-[1,1'-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutyrate and ethyl 4-((5-amino-2-chloro-2'-isopropoxy-[1,1'-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutyrate

[1151]

[1152] To a DMF (5 mL) 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-oxobutyric acid (585 mg, 2.11 mmol), EDCI (674 mg, 3.53 mmol), HOBT (537 mg, 3.53 mmol), and DIPEA (455 mg, 3.53 mmol) were added. 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. Elution with a hexane solution of 45% ethyl acetate yielded a white solid mixture of ethyl 4-((4-amino-6-chloro-2'-isopropoxy-[1,1'-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutyrate (750 mg, 71% yield). MS (ESI): 599 (M+H) + .

[1153] Step 8: Preparation of ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate

[1154]

[1155] A mixture (800 mg) of ethyl 4-((4-amino-6-chloro-2'-isopropoxy-[1,1'-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutyrate and ethyl 4-((5-amino-2-chloro-2'-isopropoxy-[1,1'-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutyrate) was treated with 15 mL of glacial acetic acid at 80 °C for 2 hours. The mixture was concentrated and purified by elution with hexane solution of 60% ethyl acetate on a silica gel column to obtain ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate (700 mg, 90% yield) as a grayish-white solid. MS(ESI):581(M+H) + .

[1156] Step 9: Preparation of (R)-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-ol and (S)-3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-ol

[1157]

[1158] At 0 °C, LiAlH4 (29 mg, 0.76 mmol) was added to a THF (20 mL) solution of ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate (440 mg, 0.76 mmol). The reaction mixture was stirred at room temperature for 1 hour. 5.0 mL of water was added, and the mixture was filtered. The filtrate was concentrated, and the crude product was purified by rapid column chromatography with hexane / ethyl acetate to obtain 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-ol (400 mg).

[1159] Chiral separation was performed (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), 0.46 cm ID × 15 cm L; mobile phase: ethanol / hexane = 6:4 (v / v); flow rate: 1.0 mL / min), the corresponding fractions were collected and concentrated under reduced pressure to obtain the title compound (183 mg, 165 mg).

[1160] Single-configuration compounds (shorter retention time)

[1161] MS(+)ES:539(M+H) + ;

[1162] Chiral HPLC analysis: retention time 6.938 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 40:60 (v / v));

[1163] 1 H NMR(400mHz,CD3OD):7.90(d,8.0Hz,2H),7.67(d,8.0Hz,2H),7.62(s,0.5H),7.49(s,0.5H),4.59(t,8.0Hz,1H),4.38( dd,8.0,11.0Hz,1H),4.27-4.11(m,1H),3.44-3.28(m,4H),3.20(q,8.0Hz,2H),2.24-2.01(m,4H),1.21(t,8.0Hz,3H).

[1164] Single-configuration compounds (longer retention time)

[1165] MS(+)ES:539(M+H) + ;

[1166] Chiral HPLC analysis: retention time 11.098 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 40:60 (v / v));

[1167] 1 H NMR(400mHz,CD3OD):7.90(d,8.0Hz,2H),7.67(d,8.0Hz,2H),7.62(s,0.5H),7.49(s,0.5H),4.59(t,8.0Hz,1H),4.38( dd,8.0,11.0Hz,1H),4.27-4.11(m,1H),3.44-3.28(m,4H),3.20(q,8.0Hz,2H),2.24-2.01(m,4H),1.21(t,8.0Hz,3H).

[1168] Examples 152 and 153

[1169] Preparation of (S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionamide and (R)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionamide

[1170]

[1171] Step 1: Preparation of 6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3,4-diamine

[1172]

[1173] A mixture of 4-bromo-5-chlorophenyl-1,2-diamine (1.5 g, 6.78 mmol), 2-(2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.2 g, 8.15 mmol), tris(dibenzylacetone)dipalladium(0) (620 mg), tri-tert-butylphosphine tetrafluoroborate (393 mg), and sodium carbonate (1.7 g, 13.7 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was degassed and heated to 90 °C for 3 hours. Volatile solvents were removed under reduced pressure. The residue was directly loaded onto an ISCO solid column and subjected to rapid chromatography with hexane / ethyl acetate to obtain a white solid product of 1.0 g (yield 51.9%), MS(+)ES: 285 (M+H). + .

[1174] Step 2: Preparation of ethyl 4-((4-amino-6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutyrate and ethyl 4-((5-amino-2-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutyrate)

[1175]

[1176] To a DMF (5 mL) 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-oxobutyric acid (500 mg, 1.47 mmol), EDCI (560 mg, 2.93 mmol), HOBT (447 mg, 2.93 mmol), and DIPEA (380 mg, 2.94 mmol) were added. 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, eluted with a hexane solution of 45% ethyl acetate to obtain a white solid mixture of ethyl 4-((4-amino-6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutyrate (600 mg, yield 62.3%). MS (ESI): 607 (M+H) + .

