Benzimidazole and azabenzimidazole IL-17 inhibitor compounds

Abstract

The present application relates to a compound having the following formula (I): 1 , R 2 , R 3 , R 4 and X are as defined herein, or a pharma- ceutically acceptable salt thereof, as well as methods of making and using the compounds disclosed herein for treating or ameliorating a syndrome, disorder, and / or disease mediated by IL-17. [Formula 1] TIFF2024536868000457.tif19128

Description

[Technical Field]

[0001] (Reference to electronically submitted sequence listing) This application contains a Sequence Listing, which has been submitted electronically as a Sequence Listing in ST.26 XML format with the file name "PRD4154WOPCT1_SL.xml" created on September 7, 2022, and has a size of 4.00 KB. The Sequence Listing is a part of the present specification and is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION Disclosed herein are benzimidazole and azabenzimidazole compounds and pharmaceutical compositions thereof that modulate interleukin-17A. Also disclosed herein are therapeutic uses of such compounds, for example, in treating and / or ameliorating IL-17A-mediated inflammatory syndromes, disorders, or diseases. [Background technology]

[0003] Interleukin-17 (IL-17), also known as IL-17A and CTLA-8, is produced primarily by CD4+ Th17 cells, as well as by other immune cells such as CD8+ T cells, γδ T cells, NK cells, NKT cells, and innate lymphoid cells (ILCs). IL-17A exists as a homodimer (A / A) or as a heterodimer with IL-17F (A / F) and signals through binding to the dimeric receptor complex IL-17RA and IL-17RC. IL-17RA is ubiquitously expressed at particularly high levels by hematopoietic cell types, whereas IL-17RC is preferentially expressed by nonhematopoietic cells (Gaffen, S. Structure and signaling in the IL-17 receptor family. Nat. Rev. Immunol. 2009, 9, 556-567). IL-17A / IL-17R signaling induces de novo gene transcription by inducing NF-kB, C / EBP, and MAPK pathways through the ACT1-TRAF6-TRAF4 complex. It can also stabilize target mRNA transcripts through the ACT1-TRAF2-TRAF5 complex (Amatya N. et al., Trends in Immunology, 2017, 38, 310-322). IL-17A stimulates the release of inflammatory mediators, including IL-6, IL-8, G-CSF, TNF-α, and IL-1β, which recruit and activate lymphocytes to sites of injury or inflammation and maintain a pro-inflammatory state.

[0004] As discussed below, preclinical and clinical data indicate an important pathological role for IL-17A in multiple autoimmune and inflammatory diseases.

[0005] In the case of psoriasis: IL-17A mRNA and / or protein levels are elevated in the lesional skin and blood of patients with psoriasis and correlate with disease severity. IL-17A directly synergizes with other cytokines (such as TNFα, IFNγ, or IL-22) in keratinocytes, triggering a self-amplifying inflammatory response in the skin and leading to the formation of psoriatic plaques. Blockade of IL-17A with antibodies against IL-17A or IL-23 resulted in a complete reversal of the molecular and clinical disease features in the majority of psoriasis patients, highlighting the important role of IL-17A and IL-17-producing T cells in the immunopathogenesis of psoriasis. (Hawkes et al., Psoriasis Pathogenesis and the Development of Novel Targeted Immune Therapies. J Allergy Clin Immunol. 2017, 140(3):645-653). The development and approval of IL-17 monoclonal antibodies, such as secukinumab, ixekizumab, and brodalumab, and their transformative efficacy for psoriasis, point to IL-17A as a valid target for the treatment of psoriasis. (Blauvelt A. and Chiricozzi A. The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis. Clin Rev Allergy Immunol. 2018, 55(3):379-390).

[0006] In psoriatic arthritis (PsA), IL-17A is mechanistically linked to PsA through NFκB activation, which induces the transcription of several PsA-related genes, including receptor activator of nuclear factor κB ligand (RANKL). RANKL induces the differentiation of osteoclast precursor cells into activated osteoclasts, resulting in bone resorption and subsequent joint deformity in PsA (Adamopoulos I. and Mellins E. Nature reviews Rheumatology 2015;11:189-94). PsA joints are enriched in IL-17+CD8+ T cells, and levels of this T cell subset correlate with disease activity (Menon B. et al., Arthritis & Rheumatology 2014;66:1272-81). Synovial fibroblasts isolated from PsA patients also contain elevated IL-17R expression ex vivo and secrete increased IL-6, CXCL8, and MMP3 compared with osteoarthritis patients. Both secukinumab and ixekizumab are FDA-approved drugs for PsA. In matched-adjusted indirect comparison analyses, secukinumab was associated with higher ACR20 / 50 / 70 response rates than anti-TNFα antibodies in patients with active PsA (Mease P. et al., Eur. J. Rheumatol. 2019 Jul 1;6(3):113-121; Strand V. et al., J. Comp. Eff. Res. 2019,8(7):497-510; Nash P. et al., Rheumatol. Ther. 2018,5(1):99-122). In a recent head-to-head study, ixekizumab was superior to adalimumab in achieving simultaneous improvement in joint and skin disease (ACR50 and PASI100) in patients with PsA and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (Mease, P. et al. Ann Rheum Diss 2020;79:123-131).By attacking the same target, IL-17A small molecule inhibitor compounds may exert similar or better efficacy than biologics, where small molecules generally appear to have better tissue penetration.

[0007] In the case of rheumatoid arthritis (RA), IL-17A is recognized as important for the progression of RA. "The recognition of IL-17 as a proinflammatory T cell-derived cytokine and its abundance in rheumatoid joints provides the strongest current candidate mechanism by which T cells can capture and localize macrophage effector function in RA" (Stamp, L. et al., Immunol. Cell Biol. 2004, 82(1):1-9). Furthermore, in RA, IL-17A acts locally on synovial cells and osteoblasts, contributing to synovitis and joint destruction. Robert and Miossec have proposed the use of synovial biopsies and / or biomarkers to accurately identify patients who will respond to IL-17A inhibition. Their paper concludes that IL-17 inhibitors should be considered today in the development of precision medicines for RA. (Robert M. and Miossec P.,Front.Med.,2019,5:364).

[0008] In the case of ankylosing spondylitis (AS): Various studies have reported elevated levels of IL-17A and Th17, as well as other cells that produce IL-17, in blood samples from AS patients (Wendling D. et al., Joint Bone Spine. 2007; 74: 304-305; Shen H. et al., Arthritis Rheum. 2009; 60(6): 1647-56; Zhang L. et al., PLoS One. 2012; 7(4): e31000; Jansen D. et al., Rheumatology (Oxford). 2015 Apr; 54(4): 728-735). In situ analysis of AS spines has revealed increased IL-17A-producing cells in the bone of the facet (facet) joints (Appel H. et al., Arthritis Res. Ther. 2011;13(3):R95). Two advanced IL-17A-neutralizing antibodies for AS, FDA-approved secukinumab and ixekizumab, have demonstrated efficacy over placebo, even in anti-TNF poor responders. In contrast, anti-IL-23 p40 and p19 biologics failed to demonstrate beneficial effects (Deodhar A. et al., Arthritis Rheumatol. 2019, 71(2):258-270; Baeten D. et al., Ann. Rheum. Dis. 2018, 77(9):1295-1302), indicating different underlying mechanisms along the IL-23 / IL-17 pathway in AS and providing strong evidence to support the continued development of IL-17A inhibitors.

[0009] Hidradenitis suppurativa (HS): Increased levels of IL-17 and IL-17-producing T helper cells have been reported in skin lesions of HS patients, and molecular proteomics and gene expression data indicate that the IL-23 / Th17 pathway is upregulated in HS lesions (Schlapbach C. et al., J. Am. Acad. Dermatol. 2011;65(4):790; Kelly G. et al., British J. Dermatol. 2015 Dec;173(6):1431-9; Moran B. et al., J. Invest. Dermatol. 2017;137(11):2389; Thomi R. et al., JAMA Dermatol. 2018;154(5):592). Seven out of nine (78%) patients with moderate-to-severe HS achieved HiSCR in an open-label pilot study with secukinumab (Prussick L. et al., British J. Dermatol. 2019 Sep;181(3):609-611), and further clinical trials with anti-IL-17 mAbs in HS are ongoing.

[0010] In bullous pemphigoid (BP), IL-17 is elevated in the blister fluid and perilesional skin of BP patients (Le Jan S. et al., J. Invest. Dermatol. 2014;134(12):2908-2917; Chakievska LJ Autoimmun. 2019,96:104-112). Exome sequencing of BP patients revealed mutations in 12 IL-17-related genes in one-third of patients, providing a genetic link between the IL-17 pathway and BP (Chakievska LJ Autoimmun. 2019,96:104-112). In experimental murine BP, IL-17A- / - mice were protected, and anti-IL-17A treatment significantly reduced skin lesions in wild-type mice (Chakievska LJ Autoimmun. 2019,96:104-112). A phase 2 study of ixekizumab in treatment-naive and refractory BP patients is ongoing (NCT03099538).

[0011] In the case of atopic dermatitis (AD), IL-17 was found to be elevated in the peripheral blood and lesions of AD patients, and Th17 cells infiltrated significantly more acutely than chronically, suggesting their role in the acute phase of AD (Koga C. et al., J. Invest. Dermatol. 2008, 128, 2625-2630). Molecular profiling analysis from a phase II trial of ustekinumab suggested the possible contribution of the IL-23 / Th17 / IL-17 pathway in AD (Khattri S. et al., Exp. Dermatol. 2017 Jan;26(1):28-35).

[0012] In the case of vitiligo: Many studies in vitiligo patients have shown increased frequencies of Th17 cells and high levels of IL-17 in both the circulation and lesions, which positively correlate with disease duration, severity, and activity (Singh R. et al., Autoimmun. Rev 2016, Apr;15(4):397-404). Mouse studies have shown that atrophy correlates with higher IL-17 expression / secretion, which regulates vitiligo development (Eby J. et al., Pigment Cell & Melanoma Res. 2014 Nov;27(6):1075-85).

[0013] In multiple sclerosis (MS), IL-17 expression is increased in PBMCs, cerebrospinal fluid (CSF), and brain lesions and cells from MS patients (Lock, C. et al., Nat. Med. 2002, 8:500-508; Matusevicius, D. et al., Mult. Scler. 1999, 5:101-104; Tzartos, J. et al., Am. J. Pathol. 2008, 172:146-155). IL-17-producing T cells are abundant in active MS lesions (Tzartos, J. et al., Am. J. Pathol. 2008, 172:146-155; Willing A. et al., J. Immunol. 2018, 200(3):974-982). IL-17A levels are elevated in the CSF of patients with relapsing-remitting MS (RRMS), and in vitro data suggest that IL-17A in combination with IL-6 reduced tight junction-related gene expression and disrupted monolayer integrity in BBB cell lines, correlating with the CSF / serum albumin index, a measure of blood-brain barrier (BBB) ​​dysfunction, highlighting the potential importance of targeting IL-17A in preserving BBB integrity in RRMS (Setiadi AF et al., J Neuroimmunol. 2019, 332:147-154). Secukinumab has shown promising initial results in a proof-of-concept study in MS patients (Havrdova, E. et al., J Neurol. 2016, 263:1287-1295).

[0014] In asthma: IL-17 expression is increased in the lungs, sputum, bronchoalveolar lavage fluid, and serum of patients with asthma, and the severity of airway hyperresponsiveness is positively correlated with IL-17 expression levels (Chakir J. et al., J. Allergy Clin. Immunol. 2003, 111(6):1293-8). IL-17 has been reported to increase in asthmatic airways and induce human bronchial fibroblasts to produce cytokines (Molet S. et al., J. Allergy Clin. Immunol. 2001, 108(3):430-8). Anti-IL-17 antibodies regulate airway responsiveness, inflammation, tissue remodeling, and oxidative stress in a chronic mouse asthma model (Camargo LdN. et al., Front Immunol. 2018;8:1835, dos Santos T. et al., Front. Physiol. 2018,9:1183).

[0015] In chronic obstructive pulmonary disease (COPD), increased Th17 cells were observed in patients with COPD compared with current smokers and healthy controls without COPD, and an inverse correlation was found between Th17 cells and lung function (Vargas-Rojas M. et al., Respir. Med. 2011 Nov;105(11):1648-54). In three recent human COPD studies, gene expression profiles in bronchial epithelium showed that characteristically higher IL-17 expression was associated with a lack of response to inhaled corticosteroids, suggesting the existence of COPD subgroups that could benefit from IL-17 inhibitor therapy (Christenson S. et al., J. Clin. Invest. 2019;129(1):169-181).

[0016] In the case of uveitis, IL-17 promotes the release of inflammatory mediators from retinal pigment epithelial cell lines and disrupts retinal pigment epithelial barrier function (Chen Y. et al., PLoS One. 2011;6:e18139). IL-17 levels were elevated in the serum or aqueous humor of patients with uveitis (El-Asrar A. et al., Clin. Immunol. 2011;139(2):177-84; Jawad S. et al., Ocul. Immunol. Inflamm. 2013;21(6):434-9; Kuiper J. et al., Am. J. Ophthalmol. 2011;152(2):177-182). Anti-IL-17 antibodies delayed the onset of ocular inflammation and significantly inhibited the development of experimental autoimmune uveitis in rats (Zhang R. et al., Curr. Eye Res. 2009 Apr;34(4):297-303). Analysis of secondary efficacy data from a phase 3 trial of subcutaneous (sc) secukinumab in uveitis suggested beneficial efficacy of secukinumab in reducing the use of concomitant immunosuppressive medications (Dick A. et al., Ophthalmology 2013;120(4):777-87). Subsequent studies of intravenous secukinumab in uveitis demonstrated higher efficacy than sc administration, suggesting that optimal exposure is required for efficacy, confirming the therapeutic potential of IL-17A inhibition (Letko E. et al., Ophthalmology 2015,122(5),939-948). Ustekinumab, which blocks the IL-23 / IL-17 pathway, has also been reported to successfully treat patients with non-infectious uveitis who had severe concomitant psoriasis and PsA and who had failed to respond to conventional immunosuppressants (Mugheddu C. et al., Dermatol. Ther. 2017 Sep;30(5);e12527.).

[0017] In multiple myeloma (MM): IL-17A serum levels were significantly higher in MM patients, and also in patients with advanced stages of the disease, compared with healthy controls (Lemancewicz D. et al., Med. Sci. Monit. 2012;18(1):BR54-BR59). In the SCIDhu model of human myeloma, weekly administration of secukinumab for 4 weeks after initial detection of tumors in mice resulted in significant inhibition of tumor growth and reduced bone damage compared with isotype control mice (Prabhala R. et al., Leukemia. 2016 February;30(2):379-389).

[0018] In the case of systemic lupus erythematosus (SLE), increased serum or plasma IL-17 levels, proliferation of IL-17-producing T cells in peripheral blood, and infiltration of Th17 cells in target organs such as the kidney have been observed in SLE patients (Wong C. et al., Lupus. 2000;9(8):589-593; Wong C. et al., Clinical Immunology. 2008;127(3):385-393; Zhao XF. et al., Mol. Biol. Rep. 2010 Jan;37(1):81-5; Chen X. et al., J. Clin. Immunol. 2010 Mar;30(2):221-5; Xing Q. et al., Rheumatol. Int. 2012 Apr;32(4):949-58). An imbalance between Th17 cells and regulatory T (Treg) cells has been observed in patients with SLE, including those in the quiescent phase (Ma J. et al., Clin. Rheumatol. 2010;29(11):1251-1258; Dolff S. et al., Clin. Immunol. 2011,141(2):197-204). Overexpression of IL-17A using adenovirus improved the severity of lupus nephritis, whereas blocking IL-17A using a neutralizing antibody reduced the severity of lupus nephritis (Wen, Z. et al., PLoS One. 2013,8:e58161). In a phase 2 study, ustekinumab, an anti-IL-12 / 23p40 monoclonal antibody that blocks the IL-23 / IL-17 pathway, showed efficacy in patients with SLE (van Vollenhoven R. et al., Lancet 2018;392:1330-39). Human expression studies, animal models, and clinical trials have shown that IL-17 blockade may be a promising therapeutic strategy for SLE (Koga T. et al., Expert Rev. Clin. Immunol. 2019,15(6)629-637).

[0019] In summary, animal and human studies indicate that IL-17A plays a critical role in the pathogenesis of multiple diseases and / or conditions discussed above. The importance of targeting IL-17A is demonstrated by the transformative efficacy of injectable IL-17A neutralizing antibodies in patients.

[0020] Despite the advances achieved with injectable IL-17A antagonist antibodies, there is a long-felt need for the development of oral small molecule IL-17A inhibitors, as these could expand treatment options for many patients without access to biologics. Additionally, safe and effective small molecule IL-17A inhibitors could offer patients significant advantages over injectable IL-17A neutralizing antibodies, such as convenient dosing regimens and reduced costs, which could in turn provide effective long-term disease management.

[0021] However, developing oral small molecule therapeutics remains challenging. For example, as of September 28, 2021, no oral small molecule IL-17A inhibitors have yet advanced to late-stage clinical trials, and only two oral small molecule IL-17A inhibitors have advanced to Phase I clinical trials (NCT04586920 and NCT04883333). Additionally, as of December 2021, one of these clinical trials (NCT04586920) was discontinued for safety review. Summary of the Invention

[0022] Therefore, there is a need for new small molecule IL-17A modulators (eg, inhibitors).

[0023] The present application provides compounds of formula I:

[0024] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 teeth,

[0025] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b independently for each occurrence, -C (1~3) Alkyl or C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1c independently for each occurrence, halo, -C (1~3) Alkyl or C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; p is 0, 1, 2, 3, or 4; n is 1 or 2, m1, m2, and m3 are each independently 0, 1, or 2; R 2 -H, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, and -C (1~3) Alkyl-OC (3~5) The cycloalkyl group may be unsubstituted or may contain 1 to 6 R 2a is substituted with a group, R 2a is independently at each occurrence fluorine, -CN, or -OC (1~3) is alkyl, R 3 is C (1~8) Alkyl, -C (1~6)Alkyl-OC (1~6) Alkyl or -C (1~6) Alkyl-OC (3~5) is cycloalkyl, C (1~8) Alkyl and -C (1~6) Alkyl-OC (1~6) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and (1~6) Alkyl-OC (3~5) cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a Halo, -C (1~6) Alkyl, -OC (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) is cycloalkyl, -C (1~6) Alkyl, -OC (1~6) Alkyl, and -C (0~2) Alkyl-C (3~6) cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, CH, CHF, CHF, CF, and —CN; X is CH, CF or N; Disclosed are compounds of formula I, or a pharmaceutically acceptable salt thereof, wherein Y is CH or CF.

[0026] The present application also discloses a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0027] The present application also discloses a method for treating or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus. DETAILED DESCRIPTION OF THE INVENTION

[0028] definition In the "Background" section and throughout this specification, various publications, articles, and patents are cited or described, and each of these references is incorporated herein by reference in its entirety. The discussion of documents, operations, materials, devices, articles and the like which is included in the specification is for the purpose of providing a context for the present invention. Such discussion is not an admission that any or all of these items constitute part of the prior art to any invention disclosed or claimed.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise defined, certain terms used herein have the meanings set forth herein. All patents, published patent applications, and publications cited herein are incorporated by reference as if fully set forth herein.