[1177] Step 3: Preparation of ethyl 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate

[1178]

[1179] A mixture (800 mg) of ethyl 4-((4-amino-6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutyrate and ethyl 4-((5-amino-2-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutyrate) was treated with 15 mL of glacial acetic acid at 80 °C for 2 hours. The solution was concentrated and purified by elution with a hexane solution of 60% ethyl acetate on a silica gel column to obtain ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate (600 mg, yield 77.3%) as a grayish-white solid. MS (ESI): 589 (M+H) + .

[1180] Step 4: Preparation of (S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionamide and (R)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionamide

[1181]

[1182] To a methanol (5 mL) solution of ethyl 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate (400 mg, 0.68 mmol), NH3 (4.8 mL, 7N in methanol, 33.9 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The mixture was concentrated, and the crude product was purified by rapid column chromatography with hexane / ethyl acetate to obtain 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionamide (177 mg).

[1183] Chiral separation was performed (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), 0.46 cm ID × 15 cm L; mobile phase: 100% methanol; flow rate: 1.0 mL / min), the corresponding fractions were collected and concentrated under reduced pressure to obtain the title compound (67 mg, 60 mg).

[1184] Single-configuration compounds (shorter retention time)

[1185] MS(+)ES:560(M+H) + ;

[1186] Chiral HPLC analysis: retention time 3.919 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 80:20 (v / v));

[1187] 1H NMR(400mHz,CD3OD):7.92(d,8.0Hz,2H),7.51-7.49(s,1H),7.65(d,8.0Hz,2H),7.56-7.5 4(m,1H),7.48-7.44(m,1H),7.33-7.32(m,2H),7.28-7.26(d,8.0Hz,1H),6.86(d,8.0Hz,1 H),4.96-4.92(t,8.0Hz,1H),3.41-3.35(dd,8.0Hz,1H),3.13-3.11(d,8.0Hz,2H),3.12-3 .06(dd,8.0Hz,1H),0.93-0.91(m,1H),0.52-0.50(d,8.0Hz,2H),0.13-0.11(d,8.0Hz,2H).

[1188] Single-configuration compounds (longer retention time)

[1189] MS(+)ES:560(M+H) + ;

[1190] Chiral HPLC analysis: retention time 8.942 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 80:20 (v / v));

[1191] 1 H NMR(400mHz,CD3OD):7.92(d,8.0Hz,2H),7.51-7.49(s,1H),7.65(d,8.0Hz,2H),7.56-7.5 4(m,1H),7.48-7.44(m,1H),7.33-7.32(m,2H),7.28-7.26(d,8.0Hz,1H),6.86(d,8.0Hz,1 H),4.96-4.92(t,8.0Hz,1H),3.41-3.35(dd,8.0Hz,1H),3.13-3.11(d,8.0Hz,2H),3.12-3 .06(dd,8.0Hz,1H),0.93-0.91(m,1H),0.52-0.50(d,8.0Hz,2H),0.13-0.11(d,8.0Hz,2H).

[1192] Example 154

[1193] Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)propionamide

[1194]

[1195] Step 1: Preparation of tert-butyl 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazolium-1-carboxylic acid

[1196]

[1197] At ambient temperature, 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 with Boc anhydride (1.25 g, 9.77 mmol), DIEA (1.7 mL, 9.77 mmol), and a catalytic amount of DMAP. After addition, the reaction solution was stirred overnight at ambient temperature. It was then concentrated. The residue was purified by elution on a silica gel column with 25% EtOAc in DCM to obtain a mixture of two isomers of the product as a grayish-white solid (10.7 g, 90% yield).

[1198] MS(+)ES:614(M+H) + .

[1199] Step 2: Preparation 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]imidazolium-1-carboxylic acid

[1200]

[1201] At -78°C, a solution of hexamethyldimethylsilylaminolithium (1M, 1mL, 1mmol) was added to a dry THF (10mL) solution of 2-(4-(cyclopropylmethylsulfonyl)benzyl)-4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazolium-1-carboxylic acid tert-butyl ester (465 mg, 0.76 mmol). After stirring at -78°C for 30 min, methyl bromoethyl acetate (233 mg, 1.52 mmol) was added, and the reaction solution was slowly warmed to ambient temperature and stirred overnight. The solution was then treated with EtOAc and water. The organic layer was concentrated and purified by elution with 25% EtOAc in DCM on a silica gel column to obtain the desired product (511 mg, 98% yield) as a white solid. MS(+)ES: 686(M+H) + .

[1202] Step 3: Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)propionamide

[1203]

[1204] In a sealed reaction flask, a solution of 1 g (1.45 mmol) 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]imidazolium-1-carboxylic acid in methanol (20 mL, containing approximately 7 N of ammonia) was stirred at 80 °C for 10 hours. The solution was concentrated and purified by elution with EtOAc on a silica gel column to obtain the desired product as a white solid (0.65 g, 78% yield). MS(+)ES: 571(M+H) + .

[1205] Examples 155 and 156

[1206] Preparation of (S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-ol and (R)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-ol

[1207]

[1208] At 0°C, LiAlH4 (35 mg, 0.93 mmol) was added to a THF (15 mL) solution of ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate (550 mg, 0.93 mmol). The reaction mixture was stirred at room temperature for 1 hour. 5.0 mL of water was added, and the mixture was filtered. The filtrate was concentrated, and the crude product was purified by rapid column chromatography with hexane / ethyl acetate to obtain 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-ol (250 mg).

[1209] Chiral separation was performed (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), 0.46 cm ID × 15 cm L; mobile phase: 100% hexane / ethanol = 80 / 20 (V / V); flow rate: 1.0 mL / min), the corresponding fractions were collected and concentrated under reduced pressure to obtain the title compound (110 mg, 100 mg).

[1210] Single-configuration compounds (shorter retention time)

[1211] MS(+)ES:547(M+H) + ;

[1212] Chiral HPLC analysis: retention time 6.374 min, chiral purity: 100% (column: CHIRALPAK IG150*4.6mm, 5μm; mobile phase: ethanol / hexane = 20:80 (v / v));

[1213] 1 H NMR(400mHz,CD3OD):7.94-7.92(d,8.0Hz,2H),7.67-7.65(d,8.0Hz,2H),7.48-7.4 4(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,4.0Hz,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).

[1214] Single-configuration compounds (longer retention time)

[1215] MS(+)ES:547(M+H) + ;

[1216] Chiral HPLC analysis: retention time 7.719 min, chiral purity: 100% (column: CHIRALPAK IG150*4.6mm, 5μm; mobile phase: ethanol / hexane = 20:80 (v / v));

[1217] 1 H NMR(400mHz,CD3OD):7.94-7.92(d,8.0Hz,2H),7.67-7.65(d,8.0Hz,2H),7.48-7.4 4(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,4.0Hz,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).

[1218] Example 157

[1219] Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)prop-1-ol

[1220]

[1221] The compound was prepared by a method similar to that used in Examples 139 and 140 (racemic mixtures) to obtain the title compound as a white solid. MS(+)ES: 558 (M+H) + .

[1222] Example 158

[1223] Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)propionamide

[1224]

[1225] The compound was prepared by a method similar to that used in Examples 148 and 149 (racemic mixtures) to obtain the title compound as a white solid. MS(+)ES: 594 (M+H)+ .

[1226] Example 159

[1227] Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)prop-1-ol

[1228]

[1229] The compound was prepared by a method similar to that used in Examples 150 and 151 (racemic mixtures) to obtain the title compound as a white solid. MS(+)ES: 581(M+H) + .

[1230] Examples 160 and 161

[1231] Preparation of (S)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)prop-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)prop-1-ol

[1232]

[1233] The two compounds were prepared by chiral separation as described in Example 157 (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), 0.46 cm ID × 15 cm L; mobile phase: 100% hexane / ethanol = 70 / 30 (V / V); flow rate: 1.0 mL / min), the fractions were collected and concentrated under reduced pressure to obtain the title compound (350 mg, 350 mg).

[1234] Single-configuration compounds (shorter retention time)

[1235] MS m / z(ESI): 557.9 [M+1];

[1236] Chiral HPLC analysis: retention time 7.378 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 15:85 (v / v));

[1237] 1H NMR(400mHz, CD3OD):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,2H),3.13-3.11(m,2H) ,2.68-2.57(m,2H),2.40-2.31(m,2H),2.11-2.14(m,4H),1.32-1.30(m,1H),0.91-0.89(m,2H),0.50(q,2H),0.12(q,2H).

[1238] Single-configuration compounds (longer retention time)

[1239] MS m / z(ESI): 557.9 [M+1];

[1240] Chiral HPLC analysis: retention time 8.738 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 15:85 (v / v));

[1241] 1 H NMR(400mHz, CD3OD):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,2H),3.13-3.11(m,2H) ,2.68-2.57(m,2H),2.40-2.31(m,2H),2.11-2.14(m,4H),1.32-1.30(m,1H),0.91-0.89(m,2H),0.50(q,2H),0.12(q,2H).

[1242] Examples 162 and 163

[1243] Preparation of (S)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)propionamide and (R)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)propionamide

[1244]

[1245] The two compounds were prepared by chiral separation as described in Example 154 (separation conditions: CHIRALCEL OZ-H (OZH00CD-VC005), 0.46 cm ID × 15 cm L; mobile phase: 100% hexane / ethanol = 45 / 55 (V / V); flow rate: 1.0 mL / min), the fractions were collected and concentrated under reduced pressure to obtain the title compound (250 mg, 250 mg).

[1246] Single-configuration compounds (shorter retention time)

[1247] MS m / z(ESI): 571.0 [M+1];

[1248] Chiral HPLC analysis: retention time 8.193 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 15:85 (v / v));

[1249] 1 H NMR(400mHz, CD3OD):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, 1H),2.40-2.31(m,2H),2.11-2.14(m,4H),1.38-1.30(m,1H),0.94-0.91(m,2H),0.50(q,2H),0.11(q,2H).

[1250] Single-configuration compounds (longer retention time)

[1251] MS m / z(ESI): 571.0 [M+1];

[1252] Chiral HPLC analysis: retention time 10.536 min, chiral purity: 100% (column: OD PhenomenexLux Cellulose-1 150*4.6mm, 5μm; mobile phase: ethanol / hexane = 15:85 (v / v));

[1253] 1H NMR(400mHz, CD3OD):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, 1H),2.40-2.31(m,2H),2.11-2.14(m,4H),1.38-1.30(m,1H),0.94-0.91(m,2H),0.50(q,2H),0.11(q,2H).