[0030] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0031] To assist the reader of this application, the description of the specification is divided into various paragraphs or sections or directed to various embodiments of the application. These separations should not be considered as separating the substance of a paragraph or section or embodiment from the substance of another paragraph or section or embodiment. To the contrary, those skilled in the art will understand that the description herein has broad applicability and encompasses all combinations of the various paragraphs, paragraphs, and sentences that may be envisioned. The discussion of any embodiment is meant to be merely illustrative and is not intended to suggest that the scope of the present disclosure, including the claims, is limited to these examples.

[0032] The term "administering" with respect to the methods of the present invention means a method for therapeutically or prophylactically preventing, treating, or ameliorating a syndrome, disorder, or disease described herein by using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical preparation thereof. Such a method comprises administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical preparation thereof simultaneously or sequentially at different times during the course of treatment, or as a combination therapy.

[0033] The term "subject" refers to a patient, which may be an animal, preferably a mammal, most preferably a human, who will be or has been treated by a method according to an embodiment of the present application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, and the like, more preferably humans.

[0034] The term "therapeutically effective amount" or "effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits the biological or medical response sought by a researcher, veterinarian, physician, or other clinician in a tissue system, animal, or human that prevents, treats, or ameliorates the symptoms of the syndrome, disorder, or disease being treated.

[0035] As used herein, "IL-17" or "IL-17A" refers to interleukin 17A. "IL-17" or "IL-17A" is also referred to as IL17, CTLA8, or CTLA-8. Interleukin 17A is a pro-inflammatory cytokine. This cytokine is produced by a group of immune cells in response to their stimulation. An exemplary amino acid sequence of human IL-17 is shown in GenBank Accession No. NP_002181.1, which can be encoded by a nucleic acid sequence such as that in GenBank Accession No. NM_002190.3.

[0036] As used herein, the term "modulator" refers to any agent or molecule capable of binding to IL-17, including small molecule compounds.

[0037] "Active moiety" refers to a molecule or ion responsible for a physiological or pharmacological action. The compounds of formula (I) exemplified in the Examples and described herein are active moieties.

[0038] As used herein, the term "composition" is intended to encompass a product containing specified ingredients in specified amounts, as well as any product that results directly or indirectly from combining specified amounts of specified ingredients.

[0039] As used herein, the terms "treat," "treating," or "treatment" of any disease, condition, syndrome, or disorder refer, in one embodiment, to ameliorating the disease, condition, syndrome, or disorder (i.e., delaying, arresting, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to alleviating or improving at least one physiological or biochemical parameter associated with or causing the disease, condition, syndrome, or disorder, including those that may not be discernible by the patient. In a further embodiment, "treat," "treating," or "treatment" refers to modulating the disease, condition, syndrome, or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat," "treating," or "treatment" refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome, or disorder.

[0040] As used herein, the term "QD" means once daily.

[0041] As used herein, the term "BID" means twice a day.

[0042] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 12 carbon atoms (i.e., C1 to C6). 12)alkyl) or 1 to 6 carbon atoms (i.e., (C1-C6)alkyl). Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-bu, n-butyl, -CH2CH2CH2CH3), 2-butyl (s-bu, s-butyl, -CH(CH3)CH2CH3), tert-butyl (t-bu, t-butyl, -CH(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2 CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), neopentyl (-CH2C(CH3)3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), heptyl (-(CH2)6CH3), octyl (-(CH2)7CH3), 2,2,4-trimethylpentyl (-CH2C(CH3)2CH2CH(CH3)2), nonyl (-(CH2)8CH3), decyl (-(CH2)9CH3), undecyl (-(CH2) 10 CH3), and dodecyl (-(CH2) 11 Any alkyl group can be unsubstituted or substituted.

[0043] The term “C (a~b) " (where a and b are integers referring to the indicated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl radical, or the radical portion of alkyl represented as a prefix root where alkyl contains a to b carbon atoms, inclusive. For example, C (1~4) represents a radical containing 1, 2, 3, or 4 carbon atoms.

[0044] The term "cycloalkyl" refers to any saturated or partially unsaturated carbocyclic ring system having 3 to 8 carbon atoms (i.e., C (3~8) cycloalkyl), preferably 3 to 6 carbon atoms (i.e., C (3~6)"cycloalkyl" refers to a cycloalkyl ring system having a single ring or multiple rings in spirocyclic or bicyclic form. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless stated otherwise specifically in the specification, cycloalkyl groups can be unsubstituted or substituted. Some cycloalkyl groups can exist as spirocycloalkyls, where two cycloalkyl rings are fused through a single carbon atom, for example, but not limited to, a spiropentyl group.

[0045] [ka] For example, but not limited to, examples of spirohexyl groups include:

[0046] [ka] For example, examples of cycloheptyl groups include, but are not limited to,

[0047] [ka] For example, but not limited to, examples of cyclooctyl groups include:

[0048] [ka] Unless stated otherwise specifically in the specification, siprocycloalkyl groups can be unsubstituted or substituted. Bicyclic cycloalkyl ring systems also include:

[0049] [ka] Examples include:

[0050] The term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon within the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur. The term "heteroaryl" includes a single aromatic ring of 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, or furyl.

[0051] The term "halogen" refers to bromo (-Br), chloro (-Cl), fluoro (-F), or iodo (-I).

[0052] When the compounds disclosed herein contain at least one stereocenter, they may accordingly exist as enantiomers or diastereomers, and it is understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0053] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0054] "Enantiomers" are a pair of stereoisomers that are not superimposable mirror images of each other. A "racemic" mixture is a 1:1 mixture of a pair of enantiomers. A "scalic" mixture of enantiomers is a mixture of enantiomers in a ratio other than 1:1.

[0055] When the process for preparing the compounds according to the present invention gives rise to a mixture of stereoisomers, these isomers can be separated by conventional methods, such as preparative chromatography. The compounds can be prepared in racemic form, and scalico mixtures or individual enantiomers can be prepared either by enantioselective synthesis or resolution. The compounds can be resolved into their constituent enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with optically active acids, such as (-)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds can also be resolved by forming diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using chiral column vial HPLC or SFC. In some cases, 1 leading to complex multiplets and peak integrals in H NMR spectra, 1 Rotamers of the compounds may exist, observable by 1 H NMR.

[0056] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. Chiral centers whose absolute configuration is known are labeled by the prefixes R and S, assigned by standard sequence rule procedures, and preceded, if necessary, by the appropriate locant (Pure & Appl. Chem. 45, 1976, 11-30). A particular example is (R * ) or (S * (R * ) or (S * When (R) is used in the name of a compound or in the chemical description of a compound, it is intended to convey that the compound is a pure single isomer at that stereocenter; however, the absolute configuration of that stereocenter has not been established. * A compound designated as (R) or (S) refers to a compound that is a single isomer pure at that stereocenter, having either the (R) or (S) absolute configuration; *A compound designated as (R) refers to a compound that is a pure single isomer at that stereocenter, having either the (R) or (S) absolute configuration. For example, 4-methyl-N-((R * )-1-(5-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1,2,5-oxadiazole-3-carboxamide:

[0057] [ka] is the following:

[0058] [ka] It refers to a compound that is either

[0059] Pseudochiral asymmetric centers are treated in the same manner as chiral centers but are given the lower case symbol r or s (Angew. Chem. Int. Ed. Engl. 1982, 21, 567-583).

[0060] During any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene & P.G.W. Buts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a subsequent convenient stage using methods known in the art.

[0061] Furthermore, within the scope of the present invention, particularly when referred to in connection with the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, any element is intended to include all isotopes and isotopic mixtures of that element, whether occurring in nature or synthetically produced, in either natural abundance or in isotopically enriched form. For example, reference to hydrogen within that scope is 1 H, 2 H (i.e., deuterium or D), and 3 H (i.e., tritium or T). In some embodiments, the compounds described herein include 2 H (i.e., deuterium) isotopes. For example, -C (1~6) A group designated as alkyl includes not only -CH but also CD, not only CHCH but also CDCD, etc. Similarly, references to carbon and oxygen within those ranges are, respectively, 12 C. 13 C, and 14 C, and 15 O, and 16 O, and 17 O, and 18 The isotopes may be radioactive or non-radioactive. Radiolabeled compounds of the present disclosure include: 3 H, 11 C. 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 The radioisotope may comprise a radioisotope selected from the group including Br. Preferably, the radioisotope is 3 H, 11 C, and 18 It is selected from the group F.

[0062] Compounds of the Disclosure The present application provides compounds of formula I:

[0063] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 teeth,

[0064] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b independently for each occurrence, -C (1~3) Alkyl or C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1c independently for each occurrence, halo, -C (1~3) Alkyl or C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; p is 0, 1, 2, 3, or 4; n is 1 or 2, m1, m2, and m3 are each independently 0, 1, or 2; R 2 -H, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, and -C (1~3) Alkyl-OC (3~5) The cycloalkyl group may be unsubstituted or may contain 1 to 6 R 2a is substituted with a group, R 2a is independently at each occurrence fluorine, -CN, or -OC (1~3) is alkyl, R 3 is C (1~8) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl or -C (1~6) Alkyl-OC (3~5) is cycloalkyl, C (1~8) Alkyl and -C (1~6) Alkyl-OC (1~6) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and (1~6) Alkyl-OC (3~5) cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a Halo, -C (1~6) Alkyl, -OC (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) is cycloalkyl, -C (1~6) Alkyl, -OC (1~6) Alkyl, and -C (0~2) Alkyl-C (3~6) cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, CH, CHF, CHF, CF, and —CN; X is CH, CF or N; Y is CH or CF.

[0065] The present application also provides compounds of formula I-1:

[0066] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 teeth,

[0067] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b independently for each occurrence, -C (1~3) Alkyl or C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1c independently for each occurrence, halo, -C (1~3) Alkyl or C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; p is 0, 1, 2, 3, or 4; n is 1 or 2, m1, m2, and m3 are each independently 0, 1, or 2; R 2 -H, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, and -C (1~3) Alkyl-OC (3~5) The cycloalkyl group may be unsubstituted or may contain 1 to 6 R 2a is substituted with a group, R 2a is independently at each occurrence fluorine, -CN, or -OC (1~3) is alkyl, R 3 is C (1~8) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl or -C (1~6) Alkyl-OC (3~5) is cycloalkyl, C (1~8) Alkyl and -C (1~6) Alkyl-OC (1~6) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and (1~6) Alkyl-OC (3~5) cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a Halo, -C (1~6) Alkyl, -OC (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) is cycloalkyl, -C (1~6) Alkyl, -OC (1~6) Alkyl, and -C (0~2) Alkyl-C (3~6) cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, CH, CHF, CHF, CF, and —CN; X is CH or N.

[0068] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth,

[0069] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) is cycloalkyl, -C (1~3)alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b independently for each occurrence, -C (1~3) Alkyl or C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1c independently for each occurrence, halo, -C (1~3) Alkyl or C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; p is 0, 1, 2, 3, or 4; n is 1 or 2, m1, m2, and m3 are each independently 0, 1, or 2; R 2 -H, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, and -C (1~3) Alkyl-OC (3~5) the cycloalkyl group is unsubstituted or substituted with one -CN group; R 3 is C (1~8) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl or -C (1~6) Alkyl-OC (3~5) is cycloalkyl, C (1~8) Alkyl and -C (1~6) Alkyl-OC (1~6) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and (1~6) Alkyl-OC (3~5)cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a Halo, -C (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) is cycloalkyl, -C (1~6) Alkyl and -C (0~2) Alkyl-C (3~6) cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine and —CN; X is CH, CF or N; Y is CH or CF.

[0070] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth,

[0071] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) is cycloalkyl, R 1b independently for each occurrence, -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) is cycloalkyl, R 1c independently for each occurrence, halo, -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) is cycloalkyl, p is 0, 1, 2, 3, or 4; n is 1 or 2, m1, m2, and m3 are each independently 0, 1, or 2; R 2 -H, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, and -C (1~3) Alkyl-OC (3~5) The cycloalkyl group may be unsubstituted or may contain 1 to 4 R 2a is substituted with a group, R 2a is independently at each occurrence fluorine or —CN; R 3 is C (1~8) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl or -C (1~6) Alkyl-OC (3~5) is cycloalkyl, C (1~8) Alkyl and -C (1~6) Alkyl-OC (1~6) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and (1~6) Alkyl-OC (3~5) cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a Halo, -C (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) is cycloalkyl, -C (1~6) Alkyl and -C (0~2) Alkyl-C (3~6)cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine and —CN; X is CH, CF or N; Y is CH or CF.

[0072] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth,

[0073] [ka] and R 1a is independently at each occurrence CH, CHF, CHF, CF, or cyclopropyl; R 1b is independently at each occurrence CH, CHF, CHF, CF, or cyclopropyl; R 1c is independently at each occurrence fluorine, CH3, CH2F, CHF2, CF3, or cyclopropyl; p is 0, 1, 2, 3, or 4; n is 1 or 2, m1, m2, and m3 are each independently 0, 1, or 2; R 2 -H, -C (1~3) Alkyl, -C (3~4) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~4) is cycloalkyl, -C (3~4) cycloalkyl is unsubstituted or substituted with one -CN group; R 3 is C (1~6) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl or -C (1~4) Alkyl-OC (3~4) is cycloalkyl, C(1~6) Alkyl and -C (1~4) Alkyl-OC (1~4) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and (1~4) Alkyl-OC (3~4) cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a is fluorine, -C (1~6) Alkyl or -C (0~1) Alkyl-C (3~4) is cycloalkyl, -C (1~6) Alkyl and -C (0~1) Alkyl-C (3~4) cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine and —CN; X is CH, CF or N; Y is CH or CF.

[0074] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth,

[0075] [ka] and R 1a is independently at each occurrence CH, CHF, CHF, CF, or cyclopropyl; R 1b is independently at each occurrence CH, CHF, CHF, CF, or cyclopropyl; R 1c is independently at each occurrence fluorine, CH3, CH2F, CHF2, CF3, or cyclopropyl; p is 0, 1 or 2; n is 1 or 2, m1, m2, and m3 are each independently 0, 1, or 2; R 2 -H, -C (1~3) Alkyl, -C (3~4) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~4) is cycloalkyl, -C (3~4) cycloalkyl is unsubstituted or substituted with one -CN group; R 3 teeth,

[0076] [ka] and R 3a , R 3b , R 3c and R 3d are each independently H or CH3; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a is fluorine, -C (1~3) Alkyl or -C (3~4) is cycloalkyl, X is CH, CF or N; Y is CH or CF.

[0077] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth,

[0078] [ka] and R 1a -C (1~3) alkyl, CH2F, CHF2, CF3, or cyclopropyl; R 1cindependently for each occurrence: fluorine, -C (1~3) alkyl, CH2F, CHF2, CF3, or cyclopropyl; m2 is 1 or 2; R 2 -H, -C (1~3) Alkyl, -C (3~4) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~4) is cycloalkyl, -C (3~4) cycloalkyl is unsubstituted or substituted with one -CN group; R 3 teeth,

[0079] [ka] and R 3a , R 3b , R 3c and R 3d are each independently H or CH3; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a is fluorine, -C (1~6) Alkyl or -C (0~1) Alkyl-C (3~4) is cycloalkyl, -C (1~6) Alkyl and -C (0~1) Alkyl-C (3~4) cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine and —CN; X is CH, CF or N; Y is CH or CF.

[0080] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth,

[0081] [ka] and R 1a -C (1~3) alkyl, CH2F, CHF2, CF3, or cyclopropyl; R 1c independently for each occurrence: fluorine, -C (1~3) alkyl, CH2F, CHF2, CF3, or cyclopropyl; m2 is 1 or 2; R 2 -H, -C (1~3) Alkyl, -C (3~4) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~4) is cycloalkyl, -C (3~4) cycloalkyl is unsubstituted or substituted with one -CN group; R 3 teeth,

[0082] [ka] and R 3a , R 3b , R 3c and R 3d are each independently H or CH3; R 4 teeth,

[0083] [ka] and R 4a is fluorine, -C (1~6) Alkyl or -C (0~1) Alkyl-C (3~4) is cycloalkyl, X is CH, CF or N; Y is CH or CF.

[0084] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0085] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) is cycloalkyl, R 1b independently for each occurrence, -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) is cycloalkyl, R 1c independently for each occurrence, halo, -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) is cycloalkyl, p is 0, 1, 2, 3, or 4; n is 1 or 2, m1, m2, and m3 are each independently 0, 1, or 2.

[0086] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0087] [ka] and R 1a is independently at each occurrence CH, CHF, CHF, CF, or cyclopropyl; R 1b is independently at each occurrence CH, CHF, CHF, CF, or cyclopropyl; R 1cis independently at each occurrence fluorine, CH3, CH2F, CHF2, CF3, or cyclopropyl; p is 0, 1 or 2; n is 1 or 2, m1, m2, and m3 are each independently 0, 1, or 2.

[0088] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0089] [ka] and R 1a -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) is cycloalkyl, R 1c independently for each occurrence, halo, -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) is cycloalkyl, m2 is 1 or 2.

[0090] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0091] [ka] and R 1a is CH3, CH2F, CHF2, CF3, or cyclopropyl; R 1c is independently at each occurrence fluorine, CH3, CH2F, CHF2, CF3, or cyclopropyl; m2 is 1 or 2.

[0092] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0093] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; p is 0, 1, 2, 3 or 4.

[0094] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) is cycloalkyl, -C (1~3) The alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; and p is 0, 1, or 2.

[0095] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1a independently for each occurrence, -C (1~3) Alkyl, CH2F, CHF2, CF3 or -C (3~4) cycloalkyl, and p is 0, 1, 2, 3, or 4. In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence, -C (1~3) Alkyl, CH2F, CHF2, CF3 or -C (3~4) cycloalkyl, and p is 0, 1, or 2.

[0096] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1a is, independently at each occurrence, CH3, CH2F, CHF2, CF3, or cyclopropyl; and p is 0, 1, 2, 3, or 4. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1a is independently at each occurrence CH3, CH2F, CHF2, CF3, or cyclopropyl; and p is 0, 1, or 2.

[0097] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0098] [ka] and R 1a -C (1~3) Alkyl or -C (3~5) is cycloalkyl, -C (1~3) The alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms. In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1a -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1a is CH3, CH2F, CHF2, CF3, or cyclopropyl.

[0099] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0100] [ka] and R 1a -C (1~3) Alkyl or -C (3~5) is cycloalkyl, -C (1~3) The alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms. In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1a -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1a is CH3, CH2F, CHF2, CF3, or cyclopropyl.

[0101] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0102] [ka] and R 1a -C (1~3) Alkyl or -C (3~5) is cycloalkyl, -C (1~3) The alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms. In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1a -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1a is CH3, CH2F, CHF2, CF3, or cyclopropyl.

[0103] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0104] [ka] and R 1b independently for each occurrence, -C (1~3) Alkyl or C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1c independently for each occurrence, halo, -C (1~3) Alkyl or C (3~5) is cycloalkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; n is 1 or 2, m1, m2, and m3 are each independently 0, 1, or 2.