[1254] Examples 164 and 165

[1255] 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

[1256]

[1257] 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)propionate

[1258]

[1259] The two compounds were prepared by chiral separation (separation conditions: CHIRALPAK IB-N(IBN5CD-VD005), 0.46 cm ID × 15 cm L; mobile phase: 100% hexane / ethanol = 80 / 20 (V / V); flow rate: 1.0 mL / min), and the corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds (690 mg, 490 mg).

[1260] The single-configuration compound Int-164A (with a shorter retention time)

[1261] MS m / z(ESI): 589.1 [M+1];

[1262] Chiral HPLC analysis: retention time 11.508 min, chiral purity: 100% (column: CHIRALPAK IG150*4.6mm, 5μm; mobile phase: ethanol / hexane = 20:80 (v / v)).

[1263] The single-configuration compound Int-164B (with a longer retention time)

[1264] MS m / z(ESI): 589.1 [M+1];

[1265] Chiral HPLC analysis: retention time 17.164 min, chiral purity: 100% (column: CHIRALPAK IG150*4.6mm, 5μm; mobile phase: ethanol / hexane = 20:80 (v / v).

[1266] Step 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)propionaldehyde

[1267]

[1268] Ethyl (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate (shorter retention time) (step 1) (45 mg, 0.076 mmol) was dissolved in DCM (3.0 mL), and diisobutylaluminum hydrogenation (0.16 mL, 0.16 mmol) was added. The mixture was stirred for 30 minutes until complete. The product was purified by rapid chromatography with hexane / ethyl acetate to obtain a white solid (22 mg, 52%).

[1269] MS m / z(ESI): 543.0 [M-1].

[1270] 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

[1271]

[1272] (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanal (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 until complete (LC-MS monitoring). The mixture was treated with a small amount of dilute HCl and purified directly by rapid chromatography with hexane / ethyl acetate to obtain a white solid (7.3 mg, 29%).

[1273] MS m / z(ESI): 616.0 [M+1].

[1274] 1 H NMR(400mHz, CDCl3):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).

[1275] Step 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)propionaldehyde

[1276]

[1277] Ethyl (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate (longer retention time) (Example 164, step 1) (100 mg, 0.17 mmol) was dissolved in DCM (10.0 mL), and diisobutylaluminum hydrogenation (1.0 mL, 0.1 mmol) was added. The mixture was stirred for 30 minutes until complete. The mixture was treated with a small amount of dilute HCl and purified directly by rapid chromatography with hexane / ethyl acetate to obtain a white solid (50 mg, 54%).

[1278] MS m / z(ESI): 543.0 [M-1].

[1279] Step 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

[1280]

[1281] (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanal (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 until complete (LC-MS monitoring). The mixture was treated with a small amount of dilute HCl and purified directly by rapid chromatography with hexane / ethyl acetate to obtain a white solid (13.7 mg, 40%).

[1282] MS m / z(ESI): 616.0 [M+1].

[1283] 1 H NMR(400mHz, CDCl3):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).

[1284] Examples 166 and 167

[1285] 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

[1286]

[1287] Step 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)prop-1-amine

[1288]

[1289] (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanal (Examples 164 and 165, step 2(1)) (45 mg, 0.08 mmol) was dissolved in MeOH (3.0 mL), acetic acid (50 mg, 0.83 mmol) and 7N NH3 in MeOH (1.2 mL, 8.4 mmol) were added, and the mixture was stirred for 0.5 h. NaBH4 (31 mg, 0.84 mmol) was added at room temperature. The mixture was stirred for 60 min until complete (LC-MS monitoring). The mixture was treated with a small amount of dilute HCl and purified directly by rapid chromatography with hexane / ethyl acetate to obtain a white solid (45 mg, 99%).

[1290] MS m / z(ESI): 546.1 [M+1].

[1291] Step 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

[1292]

[1293] (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-amine (45 mg, 0.083 mmol) was dissolved in DCM (2.0 mL), acetyl chloride (8.0 mg, 0.1 mmol) was added, followed by Et3N (9.0 mg, 0.1 mmol), and the mixture was stirred for 0.5 hours. The mixture was treated with a small amount of dilute HCl and purified directly by preparative HPLC using elution system C to obtain a white solid product (10.7 mg, 22%).

[1294] MS m / z(ESI): 587.9 [M+1].

[1295] 1 H NMR(400mHz, CD3OD):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,1H),7.32(d,2H),7.28-7.26(m,1H),6.66(d, 1H),4.61(s,1H),4.51-4.47(m,1H),3.25-3.33(m,2H),3.13(d,2H),2.67-2 .58(m,2H),2.41-2.31(m,2H),0.97-0.91(m,1H),0.50(q,2H),0.11(q,2H).

[1296] Step 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)prop-1-amine

[1297]

[1298] (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanal (Examples 164 and 165, step 2(2)) (50 mg, 0.09 mmol) was dissolved in MeOH (5.0 mL), acetic acid (55 mg, 0.92 mmol) and 7N NH3 in MeOH (1.3 mL, 9.2 mmol) were added, and the mixture was stirred for 0.5 h. NaBH4 (21 mg, 0.55 mmol) was added at room temperature. The mixture was stirred for 60 min until complete (LC-MS monitoring). The mixture was treated with a small amount of dilute HCl and purified directly by rapid chromatography with hexane / ethyl acetate to obtain a white solid (45 mg, 90%).

[1299] MS m / z(ESI): 546.1 [M+1].

[1300] Step 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

[1301]

[1302] (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)prop-1-amine (40 mg, 0.073 mmol) was dissolved in DCM (5.0 mL), acetyl chloride (7.0 mg, 0.09 mmol) was added, followed by Et3N (15 mg, 0.15 mmol), and the mixture was stirred for 0.5 hours. The mixture was treated with a small amount of dilute HCl and purified directly by preparative HPLC using elution system C to obtain a white solid product (20 mg, 46%).

[1303] MS m / z(ESI): 587.9 [M+1].

[1304] 1H NMR(400mHz, CD3OD):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,1H),7.31(d,2H),7.28-7.26(m,1H),6.66(d, 1H),4.61(s,1H),4.51-4.47(m,1H),3.25-3.33(m,2H),3.13(d,2H),2.67-2 .58(m,2H),2.41-2.31(m,2H),0.97-0.91(m,1H),0.50(q,2H),0.11(q,2H).

[1305] Example 168

[1306] Preparation of N-(3-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)acetamide

[1307]

[1308] The compound can be prepared from the corresponding racemic starting material by a method similar to that used in Examples 166 and 167.

[1309] Example 169

[1310] Preparation of 4-(3-(5-chloro-6-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)morpholine

[1311]

[1312] The compound can be prepared from the corresponding racemic starting material by a method similar to that used in Examples 164 and 165.

[1313] Example 170

[1314] 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

[1315]

[1316] Step 1: Preparation of cyclopropyl methyl 2-(4-((cyclopropylmethyl)thio)phenyl)acetic acid

[1317]

[1318] To a solution of 2-(4-mercaptophenyl)acetic acid (20 g, 118.9 mmol) in DMF (200 mL), (bromomethyl)cyclopropane (40.1 g, 297.2 mmol) and cesium carbonate (117 g, 356.7 mmol) were added. After addition, the reaction mixture was stirred at ambient temperature for 14 hours. The reaction mixture was concentrated to remove approximately half of the solvent. It was then treated with EtOAc and water. The organic layer was concentrated and purified by elution on a silica gel column with a 25% EtOAc solution in hexane to obtain a colorless, oily cyclopropyl methyl 2-(4-(cyclopropylmethylthio)phenyl)acetic acid (26.5 g, 81% yield).

[1319] Step 2: Preparation of cyclopropyl methyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid

[1320]

[1321] To a solution of cyclopropyl methyl 2-(4-(cyclopropylmethylthio)phenyl)acetate (31 g, 112.3 mmol) in dichloromethane (200 mL), m-chloroperoxybenzoic acid (58 g, 337 mmol) was added. After addition, the reaction was stirred at ambient temperature for 10 hours. The mixture was partitioned between DCM (1 L) and a saturated aqueous solution of Na₂S₂O₃ (1 L). The organic layer was washed with 2N sodium hydroxide (200 mL) and brine. It was concentrated and purified by elution on a silica gel column with 60% EtOAc in hexane to obtain a white solid of cyclopropyl 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetate (33.5 g, 96.7% yield).

[1322] Step 3: Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid

[1323]

[1324] A mixture of cyclopropyl methyl 2-(4-(cyclopropylmethanesulfonyl)phenyl)acetic acid (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. The mixture was acidified to pH 5 with concentrated hydrochloric acid and extracted with EtOAc (3 × 300 mL). The combined organic layers were concentrated to obtain the desired product, 2-(4-(cyclopropylmethanesulfonyl)phenyl)acetic acid (26.3 g, 98% yield), as a white solid.

[1325] Step 4: Preparation of 2,3,4-trichloro-6-nitroaniline

[1326]

[1327] A suspension of 4,5-dichloro-2-nitroaniline (30 g, 145 mmol) and NCS (24.2 g, 181.2 mmol) in DMF (250 mL) was heated to 100 °C for 2 hours. The suspension was then poured into ice water. The bright yellow precipitate 2,3,4-trichloro-6-nitroaniline was collected by filtration and dried under high vacuum overnight (34.2 g, 98% yield).

[1328] Step 5: Preparation of 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitroaniline

[1329]

[1330] To a DMF (30 mL) solution of 2,3,4-trichloro-6-nitroaniline (5 g, 20.7 mmol), 4,4-difluoropiperidine (3.8 g, 31.06 mmol) and DIEA (11.8 mL, 62.1 mmol) were added. The reaction was stirred at 105 °C for 2 days. TLC showed that most of the product was present. Most of the DMF was removed under vacuum. The product was then aspirated onto silica gel and purified by elution on a silica gel column with 30% EtOAc in hexane to obtain the desired product, 2,4-dichloro-3-(4,4-difluoropiperidine-1-yl)-6-nitroaniline (4.72 g, 70% yield), as a bright yellow solid.