[0105] When any one of m1, m2, or m3 is 2, it is understood that the corresponding ring-binding carbon atom is geminally disubstituted. For example, when m1 is 2, R 1 has the following structure:

[0106] [ka]

[0107] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1b independently for each occurrence, -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) is cycloalkyl, and R 1c independently for each occurrence, halo, -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4)In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1b is, independently at each occurrence, CH3, CH2F, CHF2, CF3, or cyclopropyl; R 1c is independently at each occurrence fluorine, CH3, CH2F, CHF2, CF3, or cyclopropyl. In some embodiments, n is 1. In some embodiments, m1 is 0 or 1. In some embodiments, m2 is 1 or 2. In some embodiments, m3 is 0 or 1.

[0108] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0109] [ka] and R 1c independently for each occurrence, halo, -C (1~3) Alkyl or C (3~5) is cycloalkyl, -C (1~3) The alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms, and m2 is 1 or 2. In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1c independently for each occurrence, halo, -C (1~3) Alkyl, CH2F, CHF2, CF3, or -C (3~4) cycloalkyl and m2 is 1 or 2. In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1c is independently at each occurrence fluorine, CH, CHF, CHF, CF, or cyclopropyl; and m is 1 or 2. In some embodiments, m is 2.

[0110] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0111] [ka] is.

[0112] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth,

[0113] [ka] is.

[0114] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth

[0115] [ka] is.

[0116] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 teeth

[0117] [ka] is.

[0118] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 -H, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3)Alkyl-OC (3~5) is cycloalkyl, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, and -C (1~3) Alkyl-OC (3~5) The cycloalkyl group may be unsubstituted or may contain 1 to 4 R 2a is substituted with an R 2a is independently at each occurrence fluorine or —CN.

[0119] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 -H, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, -C (1~6) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, and -C (1~3) Alkyl-OC (3~5) A cycloalkyl group is unsubstituted or substituted with one -CN group.

[0120] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 -H, -C (1~3) Alkyl, -C (3~4) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~4) is cycloalkyl, -C (3~4) A cycloalkyl group is unsubstituted or substituted with one -CN group.

[0121] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 -H, -C (1~3) Alkyl, -C (3~4) Cycloalkyl, or -C (1~3) Alkyl-OC (1~3) Alkyl, or -CH2-OC (3~4) is cycloalkyl, -C (3~4) A cycloalkyl group is unsubstituted or substituted with one -CN group.

[0122] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 is H, methyl

[0123] [ka] is.

[0124] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 teeth

[0125] [ka] is.

[0126] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 teeth

[0127] [ka] is.

[0128] In some embodiments, disclosed herein are compounds of formula Ia:

[0129] [ka] or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, disclosed herein are compounds of formula Iaa:

[0131] [ka] or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, disclosed herein are compounds of formula Ib:

[0133] [ka] or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, disclosed herein are compounds of formula Ibb:

[0135] [ka] or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is C (1~6) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl or -C (1~4) Alkyl-OC (3~4) is cycloalkyl, C (1~6) Alkyl and -C (1~4) Alkyl-OC (1~4) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and (1~4) Alkyl-OC (3~4)The cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms.

[0137] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is unsubstituted or substituted with 1 to 6 fluorine atoms; (1~8) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with 1 to 6 fluorine atoms; (1~6) It is alkyl.

[0138] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 -C (1~6) Alkyl-OC (1~6) Alkyl or -C (1~6) Alkyl-OC (3~5) is cycloalkyl, -C (1~6) Alkyl-OC (1~6) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and (1~6) Alkyl-OC (3~5) The cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms.

[0139] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 -C (1~4) Alkyl-OC (1~4) Alkyl or -C (1~4) Alkyl-OC (3~4) is cycloalkyl, -C (1~4) Alkyl-OC (1~4) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and (1~4) Alkyl-OC (3~4) The cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms.

[0140] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 -C (1~4) Alkyl-OC (1~4) Alkyl or -C (1~4) Alkyl-OC (3~4) is cycloalkyl, -C (1~4) Alkyl-OC (1~4) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms.

[0141] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is unsubstituted or substituted with 1 to 6 fluorine atoms, (1~4) Alkyl-OC (1~6) It is alkyl.

[0142] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 -C (1~6) Alkyl-OC (1~5) Alkyl-CF3 or -C (1~6) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 -C (1~4) Alkyl-OC (1~3) Alkyl-CF3 or -C (1~4) It is alkyl-O-cyclopropyl.

[0143] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 -C (1~6) Alkyl-OC (1~5) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3-C (1~4) Alkyl-OC (1~3) It is alkyl-CF3.

[0144] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 -C (1~6) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 -C (1~4) It is alkyl-O-cyclopropyl.

[0145] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 teeth,

[0146] [ka] and R 3a , R 3b , R 3c and R 3d are each independently H or CH. In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3a , R 3b , R 3c and R 3d In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3a , R 3b , R 3c and R 3d At least two of these are CH3.

[0147] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 teeth,

[0148] [ka] and R 3a , R 3b and R 3c are each independently H or CH. In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3a , R 3b , and R 3c At least one of them is CH3.

[0149] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 teeth,

[0150] [ka] is.

[0151] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 teeth,

[0152] [ka] is.

[0153] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 teeth,

[0154] [ka] is.

[0155] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 teeth,

[0156] [ka] is.

[0157] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 teeth,

[0158] [ka] is.

[0159] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 teeth,

[0160] [ka] is.

[0161] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 teeth,

[0162] [ka] is.

[0163] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is unsubstituted or substituted with 1 to 4 fluorine atoms, (1~6) Alkyl-OC (3~5) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with 1 to 4 fluorine atoms,(1~4) Alkyl-OC (3~4) It is cycloalkyl.

[0164] In some embodiments, disclosed herein are compounds of formula Ic:

[0165] [ka] or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, disclosed herein are compounds of formula Icc:

[0167] [ka] or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, disclosed herein are compounds of formula Ic-1:

[0169] [ka] or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, disclosed herein are compounds of formula Icc-1:

[0171] [ka] or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, disclosed herein are compounds of formula Id:

[0173] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 3a , R 3b , R 3c and R 3d are each independently H or CH3.

[0174] In some embodiments, disclosed herein are compounds of formula Idd:

[0175] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 3a , R 3b , R 3c and R 3d are each independently H or CH3.

[0176] In some embodiments, disclosed herein are compounds of formula Id-1:

[0177] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 3a , R 3b , R 3c and R 3d are each independently H or CH3.

[0178] In some embodiments, disclosed herein are compounds of formula Idd-1:

[0179] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 3a , R 3b , R 3c and R 3dare each independently H or CH3.

[0180] In some embodiments, disclosed herein are compounds of formula Id-2:

[0181] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 3a , R 3b , R 3c and R 3d are each independently H or CH3.

[0182] In some embodiments, disclosed herein are compounds of formula Idd-2:

[0183] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 3a , R 3b , R 3c and R 3d are each independently H or CH3.

[0184] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 4 is 1 to 2 R 4a and 5-membered heteroaryl substituted with a group.

[0185] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 4 is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from O and N, and the 5-membered heteroaryl is unsubstituted or contains 1 to 2 R 4a is substituted with a group.

[0186] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 4 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, or oxadiazolyl, each of which is unsubstituted or has one to two R 4a In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, triazolyl, or oxadiazolyl, each of which is unsubstituted or contains one to two R 4a is substituted with a group.

[0187] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 4 is pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or 1,3,4-oxadiazolyl, each of which is unsubstituted or substituted with one to two R 4a In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, 1,2,4-triazolyl, or 1,2,5-oxadiazolyl, each of which is unsubstituted or contains one to two R 4a is substituted with a group.

[0188] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 4 teeth,

[0189] [ka] is.

[0190] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 4a Halo, -C (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) is cycloalkyl, -C (1~6) Alkyl and -C (0~2) Alkyl-C (3~6) The cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine and —CN.

[0191] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 4a is fluorine, -C (1~6) Alkyl or -C (0~1) Alkyl-C (3~4) is cycloalkyl, -C (1~6) Alkyl and -C (0~1) Alkyl-C (3~4) The cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine and —CN.

[0192] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 4a is fluorine, -C (1~6) Alkyl or -C (0~1) Alkyl-C (3~4) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4a is fluorine, -C (1~3) Alkyl or -C (3~4) It is cycloalkyl.

[0193] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 4a is fluorine, methyl, isopropyl, -CD2CD3 or cyclopropyl.

[0194] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 4 teeth,

[0195] [ka] is.

[0196] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C.

[0197] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0198] In some embodiments, disclosed herein are compounds of formula Ie:

[0199] [ka] or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, disclosed herein are compounds of formula Ie-1:

[0201] [ka] or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, disclosed herein are compounds of formula Ie-2:

[0203] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R3a , R 3b , R 3c and R 3d are each independently H or CH3.

[0204] In some embodiments, disclosed herein is a compound of formula If:

[0205] [ka] or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, disclosed herein are compounds of formula If-1:

[0207] [ka] or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, disclosed herein are compounds of formula If-2:

[0209] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 3a , R 3b , R 3c and R 3d are each independently H or CH3.

[0210] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, i.e., deuterated isotopes containing 1 to 30 deuterium atoms. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, i.e., deuterated isotopes containing 1 to 15 deuterium atoms. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, i.e., deuterated isotopes containing 1 to 7 deuterium atoms.

[0211] In some embodiments, disclosed herein are compounds of Formula (I) having a structure as shown in Table 1A, Table 1B, Table 1C, Table 1D, or Table 1E, or a pharmaceutically acceptable salt thereof.

[0212] [Table 1-1]

[0213] [Table 1-2]

[0214] [Table 2-1]

[0215] [Table 2-2]

[0216] [Table 3]

[0217] [Table 4-1]

[0218] [Table 4-2]

[0219] [Table 5-1]

[0220] [Table 5-2]

[0221] [Table 5-3]

[0222] In some embodiments, disclosed herein are:

[0223] [ka] or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, disclosed herein are:

[0225] [ka] or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, disclosed herein is a compound having the following structure:

[0227] [ka] is a compound of formula I having the formula:

[0228] In some embodiments, disclosed herein is a compound having the following structure:

[0229] [ka] is a compound of formula I having the formula:

[0230] In some embodiments, disclosed herein is a compound having the following structure:

[0231] [ka] is a compound of formula I having the formula:

[0232] In some embodiments, disclosed herein is a compound having the following structure:

[0233] [ka] is a compound of formula I having the formula:

[0234] In some embodiments, disclosed herein is a compound having the following structure:

[0235] [ka] is a compound of formula I having the formula:

[0236] In some embodiments, disclosed herein is a compound having the following structure:

[0237] [ka] is a compound of formula I having the formula:

[0238] In some embodiments, disclosed herein is a compound having the following structure:

[0239] [ka] is a compound of formula I having the formula:

[0240] In some embodiments, disclosed herein is a compound having the following structure:

[0241] [ka] is a compound of formula I having the formula:

[0242] In some embodiments, disclosed herein is a compound having the following structure:

[0243] [ka] is a compound of formula I having the formula:

[0244] In some embodiments, disclosed herein is a compound having the following structure:

[0245] [ka] is a compound of formula I having the formula:

[0246] In some embodiments, disclosed herein is a compound having the following structure:

[0247] [ka] is a compound of formula I having the formula:

[0248] In some embodiments, disclosed herein is a compound having the following structure:

[0249] [ka] is a compound of formula I having the formula:

[0250] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration (e.g., a tablet or capsule).

[0251] In some embodiments, disclosed herein is a pharmaceutical composition made by mixing a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0252] In some embodiments, disclosed herein is a process for making a pharmaceutical composition, comprising mixing a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0253] therapeutic use The present application is also directed to a method for treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0254] In some embodiments, disclosed herein are methods for treating or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment or amelioration a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0256] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriasis.

[0257] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

[0258] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

[0259] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0260] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.

[0261] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.

[0262] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

[0263] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is vitiligo.

[0264] In some embodiments, disclosed herein are methods for treating or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is multiple sclerosis.

[0265] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

[0266] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is asthma.

[0267] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is uveitis.

[0268] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disorder.

[0269] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is multiple myeloma.

[0270] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered orally (e.g., as a tablet or capsule).

[0271] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg QD.

[0272] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg BID.

[0273] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0274] In some embodiments, disclosed herein is the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0275] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0276] In some embodiments, disclosed herein is a method of treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0277] In some embodiments, disclosed herein is a method of treating or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, and ankylosing spondylitis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0278] In some embodiments, disclosed herein are methods of modulating IL-17 activity in a mammal by administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof.

[0279] Also disclosed herein is a method for inhibiting the production of interleukin-17, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0280] Combination therapy The compounds of formula I or pharmaceutically acceptable salts thereof, compositions thereof, or medicaments thereof may also be used in combination with one or more additional therapeutic agents.

[0281] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, and immunosuppressive agents.

[0282] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of anti-TNFα agents, e.g., infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), etanercept (Enbrel®), thalidomide (Immunoprin®), lenalidomide (Revlimid®), and pomalidomide (Pomalyst® / Imnovid®); anti-p40 antibody agents such as ustekinumab (Stelara®); and anti-p19 antibody agents such as guselkumab (Tremfya®), tildrakizumab (Ilumya™ / Ilumetri), risankizumab (Skyrizi™), and mirikizumab.

[0283] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof, in combination therapy with one or more additional therapeutic agents, such as an anti-inflammatory agent, an immunomodulatory agent, or an immunosuppressant, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus.

[0284] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof, in combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents or immunosuppressants, wherein the syndrome, disorder, or disease is psoriasis, psoriatic arthritis, or ankylosing spondylitis. In some embodiments, the IL-17-mediated inflammatory syndrome, disorder, or disease is psoriasis. In some embodiments, the IL-17-mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis. In some embodiments, the IL-17-mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0285] Dosing regimen When used as IL-17A modulators, the compounds disclosed herein may be administered in an effective amount within the daily dosage range of about 0.5 mg to about 1 g, preferably about 0.5 mg to about 500 mg, in single or divided doses. In some embodiments, the dosage is about 5 mg to 400 mg. In some embodiments, the dosage is about 10 mg to 300 mg. In some embodiments, the dosage is about 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 300, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 10 mg to 300 mg QD. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 20 mg to 200 mg QD. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 50 mg to 100 mg QD.

[0287] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 10 mg to 300 mg BID. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 20 mg to 200 mg BID. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 50 mg to 100 mg BID.

[0288] The dosage administered will be affected by factors such as the route of administration, the health, weight, and age of the recipient, frequency of treatment, and the presence of concurrent and unrelated treatments.

[0289] It is also obvious to those skilled in the art that the therapeutically effective dose of the compound of the present invention or its pharmaceutical composition varies depending on the desired effect.Therefore, the optimal dosage can be easily determined by those skilled in the art and varies depending on the specific compound used, the administration method, the strength of the preparation, and the progression of the disease.In addition, factors related to the specific subject being treated, including the subject's age, weight, diet, and administration time, will cause the need to adjust the dosage to an appropriate therapeutic level.Therefore, the above dosage is an example of an average case.Of course, there may be individual cases in which higher or lower dosage ranges are effective, and such cases are also within the scope of the present invention.

[0290] pharmaceutically acceptable salts Pharmaceutically acceptable acidic / anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinolate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, Examples of suitable salts include, but are not limited to, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucoate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, diacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide. Also, examples of suitable organic or inorganic acids include, but are not limited to, hydroiodic acid, perchloric acid, sulfuric acid, phosphoric acid, propionic acid, glycolic acid, methanesulfonic acid, hydroxyethanesulfonic acid, oxalic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, saccharinic acid, and trifluoroacetic acid.

[0291] Pharmaceutically acceptable basic / cationic salts include, but are not limited to, aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethane, or "TRIS"), ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH, NHOH, N-methyl-D-glucamine, piperidine, potassium, potassium t-butoxide, potassium hydroxide (aqueous), procaine, quinine, sodium, sodium carbonate, sodium 2-ethylhexanoate, sodium hydroxide, triethanolamine, or zinc.

[0292] Pharmaceutical Composition The compound of Formula I or its pharmaceutically acceptable salt can be formulated into a pharmaceutical composition containing any known pharmaceutically acceptable carrier.Exemplary carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antibacterial and antifungal agent, and isotonicity agent.Exemplary excipients that can also be components of the formulation include fillers, binders, disintegrants, and lubricants.

[0293] Pharmaceutically acceptable salts of the compounds of Formula I include conventional non-toxic salts or quaternary ammonium salts formed from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecyl sulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate, and tartrate. Base salts include ammonium salts, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with organic bases such as dicyclohexylamino salts, and salts with amino acids such as arginine. In addition, basic nitrogen-containing groups may be quaternized, for example, with alkyl halides.

[0294] The pharmaceutical composition of the present invention can be administered by any means that achieves its intended purpose. Examples include parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular administration. Alternatively, or simultaneously, it may be administered orally. Suitable formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form, such as a water-soluble salt, acidic solution, alkaline solution, aqueous dextrose solution, isotonic carbohydrate solution, and cyclodextrin inclusion complex.

[0295] Also disclosed herein is a method of making a pharmaceutical composition, comprising mixing a pharmaceutically acceptable carrier with any of the compounds of Formula I, or pharmaceutically acceptable salts thereof. Additionally, the present application includes pharmaceutical compositions made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention. [Example]

[0296] abbreviation The following abbreviations may be used throughout this specification and application:

[0297] [Table 6-1]

[0298] [Table 6-2]

[0299] In some embodiments, provided herein are processes and intermediates disclosed herein that are useful for preparing the disclosed compounds, or pharmaceutically acceptable salts thereof.

[0300] [ka]

[0301] The compounds of Formula I of the present invention can be prepared as shown in Scheme 1. Deprotection of the phthalimide group in Compound AI using a reagent such as hydrazine in a solvent such as ethanol affords amine A-II. These conditions are hereafter known as "phthalimide deprotection conditions." Compound A-II can be converted to Compound A-III by a series of reactions known as "urea-forming conditions." This can be accomplished, for example, by (1) preparing a diamine by reacting the amine present in Compound A-II with an activated amino alcohol such as (S)-benzyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide. The adduct formed from this reaction can then be subjected to reducing conditions, such as hydrogenation conditions, to afford the diamine. The resulting diamine can then be treated with CDI or triphosgene in a solvent such as THF or DCM to afford Compound A-III. Deprotection of the sulfinamide and SEM protecting groups using a reagent such as hydrochloric acid in a solvent such as methanol, 1,4-dioxane, or EtOAc, or a mixture thereof, affords amine A-IV. These conditions are known as "SEM deprotection conditions." Compounds of formula I can be prepared from amine A-IV by a variety of methods, some of which are described below. Reaction of amine A-IV with a carboxylic acid (R 4 Amide bond formation between a carboxylic acid chloride (R COH) can be achieved using a coupling agent such as HATU, T3P, or EDCI in the presence of a base such as DIPEA in a solvent such as DMF, MeCN, or DCM, with or without an additive such as HOBt, to give a compound of formula I. Alternatively, amide bond formation can be achieved by coupling a carboxylic acid chloride (R COH) with a carboxylic acid chloride (R COH) in the presence of an additive such as DIPEA in a solvent such as DCM or THF. 4 This can be achieved by treating amine A-IV with a reagent such as COCl) to provide compounds of formula I. Additionally, amine A-IV can be treated with an N-hydroxysuccinic acid ester in the presence of a reagent such as DIPEA in a solvent such as acetonitrile to provide compounds of formula I.