[1331] Step 6: Preparation of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine

[1332]

[1333] To a suspension of 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitroaniline (3.5 g, 10.8 mmol) in THF (30 mL), zinc powder (7 g, 108 mmol) and concentrated HCl (2 mL) were added. The reaction mixture was stirred at room temperature for 14 hours. It was filtered, the filtrate was concentrated, and purified directly by elution with EtOAc on a silica gel column to obtain a grayish-white solid of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine (1.83 g, 57% yield).

[1334] Step 7: Preparation of N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetamide

[1335]

[1336] EDC (1.61 g, 8.40 mmol), HBTU (3.15 g, 8.40 mmol), and 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl-1,2-diamine (1.65 g, 5.59 mmol) were added to a solution of 2-(4-(cyclopropylmethanesulfonyl)phenyl)acetic acid (1.71 g, 6.71 mmol) in dichloromethane (20 mL). After addition, the reaction solution was stirred at ambient temperature for 2 hours. The solution was then aspirated onto silica gel and eluted with a 50% EtOAc solution in hexane to obtain a grayish-white solid, N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethanesulfonyl)phenyl)acetamide (2.9 g, 97% yield).

[1337] Step 8: Preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-6-(4,4-difluoropiperidin-1-yl)-1H-benzimidazole

[1338]

[1339] N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethanesulfonyl)phenyl)acetamide (2.9 g, 5.45 mmol) was treated with acetic acid (20 mL) at 80 °C for 2 h. The acid was removed under high vacuum. The residue was neutralized with NaHCO3 and absorbed onto silica gel. It was purified in dichloromethane with 40% ethyl acetate as eluent to obtain 2-(4-(cyclopropylmethanesulfonyl)benzyl)-5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole (2.3 g, 82% yield) as a bright white solid.

[1340] Step 9: Preparation of tert-butyl 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazolium-1-carboxylic acid

[1341]

[1342] 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), di-tert-butyl dicarbonate (1.25 g, 9.77 mmol), N,N-diisopropylethylamine (1.7 mL, 9.77 mmol), and a catalytic amount of DMAP were added. After addition, the reaction solution was stirred at ambient temperature for 6 hours. It was concentrated and purified by elution with 50% ethyl acetate in dichloromethane on a silica gel column to obtain a white solid of 2-(4-(cyclopropylmethylsulfonyl)benzyl)-5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (3.62 g, 90% yield).

[1343] 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]imidazolium-1-carboxylic acid

[1344]

[1345] At -78°C, lithium bis(trimethylsilyl)amino (1M in THF, 17.4 mL) was added to a THF solution of 2-(4-(cyclopropylmethylsulfonyl)benzyl)-5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazolium-1-carboxylic acid tert-butyl ester. After stirring at -78°C for half an hour, methyl 2-bromoacetate (4.1 g, 26.70 mmol) was added, and the reaction was slowly heated to ambient temperature and stirred for 12 hours. The mixture was then treated with ethyl acetate and water. The organic layer was concentrated and purified by elution with 40% ethyl acetate in dichloromethane on a silica gel column to obtain a white solid tert-butyl 5,7-dichloro-2-(1-(4-(cyclopropylmethylsulfonyl)phenyl)-3-methoxy-3-oxopropyl)-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazolium-1-carboxylic acid (6.3 g, yield 68.7%).

[1346] Step 11: Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1-morpholinopropyl-1-one

[1347]

[1348] Morpholine (1 mL) was added to a methanol (3 mL) solution of 350 mg (0.51 mmol) of 5,7-dichloro-2-(1-(4-(cyclopropylmethylsulfonyl)phenyl)-3-methoxy-3-oxopropyl)-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-carboxylic acid tert-butyl ester (0.51 mmol). The reaction solution was stirred at 100 °C for 14 hours. The solution was then aspirated onto silica gel and eluted with 60% ethyl acetate to obtain a grayish-white solid of 3-(4-(cyclopropylmethylsulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1-morpholinopropyl-1-one (310 mg, 94% yield).

[1349] 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

[1350]

[1351] At 0 °C, LAH (1 M in THF, 10 mL) was added to a dry THF (10 mL) solution of 3-(4-(cyclopropylmethylsulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1-morpholinopropyl-1-one (305 g, 0.48 mmol). After addition, the reaction solution was stirred at 0 °C for 14 hours. It was purified on a reverse-phase column to obtain a white solid of 5,7-dichloro-2-(1-(4-(cyclopropylmethylsulfonyl)phenyl)-3-morpholinopropyl)-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazolium (100 mg, 33% yield).

[1352] MS m / z(ESI): 627[M+1].

[1353] 1 H NMR(400mHz,CD3OD):7.92(d,10Hz,2H),7.69(d,10Hz,2H),7.55(s,1H),3.67(m,6H),3.58(m,1H),3.13(m,2H),2.62(m,1H) ,2.48-2.41(m,4H),2.38-2.31(m,2H),2.13(m,4H),1.61(m,1H),1.32(m,2H),0.95-0.91(m,2H),0.50(m,2H),0.11(m,2H).

[1354] Example 171

[1355] Preparation of N-(3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)propyl)acetamide

[1356]

[1357] The compound can be prepared by a method similar to that in Example 170.

[1358] Biological tests

[1359] The invention will be further described with reference to the following test examples, but these embodiments should not be considered as limiting the scope of the invention.

[1360] Test Example 1. Time-resolved fluorescence energy resonance transfer (LanthaScreen) TR-FRET) Retinoic Acid-Related Orphans Receptor γ (RORγ) coactivator assay

[1361] Materials and reagents

[1362] 1. RORγLBD-GST labeled (Catalog No.: RORC-114H, Creative Biomart)

[1363] 2. Fluorescein-D22 coactivator peptide (Catalog No.: PV4386, Invitrogen)

[1364] 3. LanthaScreen TM Tb anti-GST antibody (Catalog No.: PV3550, Invitrogen)

[1365] 4. TR-FRET Co-regulation Buffer D (Catalog No.: PV4420, Invitrogen)

[1366] 5. DTT (Item No.: P2325, Fisher)

[1367] 6.384-well test board (part number: 6008280, Perkin Elmer)

[1368] 7. Tecan Infinite M1000 ELISA reader (Tecan)

[1369] Experimental Procedure

[1370] Complete TR-FRET co-regulation buffer D was prepared by adding 1M DTT to TR-FRET co-regulation buffer D to a final concentration of 5mM DTT. The compound was diluted in complete TR-FRET co-regulation buffer D. The highest dose was 3μM, and a total of 7 doses were obtained by 7-fold dilution. 10μL was added to each well of a 384-well plate. For negative and positive controls, 10μL of complete TR-FRET co-regulation buffer D was added.

[1371] RORγLBD was prepared using complete TR-FRET co-regulation buffer D. The final concentration of RORγLBD was 25 ng / reaction. 5 μL of RORγLBD was added to all wells of the 384-well test plate except for the negative wells, while 5 μL of complete TR-FRET co-regulation buffer D was added to the negative wells.

[1372] Prepare a solution containing 0.6 μM fluorescein-D22 and 8 nM Tb anti-GST antibody using complete TR-FRET co-regulation buffer D. Add 5 μL to all wells of the 384-well test plate.

[1373] Briefly and gently mix the 384-well plate on a flatbed shaker and incubate at room temperature in the dark for 1 hour. The plate can be sealed with a lid to minimize evaporation.

[1374] Readouts were performed at 520 nm and 495 nm wavelengths on a Tecan Infinite M1000. IC50 was calculated using GraphPad Prism by plotting a logarithmic graph of compound concentration versus inhibition percentage. 50 Value. IC50 of the compound in the examples. 50 The values ​​are shown in Table I.

[1375] Test Example 2. IL-17 generation test using human PBMC

[1376] Materials and reagents

[1377] 1. Human PBMC cells (Catalog No.: 70025.1, Zenbio)

[1378] 2. Lymphocyte mediator (Catalog No.: LYMPH-1, Zenbio)

[1379] 3. TexMACS (Item No.: 130-097-196, Miltenyi)

[1380] 4.Cytostim-Human (Product No.: 1130-092-173, Miltenyi)

[1381] 5. Human IL-17 ELISA (Catalog No.: D1700, R&D Systems)

[1382] 6. Tecan Infinite M1000 ELISA reader (Tecan)

[1383] Experimental procedures for IL-17 generation testing

[1384] Frozen peripheral blood human mononuclear cells (PBMCs) were rapidly thawed in warm lymphocyte medium, and the cell suspension was centrifuged at 1000 rpm for 10 minutes. The supernatant was removed, and the cell pellet was gently resuspended in TexMACS medium.

[1385] Three copies of human PBMC cells in TexMACS medium were prepared at 1x10⁻¹. 5 Cells were seeded per well. Various concentrations of test compounds or vector controls (<0.5% DMSO) were added to the cell culture. Cells were stimulated for 3 days at 37°C in a humidified 5% CO2 incubator with cytostim (10 μL / mL).

[1386] After incubation, the cell culture supernatant was collected, and particles were removed by centrifugation. Human IL-17 in the supernatant was measured using a human IL-17 ELISA kit according to the manufacturer's instructions. The IC50 was determined using GraphPad Prism by plotting compound concentration versus percentage of inhibition. 50 Value. IC50 of the compound in the examples. 50 The values ​​are shown in Table I.

[1387] Table I

[1388]

[1389]

[1390]

[1391]

[1392]

[1393]

[1394]

[1395] N / T: Not tested

[1396] The foregoing description of the embodiments and preferred embodiments should be considered illustrative rather than limiting of the invention as defined in the claims. Various variations and combinations of the above features can be utilized without departing from the invention as set forth in the claims.