[0302] [ka]

[0303] Amines A-IV can also be prepared as shown in Scheme 2. Deprotection of the SEM and sulfinimide protecting groups in AV using SEM deprotection conditions, followed by protection of the resulting amine with a Boc group using a reagent such as di-tert-butyl dicarbonate in the presence of a base such as sodium carbonate, affords compounds A-VI. Intermediate A-VI can be converted to aldehydes A-VII via a two-step sequence: 1) vinylation in a solvent such as dichloromethane with a reagent such as potassium trifluoro(vinyl)boranide, an additive such as KPO, and a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex, and 2) oxidative cleavage of the olefin prepared in the previous step using reagents such as KOsO·2HO and NaIO. Treatment of aldehyde A-VII with diamine (b-VI) under reductive amination conditions such as NaCNBH in a solvent such as methanol in the presence of an additive such as acetic acid, followed by treatment with a reagent such as triphosgene or CDI in a solvent such as DCM, affords the corresponding cyclic urea A-VIII. Boc deprotection of A-VIII using a reagent such as TFA in a solvent such as DCM then affords amine A-IV.

[0304] [ka]

[0305] Sulfinamide AA may be prepared as shown in Scheme 3. Deprotonation of compound BB using a base such as LDA in a solvent such as THF, followed by treatment with sulfinimine CI, provides sulfinamide AA.

[0306] [ka] H, halo,

[0307] [ka] is.

[0308] [ka]

[0309] Compounds BV and B-IV can be prepared as shown in Scheme 4. Aldehyde BI can be treated with 2-methylpropane-2-sulfinamide in the presence of additives such as PPTS and copper sulfate in a solvent such as DCM to give sulfinimide B-II. 2 Addition of a suitable nucleophile, such as M (where M is Li, MgCl, or MgBr), to compound B-II affords the corresponding adduct (structure not shown), followed by removal of the sulfinamide using a reagent such as HCl in a solvent such as a solvent mixture of 1,4-dioxane. MeOH then affords the corresponding amine B-III. Protection of the amine in B-III as a phthalimide using a reagent such as N-carbethoxyphthalimide or ethyl 1,3-dioxoisoindoline-2-carboxylate in a solvent such as THF in the presence of a base such as triethylamine generates imide B-IV. Alternatively, aldehyde B-I can first be treated with a diamine (e.g., diamine b-VI) under reductive amination conditions such as NaCNBH3 in a solvent such as methanol in the presence of an additive such as acetic acid, followed by treatment with a reagent such as triphosgene or CDI in a solvent such as DCM to afford the corresponding cyclic urea BV.

[0310] [ka]

[0311] Amines A-IVa can be prepared as shown in Scheme 5. Deprotection of the sulfinimide protecting group in AV using a reagent such as iodine in a solvent such as THF and water, followed by protection of the resulting amine (structure not shown) with a Boc group using a reagent such as di-tert-butyl dicarbonate in the presence of a base such as sodium carbonate or TEA, affords compound C-II. The halogenated intermediate C-II can be converted to ketone C-IV via a two-step sequence: 1) vinylation with a reagent such as C-III using additives such as bis(pinacolato)diboron, potassium acetate, and K3PO4 in a solvent such as dichloromethane, and a catalyst such as [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate; and 2) oxidative cleavage of the olefin prepared in the previous step using reagents such as KOsO4·2HO and NaIO4. Ketone C-IV can be converted to compound CV via a two-step process: (1) treatment of compound C-IV with diamine (b-VI) in a solvent such as methanol in the presence of an additive such as acetic acid, with or without an additive such as titanium tetraisopropoxide, under reductive amination conditions such as NaCNBH, followed by (2) treatment of the adduct formed in step (1) with a reagent such as triphosgene or carbonyldiimidazole (CDI) in a solvent such as DCM to afford the corresponding cyclic urea CV. Boc and SEM deprotection of CV using a reagent such as HCl in a solvent such as 1,4-dioxane affords amine A-IVa.

[0312] [ka]

[0313] Amines A-IV can also be prepared as shown in Scheme 6. Protection of the aldehyde in compound C-VI with a reagent such as ethylene glycol in the presence of a catalyst such as p-toluenesulfonic acid monohydrate affords compound C-VII. Deprotonation of compound C-VII using a base such as LDA in a solvent such as THF, followed by treatment with sulfinimine CI, affords sulfinamide C-VIII. Deprotection of the sulfinamide and acetal protecting groups by treatment with a reagent such as iodine in a solvent such as THF and water, followed by protection of the resulting amine with a Boc group using a reagent such as di-tert-butyl dicarbonate in the presence of a base such as sodium carbonate or triethylamine, affords compound A-VIIa. Treatment of aldehyde A-VIIa with diamine (b-VI) under reductive amination conditions such as NaCNBH3 in a solvent such as methanol in the presence of an additive such as acetic acid, followed by treatment with a reagent such as triphosgene or CDI in a solvent such as DCM, affords the corresponding cyclic urea A-VIIIa. Compound A-VIIIa is then Boc-deprotected using a reagent such as TFA in a solvent such as DCM to give amine A-IV.

[0314] [ka]

[0315] Compound A-IV can also be prepared as shown in Scheme 7. Treatment of aldehyde A-VIIa with (R)-2,4,6-trimethylbenzenesulfinamide in the presence of an additive such as titanium isopropoxide in a solvent such as THF provides sulfinimide DI. Treatment of sulfinimide DI with dioxoisoindoline D-II in the presence of a reagent such as Hantzsch's ester and a base such as DIPEA in a solvent such as DMSO provides compound D-III. Treatment of compound D-III with an acid such as HCl in a solvent such as EtOAc provides amine D-IV. Compound D-IV can be converted to amine A-IV using methods similar to those described for the conversion of compound A-II to compound A-IV, as shown in Scheme 1.

[0316] [ka]

[0317] Amines A-IVb can be prepared as shown in Scheme 8. The halogenated intermediate C-II can be converted to aldehyde DV via a two-step sequence: 1) vinylation in a solvent such as dichloromethane or 1,4-dioxane with a reagent such as potassium trifluoro(vinyl)boranide, an additive such as KPO, and a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex, and 2) oxidative cleavage of the olefin prepared in the previous step with reagents such as KOsO·2HO and NaIO. Treatment of aldehyde DV with diamine (b-VI) under reductive amination conditions such as NaCNBH in a solvent such as methanol in the presence of an additive such as acetic acid, followed by treatment with a reagent such as triphosgene or CDI in a solvent such as DCM or THF, affords the corresponding cyclic urea D-VI. Subsequent Boc and SEM deprotection of compound D-VI using reagents such as HCl in a solvent such as 1,4-dioxane provides amine A-IVb.

[0318] Intermediate 1: (R,E)-2-methyl-N-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2-sulfinamide

[0319] [ka]

[0320] Step A: 3-((1,1,1-Trifluoro-2-methylpropan-2-yl)oxy)prop-1-ene. To a suspension of NaH (6.9 g, 172 mmol, 60% dispersion in mineral oil) in NMP (40 mL) at 0° C. was slowly added 2-trifluoromethyl-2-propanol (20 g, 156 mmol) and the mixture was stirred at 0° C. until gas evolution ceased. Allyl bromide (13.3 mL, 156 mmol) was added and the reaction mixture was stirred for 16 h while gradually warming to room temperature. This material was purified by distillation (atmospheric pressure, 190° C.) to afford the title compound as a clear oil in 57% yield.

[0321] Step B: (R,E)-2-Methyl-N-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2-sulfinamide. A solution of 3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)prop-1-ene (15.0 g, 89.2 mmol, Step A) in CHCl (300 mL) was cooled to −78 °C and then treated with ozone for 20 min. The reaction headspace was purged with N, then dimethyl sulfide (7.3 mL, 98 mmol) was added and the mixture was allowed to warm to room temperature. After stirring for 4 h, (R)-2-methylpropane-2-sulfinamide (10.8 g, 89.2 mmol) and copper sulfate (43.6 g, 268 mmol) were added and stirring was continued for 16 h. The mixture was filtered through diatomaceous earth (eg, Celite®), concentrated under reduced pressure, and purified by silica gel chromatography (0-60% EtOAc / hexanes) to afford the title compound in 34% yield.

[0322] Intermediate 2: (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanoic acid

[0323] [ka]

[0324] Sodium hydride (3.5 g, 88 mmol, 60% dispersion in mineral oil) was added portionwise to a solution of (R)-1,1,1-trifluoropropan-2-ol (5.0 g, 44 mmol) in DMF (70 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 30 min and then cooled to 0 °C again. Another solution of (S)-2-bromopropanoic acid (6.0 g, 40 mmol) in DMF (5 mL) was added at 0 °C, and the resulting mixture was warmed to room temperature and stirred for 12 h. After this time, the reaction mixture was poured into ice-cold water (100 mL) and extracted with MTBE (25 mL). The pH of the aqueous layer was adjusted by adding 2 N aqueous HCl (15 mL) until the pH of the mixture was pH 5–6. This aqueous layer was extracted with MTBE (80 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil in 93% yield, which was used without further purification.

[0325] Intermediate 3: (R)-N-methoxy-N-methyl-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanamide

[0326] [ka]

[0327] A round-bottom flask was charged with (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanoic acid (7.6 g, 41 mmol, Intermediate 2), DMF (70 mL), HATU (20 g, 53 mmol), and DIPEA (18 mL, 102 mmol). The mixture was stirred for 5 minutes, after which N,O-dimethylhydroxylamine hydrochloride (6.0 g, 61 mmol) was added. The resulting solution was stirred for 12 hours, after which time the reaction was quenched with water (30 mL) and diluted with MTBE (50 mL). The organic layer was separated, and the aqueous layer was extracted with MTBE (80 mL × 2). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (9-17% EtOAc / petroleum ether) to afford the title compound in 58% yield as a yellow oil.

[0328] Intermediate 4: (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanal

[0329] [ka]

[0330] A round-bottom flask was charged with (R)-N-methoxy-N-methyl-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanamide (5.4 g, 24 mmol, Intermediate 3) and THF (300 mL) and cooled to −78° C., and LAH (4.5 g, 120 mmol) was added portionwise. The resulting mixture was stirred at −78° C. for approximately 1 h and then quenched by the dropwise addition of water (20 mL) at −78° C. A saturated solution of potassium sodium tartrate (120 mL) was added, and the solution was stirred for 30 min and then extracted with MTBE (120 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound in 100% yield, which was used without further purification.

[0331] Intermediate 5: (R,E)-2-methyl-N-((R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide

[0332] [ka]

[0333] A round-bottom flask was charged with (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanal (4.0 g, 24 mmol, Intermediate 4), DCM (200 mL), CuSO (15 g, 94 mmol), 4 Å molecular sieves (4.0 g), (R)-2-methylpropane-2-sulfinamide (5.7 g, 47 mmol), and PPTS (0.59 g, 2.4 mmol). The resulting mixture was stirred at room temperature for 12 h. The suspension was filtered through diatomaceous earth (e.g., Celite®), the filter cake was rinsed with EtOAc (100 mL), and the filtrate was concentrated under reduced pressure. The product was purified by silica gel chromatography (17–25% EtOAc / petroleum ether) to afford the title compound in 40% yield as a yellow oil.

[0334] Intermediate 6: (R)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanoic acid

[0335] [ka]

[0336] The title compound was prepared in 80% yield as described for the synthesis of intermediate 2, using (S)-1,1,1-trifluoropropan-2-ol instead of (R)-1,1,1-trifluoropropan-2-ol.

[0337] Intermediate 7: (R)-N-methoxy-N-methyl-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanamide

[0338] [ka]

[0339] The title compound was prepared in 46% yield as described for the synthesis of Intermediate 3, using (R)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanoic acid (Intermediate 6) instead of (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanoic acid.

[0340] Intermediate 8: (R)-2-(((S-1,1,1-trifluoropropan-2-yl)oxy)propanal

[0341] [ka]

[0342] The title compound was prepared in 80% yield as described for the synthesis of Intermediate 4, using (R)-N-methoxy-N-methyl-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanamide (Intermediate 7) instead of (R)-N-methoxy-N-methyl-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanamide.

[0343] Intermediate 9: (R)-2-methyl-N-((R,E)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide

[0344] [ka]

[0345] The title compound was prepared in 51% yield as described for the synthesis of Intermediate 5, using (R)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanal (Intermediate 8) instead of (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanal.

[0346] Intermediate 10: 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbaldehyde

[0347] [ka]

[0348] Step A: 2-(4-Fluoro-3-nitrophenyl)-1,3-dioxolane. To a 2 L single-neck round-bottom flask equipped with a Dean-Stark trap under N2, 4-fluoro-3-nitrobenzaldehyde (50.0 g, 296 mmol) and toluene (1.0 L) were added. Ethane-1,2-diol (55.0 g, 886 mmol) and TsOH (1.0 g, 5.8 mmol) were added sequentially with stirring at 25 °C, and the resulting mixture was stirred at 110 °C under N2 for 5 h. The mixture was cooled to 25 °C and concentrated under reduced pressure. The resulting mixture was dissolved in EtOAc (1 L), washed with water (3 × 1 L) and brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound as an off-white solid in 93% yield.

[0349] Step B: N-(4-(1,3-dioxolan-2-yl)-2-nitrophenyl)formamide. A 2 L three-neck round-bottom flask was charged with t-BuOK (78.9 g, 703 mmol) and NMP (720 mL) under N. A solution of 2-(4-fluoro-3-nitrophenyl)-1,3-dioxolane (60.0 g, 281 mmol, Step A) and formamide (57.0 g, 1.27 mol) in NMP (480 mL) was added dropwise over 10 minutes with stirring at 5° C. The reaction was stirred at 5° C. for 30 minutes, then cooled to 0° C. and quenched with 7 L of saturated aqueous NH4Cl, and the resulting mixture was extracted with EtOAc (2×2 L). The combined organic layers were washed with brine (5×4 L), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a yellow solid. A mixture of MTBE / EtOAc (10:1, 45 mL) was added to the solid and the resulting slurry was stirred for 16 h. After filtration, the filter cake was collected to give the title compound as a yellow solid in 62% yield.

[0350] Step C: N-(4-(1,3-dioxolan-2-yl)-2-nitrophenyl)-N-((2-(trimethylsilyl)ethoxy)methyl)formamide. A 2 L three-neck round-bottom flask was charged with N-(4-(1,3-dioxolan-2-yl)-2-nitrophenyl)formamide (40.8 g, 171 mmol, Step B), SEM-Cl (32.9 g, 197 mmol), BTEAC (11.2 g, 49.1 mmol), and DCM (400 mL). The mixture was cooled to 5° C., and aqueous NaOH (10% w / v, 400 mL) was added dropwise over 10 min. The reaction was warmed to 25° C. and stirred for 3 h. The layers were separated and the organic layer was washed with water (3 x 600 mL) and brine (600 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to afford the title compound in 83% yield as a brown oil, which was used without further purification.

[0351] Step D: 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbaldehyde. A 2 L three-neck round-bottom flask was charged with N-(4-(1,3-dioxolan-2-yl)-2-nitrophenyl)-N-((2-(trimethylsilyl)ethoxy)methyl)formamide (73.0 g, 198 mmol, Step C), Fe° (14.4 g, 259 mmol), AcOH (300 mL), and EtOH (730 mL). The resulting mixture was stirred at 80° C. for 16 h, after which time the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc (1 L) and filtered. The filtrate was washed successively with water (5 x 1 L), saturated aqueous Na2CO3 (1 L), and brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a brown oil that was used directly in the next step.

[0352] Intermediate 11: (S,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)propane-2-sulfinamide

[0353] [ka]

[0354] A 2 L three-neck round-bottom flask was charged with 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbaldehyde (44.0 g, 95.8 mmol, Intermediate 10), (S)-2-methylpropane-2-sulfinamide (13.9 g, 115 mmol), KHSO (43.4 g, 319 mmol), and toluene (800 mL). The resulting mixture was stirred at 40 °C for 4 h, after which time the reaction was cooled to 25 °C. The reaction mixture was washed with water (3 × 1 L) and brine (1 L), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1:1 petroleum ether / EtOAc), concentrated, slurried in n-heptane (10 V) for 4 h, and filtered. The resulting filter cake was collected to give the title compound in 70% yield as a yellow solid.

[0355] Intermediate 12: (R,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)propane-2-sulfinamide

[0356] [ka]

[0357] To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbaldehyde (16.4 g, 59.3 mmol, Intermediate 10) and (R)-2-methylpropane-2-sulfinamide (14.4 g, 119 mmol) dissolved in THF (500 mL) was added pyridin-1-ium 4-methylbenzenesulfonate (1.81 g, 6.12 mmol) and copper(II) sulfate (29.4 g, 184 mmol). The reaction mixture was heated at 80° C. for 16 h. After that time, the reaction was cooled to room temperature and filtered through a pad of diatomaceous earth (e.g., Celite®), and the filter cake was washed with EtOAc (2×200 mL). The filtrate was concentrated under reduced pressure and the isolated material was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to afford the title compound as a colorless oil (59% yield).

[0358] Intermediate 13: 5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole and 6-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

[0359] [ka]

[0360] To a solution of 5-bromo-1H-benzo[d]imidazole (20.0 g, 102 mmol) in THF (135 mL) was added NaH (6.09 g, 152 mmol, 60% suspension in mineral oil), and the resulting mixture was stirred at 0 °C for 30 min. The purple mixture was then cooled to 0 °C, and SEM-Cl (46.5 g, 279 mmol, 49.4 mL) was added portionwise over 1 h. The yellow mixture was then slowly warmed to 20 °C and stirred at that temperature for 4 h. The reaction mixture was cooled to 0 °C, slowly quenched with water, and extracted with EtOAc (3 × 75 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–100% acetone / hexanes) to afford the mixture of title compounds as a yellow oil in 89% yield.

[0361] Intermediate 14: 1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-benzo[d]imidazole and 1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinyl-1H-benzo[d]imidazole

[0362] [ka]

[0363] A solution of 1,4-dioxane (100 mL) and water (20 mL) was sparged with nitrogen for 10 minutes, followed by the addition of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole and 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (7.00 g, 21.4 mmol, Intermediate 13), potassium trifluoro(vinyl)boranide (5.40 g, 40.3 mmol), KPO (13.6 g, 64.1 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (875 mg, 1.07 mmol). The brown mixture was stirred at 85 °C for 3 hours. The reaction mixture was then cooled to room temperature, diluted with HO (100 mL), and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the mixture of title compounds in 91% yield as a black oil, which was used directly without purification.

[0364] Intermediate 15: 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbaldehyde and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbaldehyde

[0365] [ka]

[0366] To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-benzo[d]imidazole and 1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinyl-1H-benzo[d]imidazole (560 g, 2.04 mol Intermediate 14) and NaIO (1.75 kg, 8.16 mol) in 1,4-dioxane (5.60 L) and HO (2.24 L) was added KOsO 2HO (2.42 g, 6.56 mmol) in HO (100 mL) dropwise over 30 min at 5–10 °C. The yellow suspension was stirred at 25 °C for 5 h. The reaction was then diluted with HO (5 L) and extracted with EtOAc (3 × 5 L). The combined organic layers were washed with brine (3×5 L), dried over anhydrous sodium sulfate, filtered, and concentrated onto silica gel under reduced pressure. The residue was purified by silica gel chromatography (33% EtOAc / petroleum ether) to give the mixture of title compounds as a yellow solid in 78% yield.