Claims

1. Compound of formula (I): Or its pharmaceutically acceptable salt. in: It can be a single bond or a double bond; when When it is a double bond, then For a single bond, R a It does not exist and R b For hydrogen; when When it is a double bond, then For a single bond, R a It is hydrogen and R b It does not exist; Ring A is selected from 3- to 6-membered heterocyclic groups, phenyl groups, and 5- or 6-membered heteroaryl groups; R1, R2, and R3 are each independently selected from hydrogen, halogens, and C. 1-6 alkyl; Each R4 is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, -OR8 and -NR 11 R 12 ; R 5a It is hydrogen; R 5b Selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Hydroxyalkyl, -OR8, -(CH2) x NR 10 COR9, -NR 10 COR9, -NR 10 COCH2OR8、-(CH2) x C(O)OR8、-(CH2) x CONR 11 R 12 and -(CH2) x NR 11 R 12 Wherein C 1-6 The alkyl group is optionally replaced by a 3- to 6-membered heterocyclic group; Or R 5a and R 5b Together R6 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and NR 11 R 12 Wherein C 1-6 Alkyl groups are optionally selected from C 1-6 The alkoxy group is substituted with one or more groups in a 3- to 6-membered cycloalkyl group; Each R7 is independently hydrogen or halogen; R8 is selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups are optionally separated by a C 1-6 Alkyl groups are substituted; R9 is C 1-6 Alkyl or 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally selected from halogens and C 1-6 One or more groups in an alkyl group are substituted; R 10 It is hydrogen or C 1-6 alkyl; R 11 and R 12 Each is independently selected from hydrogen and C. 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups; 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 a pharmaceutically acceptable salt thereof, having the structure of formula (Ia) or formula (Ib): in: R1~R4, R 5a R 5b R6, R7, n and s are as defined in claim 1.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is piperidinyl, phenyl, thiophene, furanyl or pyridinyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure of formula (II): in: R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in claim 1.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure of formula (IIa): in: R a R b R1~R4, R 5a R 5b R6, R7 and n are as defined in claim 1.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure of formula (III): in: R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in claim 1.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure of formula (IIIa): in: R 4a and R 4b Each is independently selected from halogens, hydrogen, and carbon. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R a R b R1~R3, R 5a R 5b R6, R7 and n are as defined in claim 1.

8. Compound of formula (IA): Or its pharmaceutically acceptable salt. in: It can be a single bond or a double bond; when When it is a double bond, then For a single bond, R a It does not exist and R b For hydrogen; when When it is a double bond, then For a single bond, R a It is hydrogen and R b It does not exist; R1, R2, and R3 are each independently selected from hydrogen, halogens, and C. 1-6 alkyl; R 5a and R 5b Selected from hydrogen; R6 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -NR 11 R 12 Wherein C 1-6 The alkyl group is optionally replaced by a 3- to 6-membered cycloalkyl group; Each R7 is independently selected from hydrogen and halogens; R 11 and R 12 Each is independently selected from hydrogen and C. 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups; n can be 0, 1, 2, 3, or 4.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

10. A compound of formula (IC) or formula (ID) or a pharmaceutically acceptable salt thereof, in: R a and R b It is hydrogen; Ring A is selected from 3- to 6-membered heterocyclic groups and phenyl groups; R1, R2, and R3 are each independently selected from hydrogen, halogens, and C. 1-6 alkyl; Each R4 is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R 5a It is hydrogen; R 5b Selected from hydrogen, C 1-6 Hydroxyalkyl and -(CH2) x C(O)OR8; R6 is selected from C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally replaced by a 3- to 6-membered cycloalkyl group; Each R7 is independently selected from hydrogen and halogens; R8 is 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. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

12. A method 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: in: G is a leaving group; and Ring A, R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in claim 1.

13. The method for preparing compound (I) according to claim 12, wherein G is a borate group or a borate ester group.

14. A method for preparing a compound of formula (I), comprising the step of cyclizing a compound of formula (IC) or formula (ID): in: Ring A, R a R b R1~R4, R 5a R 5b R6, R7, n and s are as defined in claim 1.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 15, in the preparation of a medicament for inhibiting RORγ.

17. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 15, in the preparation of a medicament for treating RORγ-mediated diseases or conditions.

18. The use according to claim 15, wherein the RORγ-mediated disease or condition is selected from inflammation, autoimmune diseases, and cancer, wherein the inflammation and autoimmune diseases include arthritis, psoriasis, ulcerative colitis, ankylosing spondylitis, autoimmune diabetes, type I diabetes, autoimmune ophthalmopathy, autoimmune thyroid disease, type I autoimmune polyendocrine syndrome, type II autoimmune polyendocrine syndrome, multiple sclerosis, inflammatory bowel disease, Sjögren's syndrome, Kawasaki disease, infectious diseases, ankylosing spondylitis, lung diseases, glomerulonephritis, myocarditis, thyroiditis, dry eye syndrome, uveitis, Behcet's disease, asthma, atopic dermatitis, contact dermatitis, allogeneic transplant rejection, polymyositis, graft-versus-host disease, acne, systemic lupus erythematosus, scleroderma, bronchitis, dermatomyositis, and allergic rhinitis.

19. The use according to claim 18, wherein the arthritis is selected from rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, and juvenile idiopathic arthritis; wherein the thyroiditis is Hashimoto's thyroiditis; wherein the inflammatory bowel disease is selected from Crohn's disease, regional enteritis, and inflammatory bowel syndrome; and wherein the lung disease is chronic obstructive pulmonary disease (COPD).

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