[0367] Intermediate 16: (S,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)propane-2-sulfinamide and (S,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)methylene)propane-2-sulfinamide

[0368] [ka]

[0369] 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbaldehyde and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbaldehyde (3.0 g, 11 mmol, Intermediate 15), (S)-2-methylpropane-2-sulfinamide (2.0 g, 17 mmol), CuSO (5.0 g, 31 mmol), and DCM (20 mL) were combined, followed by the addition of PPTS (300 g, 1.2 mmol). The blue mixture was stirred at 35° C. for 12 hours. After that time, the reaction mixture was filtered through diatomaceous earth (e.g., Celite®) and the filter cake was washed with DCM (20 mL). The filtrate was concentrated to dryness and the residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to afford the mixture of title compounds in 47% yield as a yellow gum.

[0370] Intermediate 17: (R,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)propane-2-sulfinamide and (R,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)methylene)propane-2-sulfinamide

[0371] [ka]

[0372] The title compound was prepared in 60% yield as described for Intermediate 16, using (R)-2-methylpropane-2-sulfinamide instead of (S)-2-methylpropane-2-sulfinamide.

[0373] Intermediate 18: 4-Methyl-1,2,5-oxadiazole-3-carbonyl chloride

[0374] [ka]

[0375] A flame-dried round-bottom flask was charged with 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (5.0 g, 39 mmol), DCM (78 mL), and oxalyl chloride (6.7 mL, 78 mmol). The solution was cooled to 0 °C, and DMF (0.30 mL, 4.0 mmol) was added to the solution. The mixture was stirred for 4 hours while warming to room temperature. The mixture was then concentrated to a yellow oil and dissolved in DCM to give a 2 M solution of the title compound, which was used in subsequent reactions without further purification, assuming a 100% yield.

[0376] Intermediate 19: 2,5-dioxopyrrolidin-1-yl 4-methyl-1,2,5-oxadiazole-3-carboxylate

[0377] [ka]

[0378] A flame-dried round-bottom flask was charged with N-hydroxysuccinimide (6.95 g, 58.6 mmol), DCM (98 mL), and DIPEA (10.1 mL, 58.6 mmol). The reaction mixture was cooled to 0 °C, and 4-methyl-1,2,5-oxadiazole-3-carbonyl chloride (19.5 mL, 39.0 mmol, Intermediate 18) was added dropwise. The reaction was stirred at room temperature overnight. Without the addition of additional solvent, the reaction mixture was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0–100% EtOAc (with 10% MeOH) / hexanes) to afford the title compound in 50% yield as a colorless solid.

[0379] Intermediate 20: Ethyl 1-(ethyl-d5)-1H-pyrazole-5-carboxylate

[0380] [ka]

[0381] To a mixture of 1H-pyrazole-3-carboxylate (6.2 g, 44 mmol), K2CO3 (9.1 g, 66 mmol), and DMF (55 mL) was added bromoethane-d5 (5.0 g, 44 mmol), and the resulting mixture was stirred at room temperature for 15 h. The reaction mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was further extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound and its regioisomer. The residue was purified by silica gel chromatography (10–60% EtOAc / hexanes) to give the title compound as a colorless oil in 47% yield as the first eluting fraction.

[0382] Intermediate 21: 1-(ethyl-d5)-1H-pyrazole-5-carboxylic acid

[0383] [ka]

[0384] To a mixture of ethyl 1-(ethyl-d5)-1H-pyrazole-5-carboxylate (3.51 g, 20.2 mmol, Intermediate 20) in THF (61 mL) was added 2 M aqueous NaOH (61 mL, 122 mmol), and the mixture was stirred at room temperature for 3 h. After that time, the mixture was concentrated to remove THF and then washed with DCM (2 × 50 mL). The aqueous layer was then acidified to pH 1 by the addition of 1 N aqueous HCl and extracted with DCM (3 × 50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness to provide the title compound as a white solid in 85% yield.

[0385] Intermediate 22: 4-Cyclopropyl-1,2,5-oxadiazole-3-carbonyl chloride

[0386] [ka]

[0387] The title compound was prepared as described for the synthesis of intermediate 18, using 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid instead of 4-methyl-1,2,5-oxadiazole-3-carboxylic acid, assuming 100% yield.

[0388] Intermediate 23: 2,5-Dioxopyrrolidin-1-yl 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylate

[0389] [ka]

[0390] The title compound was prepared in 76% yield as described for the synthesis of Intermediate 19, using 4-cyclopropyl-1,2,5-oxadiazole-3-carbonyl chloride (Intermediate 22) instead of 4-methyl-1,2,5-oxadiazole-3-carbonyl chloride.

[0391] Intermediate 24: Benzyl (S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

[0392] [ka]

[0393] Step A: (S)-Benzyl (1,1,1-trifluoro-3-hydroxypropan-2-yl)carbamate. (S)-2-Amino-3,3,3-trifluoropropan-1-ol hydrochloride (5.0 g, 30 mmol), NaHCO (7.6 g, 91 mmol), a stir bar, and HO (50 mL) were added to a round-bottom flask, and the resulting solution was treated with CbzCl (6.2 g, 36 mmol). The mixture was stirred under N at 30 °C for 16 h. After that time, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The resulting material was purified by silica gel chromatography (0–20% EtOAc / DCM) to afford the title compound as a white solid in 80% yield.

[0394] Step B: Benzyl (4S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide. A stir bar, CHCN (70 mL), and SOCl (4.5 mL, 62 mmol) were added to a dry round-bottom flask under nitrogen, and the resulting solution was cooled to −30 °C. Next, a solution consisting of (S)-benzyl (1,1,1-trifluoro-3-hydroxypropan-2-yl)carbamate (6.3 g, 24 mmol, Step A) and CHCN (30 mL) was added dropwise to the reaction vessel over 10 min, followed by the dropwise addition of pyridine (10.3 mL, 127 mmol) over 10 min. The mixture was stirred at −30 °C for 2 h, then poured onto crushed ice (100 g) and treated with 10% aqueous KHSO until the pH of the reaction mixture reached pH 4. The resulting mixture was extracted with DCM (3 × 50 mL), and the combined organic extracts were washed with saturated aqueous NaHCO (50 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (0-25% EtOAc / petroleum ether) to give the title compound in 61% yield.

[0395] Step C: Benzyl (S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide. Benzyl (4S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (4.5 g, 15 mmol, Step B), a stir bar, and CHCN (30 mL) were added to a round-bottom flask, which was then cooled to 0 °C, followed by RuCl (302 mg, 1.46 mmol), NaIO (3.4 g, 16 mmol), and water (30 mL). The resulting mixture was stirred at 0 °C for 15 min, removed from the ice bath, and then stirred for an additional 4 h. The reaction mixture was then treated with brine (50 mL) and extracted with MTBE (4 × 50 mL). The combined organic extracts were washed with saturated aqueous NaHCO (50 mL) and brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The isolated material was purified by silica gel chromatography (20-30% EtOAc / petroleum ether) to afford the title compound in 46% yield as a white solid.

[0396] Intermediate 25: Benzyl (S * )-(1,1,1-trifluoro-3-hydroxypropan-2-yl-3,3-d2)carbamate

[0397] [ka]

[0398] Step A: Methyl 2-(((benzyloxy)carbonyl)amino)-3,3,3-trifluoropropanoate. A 500 mL round-bottom flask was charged with NaHCO (55 g, 650 mmol) and water (100 mL) and cooled to 0 °C. THF (200 mL) was then added, followed by the portionwise addition of methyl 2-amino-3,3,3-trifluoropropanoate hydrochloride (25 g, 130 mmol). After 5 min, benzyl chloroformate (36.5 mL, 259 mmol) was added dropwise. After 1 h at 0 °C, the reaction was diluted with EtOAc and the biphasic solution was separated. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated to dryness to give a colorless solid. The product was purified by silica gel chromatography (0-30% EtOAc / hexanes) to afford the title compound in 40% yield as a white solid.

[0399] Step B: Benzyl (S * )-(1,1,1-Trifluoro-3-hydroxypropan-2-yl-3,3-d2)carbamate. A round-bottom flask was charged with methyl 2-(((benzyloxy)carbonyl)amino)-3,3,3-trifluoropropanoate (2.3 g, 7.8 mmol, Step A) and MeOH (30 mL) and cooled to 0 °C. NaBD4 (1.0 g, 24 mmol) was added portionwise, and after the addition was complete, the sides of the flask were rinsed with MeOH (5 mL). After 1.5 h at 0 °C, the reaction mixture was quenched with a small amount of water and poured into brine. The solution was extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to yield a colorless oil that solidified over time. The product was purified by silica gel chromatography (0–50%, EtOAc / hexanes) to give the racemic title compound in 90% yield. The diastereomeric mixture was separated for SFC using the following conditions: Stationary phase: Lux Cellulose 2, 5 um 250 x 21 mm, Mobile phase: 15% methanol:isopropanol (1:1), 85% CO2, Flow rate 96 mL / min. The retention time of the title compound was 1.66 min.

[0400] Intermediate 26: Benzyl (S* )-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d2 2,2-dioxide

[0401] [ka]

[0402] Step A: Benzyl (4S * )-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide. A stir bar, CH3CN (39 mL), and SOCl2 (2.0 mL, 27 mmol) were added to a dry round-bottom flask under nitrogen, and the resulting solution was cooled to -48 °C. Benzyl (S * A solution of )-(1,1,1-trifluoro-3-hydroxypropan-2-yl-3,3-d2)carbamate (2.8 g, 11 mmol, Intermediate 25) and CH3CN (17 mL) was added dropwise to the reaction vessel over 10 min, followed by the dropwise addition of pyridine (4.5 mL, 56 mmol). The mixture was stirred at -45 °C for 15 min and at -35 °C for an additional 2 h. The reaction was then poured onto crushed ice (100 g) and diluted with CHCl2 (50 mL). The aqueous layer was saturated with NaCl, the layers were separated, and the organic layer was concentrated to give a residue. The residue was redissolved in EtOAc (30 mL), washed with 0.1 N aqueous HCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the product as a colorless oil in 99% yield, which was used without further purification.

[0403] Step B: Benzyl (S * )-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-dioxide. In a round-bottom flask, add benzyl (4S) in MeCN (26 mL). *)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide (1.0 g, 3.3 mmol, Step A) was added and cooled to 0 °C. NaIO (0.91 g, 4.3 mmol), RuCl·3H2O (11 mg, 0.043 mmol), and water (20 mL) were added sequentially, and the reaction mixture was stirred at 0 °C for 40 min. After complete consumption of the starting material was observed by LCMS analysis, the reaction mixture was diluted with additional water (20 mL), warmed to room temperature, and stirred for an additional 30 min. The biphasic solution was separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–50% EtOAc / hexanes) to afford the title compound as a white solid in 40% yield.

[0404] Intermediate 27: Benzyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide

[0405] [ka]

[0406] Step A: Benzyl (1,1,1-trifluoro-3-hydroxypropan-2-yl-3,3-d2)carbamate. The title compound was prepared as described for the synthesis of Example 25. However, in Step B, benzyl (1,1,1-trifluoro-3-hydroxypropan-2-yl-3,3-d2)carbamate was not subjected to chiral SFC separation.

[0407] Step B: Benzyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide. A round-bottom flask was charged with imidazole (2.3 g, 33 mmol), EtN (2.5 mL, 18 mmol), and DCM (69 mL), and the mixture was cooled to −40° C. Thionyl chloride (0.70 mL, 9.5 mmol) was then added dropwise, and the resulting solution was stirred for 5 min. Benzyl (1,1,1-trifluoro-3-hydroxypropan-2-yl-3,3-d2 carbamate (2.2 g, 8.3 mmol, Step A) in DCM (49 mL) was then added dropwise via addition funnel. Once the addition was complete, the reaction was warmed to 0 °C and stirred for 1 h. After this time, water was added and the biphasic mixture was extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The product was carried on without further purification (assuming 100% yield).

[0408] Intermediate 28: Benzyl (trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d2 2,2-dioxide

[0409] [ka]

[0410] The title compound was prepared as described for the synthesis of Intermediate 26, using benzyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide (Intermediate 27) instead of benzyl (4S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide to give the title compound in 37% yield.

[0411] Intermediate 29: tert-butyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide

[0412] [ka]

[0413] Step A: tert-Butyl (1,1,1-trifluoro-3-hydroxypropan-2-yl-3,3-d2)carbamate. The title compound was prepared as described for the synthesis of Intermediate 25, using methyl 2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoropropanoate instead of 2-(((benzyloxy)carbonyl)amino)-3,3,3-trifluoropropanoate, and used without further purification.

[0414] Step B: tert-Butyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide. The title compound was prepared as described for the synthesis of Intermediate 27, using tert-butyl (1,1,1-trifluoro-3-hydroxypropan-2-yl-3,3-d2)carbamate (Step A) instead of benzyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide to give the title compound in 91% yield.

[0415] Intermediate 30: (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)isoindoline-1,3-dione

[0416] [ka]

[0417] Step A: (SN-((R)-cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)-2-methylpropane-2-sulfinamide. A 1 L three-necked round-bottom flask was charged with cyclopropylmagnesium bromide (118 mL, 1 M in THF). A solution of TMEDA (13.4 g, 115 mmol) in THF (64 mL) was then added dropwise over 5 min at 25 °C, and the resulting mixture was stirred at this temperature for 0.5 h. The reaction mixture was then cooled to -78 °C and (S,E)- A solution of 2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)propane-2-sulfinamide (16.0 g, 42.2 mmol, Intermediate 11) was added dropwise over 30 min, and the resulting mixture was stirred at −78 °C for 1 h. The reaction mixture was quenched with saturated NH Cl (aq, 500 mL) at 0 °C, and the layers were separated. The organic layer was washed with water (2 × 500 mL) and brine (500 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (15:1 CHCl / MeOH). The product-containing fractions were concentrated under reduced pressure, and the residue was further purified by crystallization in n-heptane:MTBE (25:1.52 V) to afford the title compound as an off-white solid in 92% yield.

[0418] Step B: (R)-Cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanamine. To a solution of (SN-((R)-cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)-2-methylpropane-2-sulfinamide (2.0 g, 4.7 mmol, Step A) in EtOAc (20 mL) was added 4 M HCl in 1,4-dioxane (5.0 mL, 20 mmol) under nitrogen at 0 °C. The mixture was stirred at 0 °C for 30 min, then the mixture was warmed to room temperature and stirred for 16 h. Petroleum ether (200 mL) was added to the reaction, and the mixture was filtered. Saturated aqueous NaHCO3 was added to the filtered solid, and then the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound as a yellow oil in 86% yield.

[0419] Step C: (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)isoindoline-1,3-dione. (R)-Cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanamine (13.2 g, 37.29 mmol, Step B) and THF (250 mL, 50 mmol) were combined and stirred at room temperature under nitrogen, followed by the addition of Hunig's base (20 mL, 116 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then ethyl 1,3-dioxoisoindoline-2-carboxylate (8.57 g, 39.1 mmol) was added. A reflux condenser was attached, and the contents were heated to reflux for 2 days. The contents were cooled to room temperature and transferred to a separatory funnel using EtOAc dilution, then washed twice with deionized water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-100% EtOAc / hexanes) afforded the title compound in 79% yield.

[0420] Intermediate 31: (R)-N-((R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0421] [ka]

[0422] To a −78° C. solution of (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)isoindoline-1,3-dione (3190 mg, 6.97 mmol, Intermediate 30) and (R,E)-2-methyl-N-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2-sulfinamide (2.86 g, 10.5 mmol, Intermediate 1) in THF (70 mL) was added LDA (11 mL, 13 mmol, 1.2 M in THF / hexanes). The reaction mixture was stirred at −78° C. for 30 min, then quenched with AcOH (0.8 mL), warmed to room temperature, and poured into a mixture of saturated aqueous ammonium chloride (20 mL) and brine (50 mL). The mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-100% EtOAc / DCM) afforded the title compound in 57% yield.

[0423] Intermediate 32: (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0424] [ka]

[0425] To a solution of (R)-N-((R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (5640 mg, 7.82 mmol, Intermediate 31) in EtOH (78 mL) was added hydrazine monohydrate (3.5 mL, 48 mmol). The reaction mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue was dissolved in EtOAc, the precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound, which was used without further purification (assuming 100% yield).

[0426] Intermediate 33: (R)-N-((R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0427] [ka]

[0428] Step A: benzyl ((S)-3-(((R)-(2-((R)-1-(((R)-tert-butylsulfinyl)amino)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)amino)-1,1,1-trifluoropropan-2-yl)carbamate. A round-bottom flask was charged with (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (1.2 g, 2.0 mmol, Intermediate 32), CsCO (2.0 g, 6.1 mmol), (S)-benzyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.8 g, 5.5 mmol, Intermediate 24), and anhydrous DMF (30 mL), and the resulting mixture was heated to 30 °C. The reaction mixture was stirred for approximately 16 h until complete consumption of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide was determined by LCMS analysis, at which point the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to afford the product, which was purified by preparative HPLC (Boston Uni C18 40 × 150 mm, 5 μm, 50–80% CHCN / HO with 0.23% formic acid) to afford the title compound as a white solid in 77% yield.

[0429] Step B: (R)—N—((R)-1-(5-((R)-(((S)-2-amino-3,3,3-trifluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide. Benzyl ((S)-3-(((R)-cyclopropyl(2-((R)-1-((R)-1,1-dimethylethylsulfinamido)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)amino)-1,1,1-trifluoropropan-2-yl)carbamate (1.3 g, 1.6 mmol, Step A), MeOH (30 mL), and 10% Pd / C (1.3 g, 10% Pd (50% wet with water)) were added to a 75 mL hydrogenation bottle and the resulting mixture was stirred under H (45 Psi) for 1.5 h. The reaction mixture was then filtered through diatomaceous earth (e.g., Celite®), the filter cake was rinsed with MeOH (30 mL), and the filtrate was concentrated to dryness under reduced pressure to provide the product. The isolated material was purified by silica gel chromatography (0-8% MeOH / DCM) to afford the title compound in 92% yield as a colorless solid.

[0430] Step C: (R)—N—((R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide. To a nitrogen-purged 100 mL three-neck round-bottom flask was added (R)—N—((R)-1-(5-((R)-(((S)-2-amino-3,3,3-trifluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (1.5 g, 2.1 mmol, Step B), DCM (30 mL), and DIPEA (1.1 mL, 6.4 mmol) and then cooled to 0° C. The resulting mixture was then treated with triphosgene (400 mg, 1.35 mmol) and stirred at this temperature for 30 min. The reaction mixture was then treated with water (50 mL), extracted with DCM (2 x 30 mL), and the combined extracts were concentrated under reduced pressure to give the product. The isolated material was purified by silica gel chromatography (0-8% MeOH / DCM) to give the title compound in 58% yield as a yellow solid.

[0431] Intermediate 34: (S)-1-((R)-(2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)-4-(trifluoromethyl)imidazolidin-2-one

[0432] [ka]

[0433] A round-bottom flask was charged with (R)-N-((R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (800 mg, 1.10 mmol, Intermediate 33), anhydrous MeOH (10 mL), and methanolic HCl (4 M, 10 mL, 40 mmol). The resulting mixture was stirred at 55 °C for 3 h. The reaction mixture was then cooled to room temperature, concentrated to dryness under reduced pressure, treated with saturated aqueous NaHCO until the pH of the mixture reached pH 8–9, and extracted with EtOAc (30 mL × 3). The combined extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness to give the crude product. The isolated material was purified by silica gel chromatography (0-7% MeOH / DCM) to give the title compound in 41% yield as a pale yellow solid.

[0434] Intermediate 35: tert-Butyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d2 2,2-dioxide

[0435] [ka]

[0436] The title compound was prepared as described for the synthesis of Intermediate 26, using tert-butyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide (Intermediate 29) instead of benzyl (4S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide to give the title compound in 43% yield.

[0437] Intermediate 36: (R)-N-((R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0438] [ka]

[0439] Step A: (R)—N—((R)-1-(5-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide. To a stirred solution of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (300 mg, 0.508 mmol, Intermediate 32) and 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl trifluoromethanesulfonate (379 mg, 1.02 mmol, described in WO 2010 / 011959) in acetonitrile (2.50 mL) was added DIPEA (97.1 μL, 0.559 mmol). The reaction mixture was heated at 50° C. for 36 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (20-70% acetone / (hexanes with 0.1% TEA)) to give the title compound (306 mg, 74%).

[0440] Step B: (R)—N—((R)-1-(5-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide. To a solution of (R)—N—((R)-1-(5-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (510 mg, 0.627 mmol, Step A) in EtOH (3.13 mL) was added hydrazine monohydrate (93.0 μL, 1.88 mmol). After 1 h at room temperature, the reaction mixture was warmed to 35° C. and stirred for an additional 14 h, at which point a thick slurry had formed. The reaction mixture was cooled in an ice bath, filtered, the filter cake washed with 10 mL of ice-cold EtOH, and the filtrate concentrated to give the title compound, which was used in the next step without further purification.

[0441] Step C: (R)—N—((R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide. To a stirred solution of (R)—N—((R)-1-(5-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (material from Step B) in THF (12 mL) was added CDI (152 mg, 0.94 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with THF (20 mL) and heated at 60° C. for an additional 3 h. The reaction mixture was cooled to room temperature, treated with 3 M aqueous NaOH (2 mL) with stirring for 10 min, diluted with brine (10 mL), and the layers were separated. The organic layer was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound, which was used without further purification.

[0442] Intermediate 37: 1-((R)-(2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0443] [ka]

[0444] To a solution of (R)—N—((R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (0.625 mmol (assumed), Intermediate 36) in 1,4-dioxane (36.6 mL) and MeOH (3.0 mL) at 65° C. was added HCl (2.35 mL, 4 M in 1,4-dioxane). After 2.5 h at this temperature, the reaction mixture was cooled to room temperature, concentrated to dryness under reduced pressure, and diluted with water (60 mL). The aqueous layer was washed with hexane (2 × 20 mL), and the pH of the aqueous layer was adjusted to pH 11 with saturated aqueous NaHCO and 3 M aqueous NaOH. The mixture was then diluted with brine (20 mL) and extracted with EtOAc (4 × 30 mL). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated to give the title compound as a tan solid, which was used without further purification.

[0445] Intermediate 38: (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)propane-2-sulfinamide and (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethyl)propane-2-sulfinamide

[0446] [ka]

[0447] To a mixture of (S,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)propane-2-sulfinamide and (S,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)methylene)propane-2-sulfinamide (120 g, 316 mmol, Intermediate 16) in DCM (1.2 L) at −70° C. was added methylmagnesium bromide (3 M in THF, 948 mL, 2.84 mol). The brown mixture was gradually warmed to 20° C. and stirred for 12 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (1 L). The reaction mixture was extracted with CH2Cl2 (2 × 1000 mL), and the combined organic layers were washed with brine (2 × 1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with a mixture of MTBE (100 mL) and petroleum ether (400 mL) at 40 °C for 30 min, and the precipitate was filtered to give the title compound as a white solid in 30% yield.

[0448] Intermediate 39: (R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethan-1-amine and (R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethan-1-amine

[0449] [ka]

[0450] To a suspension of (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethyl)propane-2-sulfinamide and (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)propane-2-sulfinamide (2.00 g, 5.06 mmol, Intermediate 38) in EtOAc (25 mL) was added HCl (5.1 mL, 20 mmol, 4 M in 1,4-dioxane). The reaction was stirred at room temperature for 1 h and then diluted with HO (50 mL). The resulting solution was washed twice with hexane, and these hexane extracts were discarded. The pH of the aqueous layer was adjusted to pH 10 with NaOH (0.81 g) in a minimal amount of HO and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a mixture of the title compounds in 98% yield.

[0451] Intermediate 40:(R)-N-((R * )-1-(6-((R)-1-aminoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R * )-1-(5-((R)-1-aminoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0452] [ka]

[0453] To a −78° C. solution of (R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethan-1-amine and (R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethan-1-amine (142 mg, 0.488 mmol, Intermediate 39) in THF (5 mL) was added n-BuLi (0.37 mL, 0.59 mmol, 1.6 M in hexanes). After stirring at −78° C. for 30 min, (R,E)-2-methyl-N-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2-sulfinamide (200 mg, 0.732 mmol, Intermediate 1) was added as a solution in THF (1 mL). The reaction was stirred at −78° C. for 30 min, then quenched with EtOH (0.057 mL), diluted with EtOAc, and allowed to warm to room temperature. The mixture was poured onto brine, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were then dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a mixture of the title compounds, which was used without further purification.

[0454] Intermediate 41: (R)-2-methyl-N-((R * )-1-(5-((R)-1-((S))-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)propane-2-sulfinamide and (R)-2-methyl-N-((R * )-1-(6-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)propane-2-sulfinamide

[0455] [ka]

[0456] As described for the synthesis of intermediate 33, instead of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((R * )-1-(6-((R)-1-aminoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R * The title compound was prepared using )-1-(5-((R)-1-aminoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 40) to give the title compound in 23% yield over three steps.

[0457] Intermediate 42: (S)-1-((R)-1-(2-((R * )-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-6-yl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one

[0458] [ka]

[0459] As described for the synthesis of intermediate 34, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-2-methyl-N-((R * )-1-(5-((R)-1-((S))-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)propane-2-sulfinamide and (R)-2-methyl-N-((R * The title compound was prepared using 41 from 4-(6-((R)-1-((S))-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)propane-2-sulfinamide. The product was purified by preparative HPLC (Phenomenex Gemini-NX 3 μm C18 75 × 30 mm, 28–58% MeCN / 0.05% NH3 + 10 mM NH4HCO3 in water) to give the title compound as a white powder in 41% yield after lyophilization.

[0460] Intermediate 43:(R)-N-((R * )-1-(5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R *)-1-(6-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0461] [ka]

[0462] As described for the synthesis of intermediate 36, instead of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((R * )-1-(6-((R)-1-aminoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R * The title compound (43% yield) was prepared using )-1-(5-((R)-1-aminoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 40).

[0463] Intermediate 44:1-((R)-1-(2-((R * )-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0464] [ka]

[0465] As described for intermediate 37, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((R * )-1-(5-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R * The title compound was prepared in 74% yield using 2-(6-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 43).

[0466] Intermediate 45:(R)-N-((S * )-(1-cyanocyclopropyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)-2-methylpropane-2-sulfinamide and (R)-N-((S * )-(1-Cyanocyclopropyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)methyl)-2-methylpropane-2-sulfinamide

[0467] [ka]

[0468] To a solution of cyclopropanecarbonitrile (1.1 mL, 15 mmol) in THF (35 mL) at 0° C. was added potassium bis(trimethylsilyl)amide (1 M in THF, 15 mL, 15 mmol). The mixture was stirred at this temperature for 40 minutes, then cooled to −15° C., and a solution of (R,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)propane-2-sulfinamide and (R,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)methylene)propane-2-sulfinamide (2.2 g, 5.8 mmol, Intermediate 17) in THF (15 mL) was added. The reaction was stirred at 0° C. for 30 minutes and then quenched by the addition of saturated aqueous NaHCO3. The mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed sequentially with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (20-100% (10% MeOH in EtOAc) / CH2Cl2) afforded the title compound in 47% yield.

[0469] Intermediate 46: (S * )-1-(amino(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)cyclopropane-1-carbonitrile and (S * )-1-(amino(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)methyl)cyclopropane-1-carbonitrile

[0470] [ka]

[0471] As described for the synthesis of intermediate 39, (R)-N-((S * )-(1-cyanocyclopropyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)-2-methylpropane-2-sulfinamide and (R)-N-((S * Using (S)-(1-cyanocyclopropyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)methyl)-2-methylpropane-2-sulfinamide (Intermediate 45) instead of (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethyl)propane-2-sulfinamide and (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)propane-2-sulfinamide, the title compound was prepared in 96% yield.

[0472] Intermediate 47: (S * )-1-((1,3-dioxoisoindolin-2-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)cyclopropane-1-carbonitrile and (S * )-1-((1,3-dioxoisoindolin-2-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)methyl)cyclopropane-1-carbonitrile

[0473] [ka]

[0474] As described for step C of the synthesis of intermediate 30, instead of (R)-cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanamine, (S *)-1-(amino(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)cyclopropane-1-carbonitrile and (S * The title compound was prepared in 75% yield using 2-(amino(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)methyl)cyclopropane-1-carbonitrile (Intermediate 46).

[0475] Intermediate 48:(R)-N-((R * )-1-(5-((S * )-(1-cyanocyclopropyl)(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R * )-1-(6-((S * )-(1-Cyanocyclopropyl)(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0476] [ka]

[0477] As described for the synthesis of intermediate 31, instead of (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)isoindoline-1,3-dione, (S * )-1-((1,3-dioxoisoindolin-2-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)cyclopropane-1-carbonitrile and (S* The title compound was prepared using 1-((1,3-dioxoisoindolin-2-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)methyl)cyclopropane-1-carbonitrile (Intermediate 47). Purification by silica gel chromatography (10-100% (10% MeOH in EtOAc) / CHCl) afforded the title compound in 68% yield.

[0478] Intermediate 49:(R)-N-((R * )-1-(5-((S * )-amino(1-cyanocyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R * )-1-(6-((S * )-Amino(1-cyanocyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0479] [ka]

[0480] As described for the synthesis of intermediate 32, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((R * )-1-(5-((S *)-(1-cyanocyclopropyl)(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R * )-1-(6-((S * The title compound was prepared using )-(1-cyanocyclopropyl)(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 48) and used without further purification.

[0481] Intermediate 50:(R)-N-((R * )-1-(5-((S * )-(1-cyanocyclopropyl)(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R * )-1-(6-((S * )-(1-Cyanocyclopropyl)(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0482] [ka]

[0483] As described for the synthesis of intermediate 36, instead of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((R * )-1-(5-((S * )-amino(1-cyanocyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R * )-1-(6-((S * The title compound (39% yield) was prepared using )-amino(1-cyanocyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 49).

[0484] Intermediate 51:1-((S * )-(2-((R * )-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)cyclopropane-1-carbonitrile

[0485] [ka]

[0486] As described for intermediate 37, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((R * )-1-(5-((S * )-(1-cyanocyclopropyl)(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R * )-1-(6-((S * The title compound was prepared in 31% yield using )-(1-cyanocyclopropyl)(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 50).

[0487] Intermediate 52:(R)-N-((1R * ,2R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0488] [ka]

[0489] A round-bottom flask was charged with (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)isoindoline-1,3-dione (2.2 g, 4.9 mmol, Intermediate 30) and THF (40 mL) and cooled to −78° C. Successively, a solution of (R,E)-2-methyl-N—((R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide (2.10 g, 7.72 mmol, Intermediate 5) in LDA (11 mL, 11 mmol, 1 M in THF) and THF (10 mL) was added dropwise over 10 min at −78° C. The resulting mixture was stirred at this temperature for 1 h. The reaction mixture was then quenched with THF (20 mL containing 2% AcOH), and the solution was diluted with EtOAc (50 mL) and brine (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (1–5% MeOH / DCM) followed by preparative HPLC (Boston Uni C18 40 × 150 mm × 5 μm, 62–92% MeCN / water (0.23% FA)) to afford the title compound as an off-white solid in 48% yield after lyophilization.

[0490] Intermediate 53:(R)-N-((1R * ,2R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0491] [ka]

[0492] As described for the synthesis of intermediate 32, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((1R * The title compound was prepared using 1,2R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 52) to provide the title compound.

[0493] Intermediate 54:(R)-N-((1R * ,2R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0494] [ka]

[0495] Step A: Benzyl ((S)-3-(((R)-(2-((1R *,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)amino)-1,1,1-trifluoropropan-2-yl)carbamate. In a round-bottom flask, (R)-N-((1R * ,2R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (396 mg, 0.67 mmol, Intermediate 53), CsCO (655 mg, 2.01 mmol), (S)-benzyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (327 mg, 1.0 mmol, Intermediate 24), and anhydrous DMF (6.7 mL) were added and the resulting mixture was heated to 30 °C. As determined by LCMS analysis, (R)-N-((1R * The reaction mixture was stirred for approximately 1 hour until complete consumption of the 1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide was achieved. The reaction mixture was then diluted with water (100 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to afford the product, which was purified by silica gel chromatography (0–100% ethyl acetate in hexanes (with 10% MeOH)) to afford the title compound in 78% yield as an off-white foam.

[0496] Process B:(R)-N-((1R *,2R)-1-(5-((R)-(((S)-2-amino-3,3,3-trifluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide. Benzyl((S)-3-(((R)-(2-((1R * ,2R)-1-(((R)-tert-Butylsulfinyl)amino)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)amino)-1,1,1-trifluoropropan-2-yl)carbamate (430 mg, 0.46 mmol, Step A), MeOH (18.5 mL), and 10% Pd / C (197 mg, (10% Pd (50% wet with water))) were added to a 75 mL hydrogenation bottle and the bottle was placed in a Parr shaker and shaken under H (45 Psi) for 1.5 h. The reaction mixture was then filtered through diatomaceous earth (e.g., Celite®), the filter cake was rinsed with MeOH (30 mL), and the filtrate was concentrated to dryness under reduced pressure to provide the product, which was used in the subsequent step without further purification, assuming 100% yield.

[0497] Process C:(R)-N-((1R * ,2R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide. In a nitrogen-purged round-bottom flask was added (R)-N-((1R *,2R)-1-(5-((R)-(((S)-2-amino-3,3,3-trifluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (322 mg, 0.459 mmol, Step B) and THF (22.9 mL) were added. The resulting mixture was then treated with CDI (223 mg, 1.38 mmol) and stirred for 2 hours. After 2 hours, additional CDI (446 mg, 2.75 mmol) was added and the reaction temperature was raised to reflux. After 16 hours, the reaction mixture was poured into NaOH (1 M aqueous, 50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with 0.05 M aqueous HCl and brine, and the combined organic extracts were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. This material was purified by silica gel chromatography (0 to 75% EtOAc in hexanes (with 10% MeOH)) to afford the title compound in 32% yield.

[0498] Intermediate 55:(S)-1-((R)-(2-((1R * ,2R)-1-amino-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)-4-(trifluoromethyl)imidazolidin-2-one

[0499] [ka]

[0500] (R)-N-((1R *,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide, * The title compound was prepared using 1,2R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 54) to give the title compound in 84% yield.

[0501] Intermediate 56:(R)-N-((1R * ,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0502] [ka]

[0503] Step A: Benzyl (3-(((R)-(2-((1R *,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-(((R-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)amino)-1,1,1-trifluoropropan-2-yl-3,3-d2)carbamate. In a round-bottom flask, add (R)-N-((1R * ,2R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (791 mg, 1.34 mmol, Intermediate 53), DMF (13.4 mL), CsCO (1.31 g, 4.02 mmol), and benzyl(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d2 2,2-dioxide (996 mg, 2.01 mmol, Intermediate 28) were added and the resulting mixture was stirred at 25 °C for 1 hour. The reaction was then poured into water and extracted three times with EtOAc. The combined organic layers were washed with aqueous LiCl (10% w / v) and brine, dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (0–100% EtOAc (with 10% MeOH) / hexanes) to afford the title compound as a yellow foam in 96% yield.

[0504] Process B:(R)-N-((1R * ,2R)-1-(5-((1R)-((2-amino-3,3,3-trifluoropropyl-1,1-d2)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide. In a 500 mL hydrogenation flask, add benzyl (3-(((R)-(2-((1R *,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-(((R-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)amino)-1,1,1-trifluoropropan-2-yl-3,3-d2)carbamate (1.05 g, 1.25 mmol, Step A), MeOH (50 mL), and 10% Pd / C (0.533 g, 0.501 mmol) were added. The bottle was placed in a Parr shaker and shaken under H2 (45 psi) for 1.5 h. After this time, the reaction mixture was filtered through a pad of diatomaceous earth (Celite®) and the filtrate was concentrated to give the title compound, which was used without further purification in 100% yield (assumed).

[0505] Process C:(R)-N-((1R * ,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide. In a round-bottom flask, (R)-N-((1R *,2R)-1-(5-((1R)-((2-amino-3,3,3-trifluoropropyl-1,1-d2)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (879 mg, 1.25 mmol, Step B), THF (62 mL), and CDI (607 mg, 3.74 mmol) were charged and the solution was heated at 65° C. for 2 h. After this time, additional CDI (1.21 g, 7.48 mmol) was added and the reaction was heated at 65° C. for 16 h. The solution was cooled to 25° C., poured into 1 M aqueous NaOH, and the biphasic mixture was extracted three times with EtOAc. The combined organic layers were washed with 0.05 M aqueous HCl and brine, dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (0–75% EtOAc (10% MeOH) / hexanes) to afford the title compound as an off-white foam in 26% yield.

[0506] Intermediate 57:1-((R)-(2-((1R * ,2R)-1-amino-2-(((R-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)-4-(trifluoromethyl)imidazolidin-2-one-5,5-d2

[0507] [ka]

[0508] In a round-bottom flask, add (R)-N-((1R *,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (239 mg, 0.327 mmol, Intermediate 56), 1,4-dioxane:MeOH (4:1 ratio, 3.3 mL), and 4.0 M HCl in 1,4-dioxane (0.817 mL, 3.27 mmol) were charged and the resulting mixture was heated at 60° C. for 3 hours. The reaction was then cooled to room temperature, diluted with water (10 mL), and washed with 1:1 EtOAc / hexanes (2 x 15 mL). The organic layer was discarded, and the pH of the aqueous layer was adjusted to pH 10 by the addition of 1 N aqueous NaOH. The aqueous layer was extracted with EtOAc (3 x 30 mL), and the combined organic layers were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification (85% yield).

[0509] Intermediate 58:(R)-N-((1R * ,2R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0510] [ka]

[0511] The title compound was prepared as described for the synthesis of Intermediate 52, using (R)-2-methyl-N-((R,E)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide (Intermediate 9) instead of (R,E)-2-methyl-N-((R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide to give the title compound in 57% yield.

[0512] Intermediate 59:(R)-N-((1R * ,2R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0513] [ka]

[0514] (R)-N-((1R) * ,2R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide, * The title compound was prepared using 1,2R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 58) to give the title compound in 83% yield.

[0515] Intermediate 60:(R)-N-((1R * ,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0516] [ka]

[0517] Step A: tert-Butyl (3-(((R)-(2-((1R * ,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)amino)-1,1,1-trifluoropropan-2-yl-3,3-d2)carbamate. * ,2R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide, *The title compound was prepared using tert-butyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22,2-dioxide (Intermediate 35) instead of 1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 59) and benzyl (trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22,2-dioxide to give the title compound in 78% yield.

[0518] Process B:(R)-N-((1R * ,2R)-1-(5-((1R)-((2-amino-3,3,3-trifluoropropyl-1,1-d2)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide. In a round-bottom flask, tert-butyl (3-(((R)-(2-((1R * ,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)amino)-1,1,1-trifluoropropan-2-yl-3,3-d2)carbamate (210 mg, 0.261 mmol, Step A), DCM (13 mL), and TFA (1.0 mL) were added, and the resulting solution was stirred at 25° C. for 1.4 h. The solution was then diluted with water and extracted with 1:1 hexanes / EtOAc. The pH of the aqueous layer was adjusted to pH 10 by the addition of 1 N aqueous NaOH and then extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated to give the title compound, which was used without further purification assuming 100% yield.

[0519] Process C:(R)-N-((1R * ,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide. (R)-N-((1R * ,2R)-1-(5-((1R)-((2-amino-3,3,3-trifluoropropyl-1,1-d2)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide, * ,2R)-1-(5-((1R)-((2-amino-3,3,3-trifluoropropyl-1,1-d2)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Step B), which gave the title compound in an assumed 100% yield, which was used without further purification.

[0520] Intermediate 61:1-((R)-(2-((1R * ,2R)-1-amino-2-(((S-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)-4-(trifluoromethyl)imidazolidin-2-one-5,5-d2

[0521] [ka]

[0522] (R)-N-((1R * ,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide, * The title compound was prepared using 1,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 60) to give the title compound in 85% yield.

[0523] Intermediate 62:(R)-N-((1R * ,2R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0524] [ka]

[0525] (R)-N-((1R *,2R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide, * The title compound was prepared using 1,2R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 59) to give the title compound in 21% yield over three steps.

[0526] Intermediate 63:(S)-1-((R)-(2-((1R * ,2R)-1-amino-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)-4-(trifluoromethyl)imidazolidin-2-one

[0527] [ka]

[0528] (R)-N-((1R * ,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide, *The title compound was prepared using 1,2R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 62) to give the title compound in 85% yield.

[0529] Intermediate 64: (S)-3,3,3-trifluoro-N1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)propane-1,2-diamine

[0530] [ka]

[0531] A round-bottom flask was charged with 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbaldehyde (2.5 g, 9.0 mmol, Intermediate 10) and DCM (90 mL). (S)-3,3,3-trifluoropropane-1,2-diamine bis-hydrogen chloride (3.6 g, 18 mmol) and EtN (5.5 mL, 40 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 30 min. The cloudy solution was then heated to 40 °C and stirred for 1 h. After this time, the reaction was cooled to room temperature, and sodium cyanoborohydride (2.0 g, 32 mmol), MeOH (8.2 mL), and AcOH (2.7 mL) were added sequentially, and the reaction mixture was stirred for 30 min. The reaction mixture was then concentrated under reduced pressure to a residue, which was dissolved in DCM, and the pH of the solution was adjusted to pH 7 with saturated aqueous NaHCO3 under vigorous stirring. The biphasic mixture was separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure to give the title compound, which was used without further purification.

[0532] Intermediate 65: (S)-4-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)imidazolidin-2-one

[0533] [ka]

[0534] A round-bottom flask was charged with (S)-3,3,3-trifluoro-N1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)propane-1,2-diamine (3.51 g, 9.05 mmol, Intermediate 64) and THF (100 mL), and the mixture was heated to 65 °C. CDI (4.40 g, 27.1 mmol) was then added portionwise and stirred at 65 °C for 1 h. The reaction was then cooled to room temperature and quenched with 1 M aqueous NaOH (22.6 mL, 22.6 mmol). The biphasic mixture was concentrated to one-third volume and then diluted with water and EtOAc. The biphasic mixture was separated, and the aqueous layer was extracted three more times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (0-10% MeOH / DCM) to give the title compound in 69% yield.

[0535] Intermediate 66: (R)-2-methyl-N-((R)-1-(5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)propane-2-sulfinamide

[0536] [ka]

[0537] n-BuLi (3.35 mL, 5.36 mmol, 1.6 M in hexane) was added to a 0° C. solution of diisopropylamine (0.783 mL, 5.59 mmol) in THF (3 mL) and stirred at this temperature for 30 minutes to form a solution of LDA. Another solution of (S)-4-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)imidazolidin-2-one (965 mg, 2.33 mmol, Intermediate 65) in THF (23 mL) was cooled to −78° C., and the LDA solution was added dropwise. The resulting solution was stirred at −78° C. for 30 minutes. A solution of (R,E)-2-methyl-N-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2-sulfinamide (891 mg, 3.26 mmol, Intermediate 1) in THF (4 mL) was then added dropwise. The reaction mixture was stirred at −78° C. for 1 h, then quenched with AcOH (0.4 mL) and allowed to warm to room temperature. The solution was diluted with saturated aqueous NaHCO and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10–80% EtOAc (10% MeOH) / DCM) followed by preparative HPLC ((Xbridge Prep C18, 5 μm, 50 × 100 mm), 10–100% MeCN / 20 mM aqueous NH4OH) to give the title compound in 10% yield.

[0538] Intermediate 67: (S)-1-((2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one

[0539] [ka]

[0540] (R)-N-((1R *,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide, The title compound was prepared using ((R)-1-(5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)propane-2-sulfinamide (Intermediate 66) to give the title compound in 66% yield.

[0541] Intermediate 68: (R)-N-((R)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and ((R)-N-((R)-1-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0542] [ka]

[0543] The title compound (50% yield) was prepared as described for the synthesis of Intermediate 31, using 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole and 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (Intermediate 13) instead of (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)isoindoline-1,3-dione.

[0544] Intermediate 69: tert-butyl (R)-(1-(5-bromo-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0545] [ka]

[0546] A solution of (R)-N-((R)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and ((R)-N-((R)-1-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (1.58 g, 2.63 mmol, Intermediate 68) in 1,4-dioxane:MeOH (4:1 ratio, 26 mL) was heated to 55°C. The mixture was heated to rt and HCl (4 M in 1,4-dioxane, 6.6 mL, 26 mmol) was added. The reaction was stirred at this temperature for 16 h. The reaction was then cooled to room temperature, diluted with water (75 mL), and washed with 1:1 EtOAc / hexanes (2 × 25 mL). The organic layer was discarded, and the pH of the aqueous layer was adjusted by the addition of Na2CO3 (2.8 g). To this mixture was added EtOAc (26 mL) and di-tert-butyl dicarbonate (0.58 g, 2.63 mmol), and the reaction was stirred at room temperature overnight. The layers were separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with saturated aqueous NH4Cl and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound in 98% yield.

[0547] Intermediate 70: tert-butyl (R)-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)-1-(5-vinyl-1H-benzo[d]imidazol-2-yl)ethyl)carbamate

[0548] [ka]

[0549] The title compound was prepared as described for the synthesis of Intermediate 14, using tert-butyl (R)-(1-(5-bromo-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (Intermediate 69) in place of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole and 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole, and RuPhos Pd G3 in place of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane at a reaction temperature of 100° C.

[0550] Intermediate 71: tert-butyl (R)-(1-(5-formyl-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0551] [ka]

[0552] To a solution of tert-butyl (R-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)-1-(5-vinyl-1H-benzo[d]imidazol-2-yl)ethyl)carbamate (1.33 g, 3.22 mmol, Intermediate 70) in 1,4-dioxane (50 mL) and HO (50 mL) was added KOsO·2HO (200 mg, 0.54 mmol) and NaIO (13.9 g, 64.8 mmol). The yellow suspension was stirred at 25 °C for 1 h, then the reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium metabisulfite and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10–100% (10% in EtOAc)). MeOH) / hexane) to give the title compound in 97% yield.

[0553] Intermediate 72: tert-butyl (R)-(1-(5-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0554] [ka]

[0555] Step A: tert-butyl (R)-(1-(5-(((3-amino-2,2-difluoropropyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. To a suspension of tert-butyl (R)-(1-(5-formyl-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (683 mg, 1.64 mmol, Intermediate 71) and 2,2-difluoropropane-1,3-diamine dihydrochloride (602 mg, 3.29 mmol) in CHCl (25 mL) was added triethylamine (1.15 mL, 8.22 mmol). The reaction was heated at 40° C. for 1 h, cooled to room temperature, and MeOH (3.3 mL), AcOH (0.38 mL), and sodium cyanoborohydride (620 mg, 9.87 mmol) were added. The mixture was stirred at room temperature for 15 min, then concentrated under reduced pressure and partitioned between saturated aqueous NaHCO and CHCl. ​​The layers were separated, and the aqueous layer was further extracted with CHCl. ​​The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0556] Step B: tert-butyl (R)-(1-(5-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. tert-Butyl (R)-(1-(5-(((3-amino-2,2-difluoropropyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (837 mg, 1.64 mmol, Step A) was dissolved in THF (25 mL), and the reaction was then heated to 65° C. and 1,1′-carbonyldiimidazole (800 mg, 4.93 mmol) was added. After 1 h, the reaction was cooled to room temperature and then quenched by the slow addition of NaOH (1 M in HO, 8.22 mL, 8.22 mmol). The mixture was concentrated under reduced pressure to remove THF and then partitioned between saturated aqueous NaHCO and EtOAc. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (10-100% (10% MeOH in EtOAc) / hexanes) afforded the title compound (74% yield).

[0557] Intermediate 73: (R)-1-((2-(1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0558] [ka]

[0559] A round-bottom flask was charged with tert-butyl (R)-(1-(5-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (244 mg, 0.455 mmol, Intermediate 72), DCM (2 mL), and 2,2,2-trifluoroacetic acid (0.704 mL, 9.10 mmol). The reaction was stirred at room temperature for 1 h, then diluted with EtOAc (5 mL) and washed with saturated aqueous NaHCO3 (2 x 10 mL). The aqueous layer was washed with 4:1 DCM:iPrOH (3 x 25 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0560] Intermediate 74: (R)-N-((S)-2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide

[0561] [ka]

[0562] n-BuLi (14.5 mL, 2.5 M in hexane, 26.2 mmol) was added slowly over 30 min to tributyl(methoxymethyl)stannane (12.2 g, 36.4 mol) dissolved in THF (200 mL) cooled to −78° C. The mixture was stirred at −78° C. for 30 min. Another solution of (R,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)propane-2-sulfinamide (4.6 g, 12.1 mmol, Intermediate 12) in THF (50 mL) was added dropwise to the mixture over 30 min and stirred at −78° C. until (R,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)propane-2-sulfinamide was completely consumed, as judged by LCMS analysis. The reaction was quenched with EtOH (2 mL), warmed to room temperature, and diluted with saturated aqueous NaHCO (200 mL). The mixture was then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The isolated material was purified by silica gel chromatography (0-3% MeOH / DCM) to afford the title compound (76% yield) as a yellow oil.

[0563] Intermediate 75: (S)-2-Methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethan-1-amine

[0564] [ka]

[0565] To a solution of (R)—N-((S)-2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide (3.74 g, 8.79 mmol, Intermediate 74) in EtOAc (43 mL) was added HCl (4.39 mL, 17.6 mmol, 4 M in 1,4-dioxane). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water (20 mL) and washed with 1:1 EtOAc / hexanes (2×20 mL). The organic layer was discarded and the pH of the aqueous layer was adjusted to pH 13 by the addition of 1 M aqueous NaOH. The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were dried over anhydrous NaSO, decanted, and concentrated under reduced pressure to give the title compound, which was used without further purification.

[0566] Intermediate 76: (S)-2-(2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)isoindoline-1,3-dione

[0567] [ka]

[0568] The title compound (71% yield) was prepared as described for the synthesis of Intermediate 30, Step C, using (S)-2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethan-1-amine (Intermediate 75) instead of (R)-cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanamine.

[0569] Intermediate 77:(R)-N-((R *)-1-(5-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0570] [ka]

[0571] The title compound (48% yield) was prepared as described for the synthesis of Intermediate 31, using (S)-2-(2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)isoindoline-1,3-dione (Intermediate 76) instead of (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)isoindoline-1,3-dione.

[0572] Intermediate 78:(R)-N-((R * )-1-(5-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0573] [ka]

[0574] As described for the synthesis of intermediate 32, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((R * The title compound (89% yield) was prepared using )-1-(5-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 77).

[0575] Intermediate 79:(R)-N-((R * )-1-(5-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0576] [ka]

[0577] As described for the synthesis of intermediate 33, instead of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((R *The title compound (50% yield) was prepared using )-1-(5-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 78).

[0578] Intermediate 80:(S)-1-((S)-1-(2-((R * )-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one

[0579] [ka]

[0580] As described for the synthesis of intermediate 34, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((R * The title compound (82% yield) was prepared using )-1-(5-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 79).

[0581] Intermediate 81:(R)-N-((R *)-1-(5-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0582] [ka]

[0583] As described for the synthesis of intermediate 36, instead of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((R * )-1-(5-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 78) was used to prepare the title compound and used without further purification.

[0584] Intermediate 82:1-((S)-1-(2-((R * )-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0585] [ka]

[0586] (R)-N-((1R * ,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide, * )-1-(5-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 81) was used to prepare the title compound and used without further purification.

[0587] Intermediate 83: tert-butyl ((R)-1-(5-(((R * )-2-Oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0588] [ka]

[0589] Intermediate 84: tert-Butyl ((R)-1-(5-(((S * )-2-Oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0590] [ka]

[0591] The title compound was prepared as described for the synthesis of intermediate 72, using 3,3,3-trifluoropropane-1,2-diamine dihydrochloride instead of 2,2-difluoropropane-1,3-diamine dihydrochloride. The material was purified by SFC using a chiral stationary phase (stationary phase: Chiralpak IBN-5, 5 μm 250 × 21 mm, mobile phase: 10% methanol, 90% CO). Intermediate 83 was the first eluting peak, and intermediate 84 was the second eluting peak (7% and 7% yields for the two steps, respectively).

[0592] Intermediate 85: (S * )-1-((2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one

[0593] [ka]

[0594] tert-Butyl ((R)-1-(5-(((S * )-2-Oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (50 mg, 0.09 mmol, Intermediate 84) was treated with TFA (0.28 mL, 3.6 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (2 x 2 mL), and the combined organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. This material was used without further purification.

[0595] Intermediate 86: (R *)-1-((2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one

[0596] [ka]

[0597] tert-Butyl ((R)-1-(5-(((S * )-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate, * )-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (Intermediate 83) was used to prepare the title compound and used without further purification.

[0598] Intermediate 87: 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine and 5-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine

[0599] [ka]

[0600] The title compound was prepared as described for the synthesis of intermediate 13, using 5-chloro-3H-imidazo[4,5-b]pyridine instead of 5-bromo-1H-benzo[d]imidazole and DMF instead of THF as the solvent. Purification by silica gel chromatography (0–100% (10% MeOH in EtOAc) / hexanes) afforded the title compound in 73% yield.

[0601] Intermediate 88: 1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-imidazo[4,5-b]pyridine and 3-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-3H-imidazo[4,5-b]pyridine

[0602] [ka]

[0603] The title compound was prepared as described for the synthesis of Intermediate 14, using 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine and 5-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine (Intermediate 87) in place of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole and 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole. The material was purified by silica gel chromatography (0-80% EtOAc / hexanes) to afford the title compound in 78% yield.

[0604] Intermediate 89: 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-5-carbaldehyde and 3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-5-carbaldehyde

[0605] [ka]

[0606] The title compound was prepared in 67% yield as described for the synthesis of Intermediate 15, using 1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-imidazo[4,5-b]pyridine and 3-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-3H-imidazo[4,5-b]pyridine (Intermediate 88) instead of 1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-benzo[d]imidazole and 1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinyl-1H-benzo[d]imidazole.

[0607] Intermediate 90: 3,3,3-trifluoro-N1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methyl)propane-1,2-diamine and 3,3,3-trifluoro-N1-((3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)methyl)propane-1,2-diamine

[0608] [ka]

[0609] The title compound was prepared as described for the synthesis of Intermediate 64, using 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-5-carbaldehyde and 3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-5-carbaldehyde (Intermediate 89) in place of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbaldehyde, and 3,3,3-trifluoropropane-1,2-diamine bishydrogen chloride in place of (S)-3,3,3-trifluoropropane-1,2-diamine-bishydrogen chloride, and used without further purification.

[0610] Intermediate 91: 4-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methyl)imidazolidin-2-one and 4-(trifluoromethyl)-1-((3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)methyl)imidazolidin-2-one

[0611] [ka]

[0612] As described for the synthesis of intermediate 65, The title compound was prepared in 78% yield using 3,3,3-trifluoro-N1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methyl)propane-1,2-diamine and 3,3,3-trifluoro-N1-((3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)methyl)propane-1,2-diamine (Intermediate 90) instead of (S)-3,3,3-trifluoro-N1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)propane-1,2-diamine.

[0613] Intermediate 92: (R)-2-methyl-N-((1R * )-1-(5-((2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)propane-2-sulfinamide and (R)-2-methyl-N-((1R *)-1-(5-((2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)propane-2-sulfinamide

[0614] [ka]

[0615] The title compound was prepared in 31% yield as described for the synthesis of Intermediate 66, using 4-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methyl)imidazolidin-2-one and 4-(trifluoromethyl)-1-((3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)methyl)imidazolidin-2-one (Intermediate 91) instead of (S)-4-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)imidazolidin-2-one.

[0616] Intermediate 93: 1-((2-((R * ))-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-imidazo[4,5-b]pyridin-5-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one

[0617] [ka]

[0618] (R)-N-((1R) *,2R)-1-(5-((1R)-cyclopropyl(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide, * )-1-(5-((2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)propane-2-sulfinamide and (R)-2-methyl-N-((1R * The title compound was prepared in 99% yield using 2-(5-((2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)propane-2-sulfinamide (Intermediate 92).

[0619] Intermediate 94:(R)-N-((R * )-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0620] [ka]

[0621] Step A: (R)-Cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methanamine. The title compound was prepared as described for the synthesis of Intermediate 39 using (R)-N-((R)-cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methyl)-2-methylpropane-2-sulfinamide (Intermediate 115) instead of (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethyl)propane-2-sulfinamide and (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)propane-2-sulfinamide to afford the title compound as an off-white foam. This material was used directly in the next step.

[0622] Step B: (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methyl)isoindoline-1,3-dione. The title compound was prepared as described for Intermediate 30, Step C, using (R)-cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methanamine instead of (R)-cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanamine. The resulting material was recrystallized from hot ethyl acetate to afford the title compound as a white solid (88% yield over two steps).

[0623] Process C:(R)-N-((R *)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide. A round-bottom flask was charged with (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methyl)isoindoline-1,3-dione (2.2 g, 4.9 mmol, Step B), (R,E)-2-methyl-N-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2-sulfinamide (2.0 g, 7.3 mmol, Intermediate 1), and THF (97 mL). The suspension was stirred for approximately 5 minutes until homogeneous and then cooled to −78° C. A freshly prepared, cold solution of LDA (5.4 mL, 5.4 mmol, 1 M in THF) was added dropwise, maintaining the internal temperature below −70° C. The reaction mixture was stirred for 30 minutes. To this solution was added acetic acid (2.4 mL, 24.4 mmol, 10 M in THF) dropwise, and the solution was allowed to warm to room temperature. The reaction mixture was diluted with water and ethyl acetate, the layers were separated, and the aqueous phase was extracted twice more with ethyl acetate. The combined organics were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. This material was suspended in diethyl ether and allowed to stand for 1 hour. The remaining (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methyl)isoindoline-1,3-dione formed a white precipitate that was removed by filtration. The filtrate was concentrated, and the resulting material was purified by silica gel chromatography (0–100% ethyl acetate / DCM). Product-containing fractions were concentrated to dryness to afford the title compound as a white solid (43% yield).

[0624] Intermediate 95:(R)-N-((R *)-1-(5-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0625] [ka]

[0626] Process A:(R)-N-((R * )-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide. * )-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide The title compound was prepared by using Intermediate 94) instead of (R)—N-((R-1-(5-((R-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide to afford the title compound as an off-white foam (96% yield).

[0627] Process B:(R)-N-((R *)-1-(5-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide. A flask was charged with (R)-N-((R * )-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 0.85 mmol, Step A), 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl trifluoromethanesulfonate (394 mg, 1.1 mmol, WO 2010 / 011959), MeCN (3 mL), and DIPEA (291 μL, 1.7 mmol) were added to the reaction. The reaction was stirred for 1 hour. The reaction was diluted with water and ethyl acetate. The layers were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over anhydrous MgSO, filtered, and concentrated. The crude material was purified by silica gel chromatography (1-100% ethyl acetate (with 10% MeOH) / hexanes) to afford the title compound as an off-white foam (58% yield).

[0628] Intermediate 96:(R)-N-((R * )-1-(5-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0629] [ka]

[0630] In a flask, add (R)-N-((R * )-1-(5-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (385 mg, 0.47 mmol, Intermediate 95), EtOH (2.5 mL), and hydrazine monohydrate (350 μL, 4.7 mmol) were added. The reaction was stirred at room temperature for 2 hours. After that time, the reaction was diluted with water and ethyl acetate, the layers were separated, and the aqueous phase was extracted two more times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous MgSO.sub.4, filtered, and concentrated to give the title compound as a glassy solid (98% yield).

[0631] Intermediate 97:(R)-N-((R * )-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0632] [ka]

[0633] In a flask, add (R)-N-((R *)-1-(5-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (320 mg, 0.47 mmol, Intermediate 96), THF (9 mL), DIPEA (242 μL, 1.4 mmol), and CDI (227 mg, 1.4 mmol) were added. The reaction mixture was warmed to 60° C. and stirred for 1 h. The reaction was cooled to room temperature and quenched by the addition of water. The resulting solution was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. This material was purified by silica gel chromatography (0-100% ethyl acetate (with 10% MeOH) / hexanes) to afford the title compound as a glassy solid (99% yield).

[0634] Intermediate 98:1-((R)-(2-((R * )-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-imidazo[4,5-b]pyridin-5-yl)(cyclopropyl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0635] [ka]

[0636] The flask contains a stir bar, (R)-N-((R *)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (330 mg, 0.47 mmol, Intermediate 97), ethyl acetate (11 mL), resorcinol (294 mg, 2.7 mmol), and HCl (736 μL, 2.9 mmol, 4 M in 1,4-dioxane). The reaction was warmed to 60° C. and stirred for 1 hour. The reaction was cooled to room temperature. The mixture was concentrated, and the residue was dissolved in water. The aqueous phase was washed twice with a 30% ethyl acetate solution in hexanes, and the washes were discarded. The pH of the remaining aqueous layer was adjusted to pH 6 by the addition of 1N aqueous NaOH and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. This material was purified by preparative HPLC ((Xbridge Prep C18, 5 μm, 50 × 100 mm), 10–100% MeCN / 20 mM aqueous NH4OH). The product-containing fractions were lyophilized to afford the title compound as a white solid (25% yield).

[0637] Intermediate 99:(R)-N-((1R * ,2R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0638] [ka]

[0639] The title compound was prepared as described for Intermediate 94 Step C, using (R,E)-2-methyl-N-((R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide (Intermediate 5) instead of (R,E)-2-methyl-N-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2-sulfinamide to afford the title compound as an off-white solid.

[0640] Intermediate 100:(R)-N-((1R * ,2R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0641] [ka]

[0642] As described for intermediate 32, instead of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((1R * ,2R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 99) to afford the title compound as an off-white foam (98% yield).

[0643] Intermediate 101:(R)-N-((1R * ,2R)-1-(5-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0644] [ka]

[0645] (R)-N-((R * )-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, * ,2R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 100) was used to prepare the title compound to afford the title compound as a white foam (100% yield, assumed).

[0646] Intermediate 102:(R)-N-((1R * ,2R)-1-(5-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0647] [ka]

[0648] (R)-N-((R * )-1-(5-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, * ,2R)-1-(5-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 101) to afford the title compound as an off-white foam (48% yield).

[0649] Intermediate 103:(R)-N-((1R * ,2R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0650] [ka]

[0651] (R)-N-((R * )-1-(5-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, * ,2R)-1-(5-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 102) to afford the title compound as a glassy solid (99% yield).

[0652] Intermediate 104:1-((R)-(2-((1R * ,2R)-1-amino-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1H-imidazo[4,5-b]pyridin-5-yl)(cyclopropyl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0653] [ka]

[0654] In a flask, add (R)-N-((1R *,2R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (490 mg, 0.69 mmol, Intermediate 103), 1,4-dioxane (4 mL), MeOH (1 mL), and HCl (0.69 mL, 2.8 mmol, 4 M in 1,4-dioxane) were charged. The reaction was warmed to 60° C. and stirred for 1 h. The reaction was cooled to room temperature and concentrated. The residue was dissolved in water and washed twice with hexane (washings were discarded). The pH of the resulting aqueous solution was adjusted to pH > 7 by careful addition of saturated aqueous sodium bicarbonate. This solution was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous MgSO, filtered, and concentrated to a glassy solid (91% yield).

[0655] Intermediate 105: (R,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methylene)propane-2-sulfinamide

[0656] [ka]

[0657] A mixture of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-5-carbaldehyde and 3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-5-carbaldehyde (50.0 g, 180 mmol, Intermediate 89), (R)-2-methylpropane-2-sulfinamide (26.2 g, 216 mmol), CsCO (88.1 g, 270 mmol), and anhydrous CHCl (400 mL) was added to a 1 L three-necked round-bottom flask. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), and the filtrate was concentrated under reduced pressure to give the product (70 g as a dark oil). This material was combined with two other batches for purification by silica gel chromatography (35–70% ethyl acetate / petroleum ether) to give two products. The first eluted product, (R,E)-2-methyl-N-((3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)methylene)propane-2-sulfinamide, was obtained as a dark orange oil (47 g, 26%). The second eluted product (title compound, Intermediate 105), (R,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methylene)propane-2-sulfinamide, was obtained as a yellow solid (13%).

[0658] Intermediate 106: (R)-N-((S)-2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide

[0659] [ka]

[0660] A three-neck round-bottom flask was charged with anhydrous THF (150 mL) and tributyl(methoxymethyl)stannane (21.1 g, 63 mmol). The flask was cooled to -78 °C, and n-BuLi solution (2.5 M in hexane, 25.2 mL, 63.1 mmol) was added dropwise. The mixture was stirred for 1 h and then treated with a solution of (R,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methylene)propane-2-sulfinamide (8.00 g, 21.0 mmol, Intermediate 105) in 50 mL of anhydrous THF. After stirring the reaction mixture for 2 h, it was quenched with EtOH (10 mL), warmed to room temperature, and then quenched with saturated aqueous NaHCO (10 mL) and HO (10 mL). The combined aqueous phase was extracted with EtOAc (500 mL × 3). The combined organic extracts were washed with brine (50 mL) and saturated aqueous KF (50 mL), successively dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a yellow oil. This oil was purified by silica gel chromatography (0–2% methanol / dichloromethane) to give the product as a dark orange oil, which was further purified by HPLC (YMC-Triart Prep C column, 10 μm, 250 × 50 mm; 35–70% (v / v) HO (0.225% HCOOH) / CHCN). The diastereomers were separated by SFC using a chiral stationary phase (DAICEL CHIRALPAK AS column, 10 μm, 250 mm × 50 mm; 30% (v / v) EtOH (containing 0.1% of 25% NH3 / CO2 in water) to give two products. The first eluting compound, Intermediate 106, was obtained as a pale yellow solid (61% yield). The stereochemistry of the title compound was determined by comparison with material whose stereochemistry was unambiguously assigned.

[0661] Intermediate 107: (S)-2-Methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)ethan-1-amine

[0662] [ka]

[0663] (R)-N-((S * The title compound was prepared using (R)—N-((S)-2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 106) instead of (R)—N-((S)-2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide.

[0664] Intermediate 108: (S)-2-(2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione

[0665] [ka]

[0666] The title compound was prepared as described for the synthesis of Intermediate 30, Step C, using (S)-2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)ethan-1-amine (Intermediate 107) instead of (R)-cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanamine.

[0667] Intermediate 109:(R)-N-((1R * ,2R)-1-(5-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0668] [ka]

[0669] As described for the synthesis of intermediate 31, (S)-2-(2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione was used instead of (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)isoindoline-1,3-dione. The title compound was prepared (75% yield) using (R)-2-methyl-N-((R,E)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide (Intermediate 5) instead of (Intermediate 108) and (R,E)-2-methyl-N-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2-sulfinamide.

[0670] Intermediate 110:(R)-N-((1R * ,2R)-1-(5-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0671] [ka]

[0672] As described for intermediate 32, instead of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((1R * ,2R)-1-(5-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 109) was used to prepare the title compound, affording the title compound as an off-white foam (99% yield).

[0673] Intermediate 111:(R)-N-((1R * ,2R)-1-(5-((S)-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0674] [ka]

[0675] (R)-N-((R * )-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide,* ,2R)-1-(5-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 110) was used to prepare the title compound, affording the title compound as a white foam (99% yield).

[0676] Intermediate 112:(R)-N-((1R * ,2R)-1-(5-((S)-1-((3-amino-2,2-difluoropropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0677] [ka]

[0678] (R)-N-((R * )-1-(5-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, *,2R)-1-(5-((S)-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 111) was used to prepare the title compound, affording the title compound as an off-white foam (76% yield).

[0679] Intermediate 113:(R)-N-((1R * ,2R)-1-(5-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0680] [ka]

[0681] (R)-N-((R * )-1-(5-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, *,2R)-1-(5-((S)-1-((3-amino-2,2-difluoropropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 112) was used to prepare the title compound, affording the title compound as a glassy solid (60% yield).

[0682] Intermediate 114:1-((S)-1-(2-((1R * ,2R)-1-amino-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1H-imidazo[4,5-b]pyridin-5-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0683] [ka]

[0684] Instead of (R)-N-((1R,2R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (as described for intermediate 104), * ,2R)-1-(5-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 113) was used to prepare the title compound, affording the title compound as a glassy solid (74% yield).

[0685] Intermediate 115: (R)-N-((R)-cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methyl)-2-methylpropane-2-sulfinamide

[0686] [ka]

[0687] A three-necked round-bottom flask was charged with (R,E)-2-methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)methylene)propane-2-sulfinamide (600 g, 1.57 mol, Intermediate 105) and DCM (6 L). The reaction was cooled to −78° C. and a solution of cyclopropylmagnesium bromide (7.88 L, 7.88 mol, 1 M in THF) was added dropwise to the stirred solution. The reaction was stirred at −78° C. for an additional 2 h. The reaction was warmed to 0° C. and quenched by the addition of water (5 L), and the resulting mixture was extracted with DCM (2×3 L). The combined organic layers were washed with water (2×10 L) and brine (2×10 L). The mixture was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:3). The diastereomers were separated by SFC using a chiral stationary phase. Stationary phase: CHIRALPAK IG, 5 × 30 cm, 10 μm; Mobile phase A: CO , Mobile phase B: MeOH prep; Flow rate: 160 mL / min; Gradient: Isocratic 50% B; Column temperature (°C): 35; Retention time (min): 4.13 to give the title compound as a white solid (30.6% yield).

[0688] Intermediate 116: 2-Cyclopropoxyacetic acid

[0689] [ka]

[0690] To a 0° C. suspension of NaH (3.4 g, 86 mmol) in THF (50 mL) was added dropwise cyclopropanol (2.5 g, 43 mmol). The reaction was stirred at 0° C. for 1 h, then bromoacetic acid (5.4 g, 39 mmol) was added as a solution in THF (10 mL). The reaction was allowed to warm to room temperature and stirred at this temperature for 16 h. The mixture was diluted with HO (100 mL) and then washed with CHCl (2×50 mL), discarding the organic washes. The aqueous layer was acidified with HCl (43 mL, 86 mmol, 2 M in HO) and then extracted with EtOAc (3×75 mL). The organic extracts were combined, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (94%).

[0691] Intermediate 117: 1,3-Dioxoisoindolin-2-yl 2-cyclopropoxyacetate

[0692] [ka]

[0693] To a solution of 2-cyclopropylacetic acid (5.0 g, 43 mmol, Intermediate 116) in EtOAc (36 mL) was added 1-propanephosphonic anhydride (26 mL, 43 mmol, 50% in EtOAc). The reaction was stirred at room temperature for 2 minutes, and then 2-hydroxyisoindoline-1,3-dione (5.8 g, 36 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours and then diluted with EtOAc. The mixture was washed with 1 M HCl, half-saturated aqueous NaHCO3, and brine, then dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (62%).

[0694] Intermediate 118: (R,E)-2,4,6-trimethyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)benzenesulfinamide

[0695] [ka]

[0696] To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbaldehyde (550 mg, 2.0 mmol, Intermediate 10) and (R)-2,4,6-trimethylbenzenesulfinamide (440 mg, 2.4 mmol) in anhydrous THF (10 mL) was added titanium isopropoxide (1.1 mL, 3.6 mmol). The reaction was stirred at room temperature for 20 h and then quenched with saturated aqueous NaHCO (0.29 mL) and diluted with EtOAc. The resulting suspension was filtered through a pad of Celite® and concentrated to dryness to give the title compound, which was used without further purification.

[0697] Intermediate 119: (R)-N-((S)-2-cyclopropoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)-2,4,6-trimethylbenzenesulfinamide

[0698] [ka]

[0699] A mixture of (R,E)-2,4,6-trimethyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)benzenesulfinamide (442 mg, 1.00 mmol, Intermediate 118), 1,3-dioxoisoindolin-2-yl 2-cyclopropoxyacetate (522 mg, 2.00 mmol, Intermediate 117), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylate (507 mg, 2.00 mmol) in DMSO (10 mL) was degassed by sparging with N. DIPEA (0.345 mL, 2.00 mmol) was added, and the reaction was then irradiated in a Penn Optical Coatings M1 photoreactor at 25% LED intensity for 6 h. At this point, 1,3-dioxoisoindolin-2-yl 2-cyclopropoxyacetate (261 mg, 1.00 mmol, Intermediate 117) and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylate (254 mg, 1.00 mmol) were added, and the reaction was irradiated for an additional 4 h under the conditions listed above. The mixture was diluted with 5% aqueous LiCl and then extracted three times with EtOAc. The combined organic layers were washed with 5% aqueous LiCl and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was triturated in CHCl, then filtered and concentrated to dryness. Purification by silica gel chromatography (10–100% EtOAc:hexanes) afforded the title compound (56% yield).

[0700] Intermediate 120: (S)-2-Cyclopropoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethan-1-amine

[0701] [ka]

[0702] The title compound was prepared in 82% yield as described for the synthesis of Intermediate 39, using (R)-N-((S)-2-cyclopropoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)-2,4,6-trimethylbenzenesulfinamide (Intermediate 119) instead of (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)ethyl)propane-2-sulfinamide and (S)-2-methyl-N-((R)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)propane-2-sulfinamide.

[0703] Intermediate 121: (S)-2-(2-cyclopropoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)isoindoline-1,3-dione

[0704] [ka]

[0705] The title compound was prepared in 71% yield as described for the synthesis of Intermediate 30 Step C, using (S)-2-cyclopropoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethan-1-amine (Intermediate 120) instead of (R)-cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanamine.

[0706] Intermediate 122:N-((R *)-1-(5-((S)-2-Cyclopropoxy-1-(1,3-dioxoisoindolin-2-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0707] [ka]

[0708] The title compound was prepared in 57% yield as described for the synthesis of Intermediate 31, using (S)-2-(2-cyclopropoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)isoindoline-1,3-dione (Intermediate 121) instead of (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)isoindoline-1,3-dione.

[0709] Intermediate 123:N-((R * )-1-(5-((S)-1-amino-2-cyclopropoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0710] [ka]

[0711] As described for the synthesis of intermediate 32, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, N-((R * The title compound was prepared using 2-(5-((S)-2-cyclopropoxy-1-(1,3-dioxoisoindolin-2-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 122).

[0712] Intermediate 124:N-((R * )-1-(5-((S)-2-cyclopropoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide

[0713] [ka]

[0714] As described for the synthesis of intermediate 33, instead of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, N-((R *The title compound was prepared in 39% yield using )-1-(5-((S)-1-amino-2-cyclopropoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 123).

[0715] Intermediate 125:(S)-1-((S)-1-(2-((R * )-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)-2-cyclopropoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one

[0716] [ka]

[0717] In a manner similar to the synthesis of intermediate 34, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, N-((R * The title compound was prepared using 2-(5-((S)-2-cyclopropoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 124).

[0718] Intermediate 126: 1,3-Dioxoisoindolin-2-yl 4,4,4-trifluoro-2-methoxybutanoate

[0719] [ka]

[0720] Step A: Dimethyl 2-methoxy-2-(2,2,2-trifluoroethyl)malonate. To a solution of dimethyl 2-methoxymalonate (7.5 g, 46 mmol) in THF (150 mL) was added potassium tert-butoxide (6.2 g, 56 mmol). The reaction was stirred at 60 °C for 2 hours, then 2,2,2-trifluoroethyl trifluoromethanesulfonate (12 g, 51 mmol) was added and heated to reflux for 2 days. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% EtOAc / petroleum ether) to give the title compound in 48% yield.

[0721] Step B: 4,4,4-Trifluoro-2-methoxybutanoic acid. Dimethyl 2-methoxy-2-(2,2,2-trifluoroethyl)malonate (12 g, 49 mmol, Step A) was dissolved in concentrated HCl (25 mL) and heated at 100 °C for 5 h. The reaction mixture was then diluted with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0–30% EtOAc / petroleum ether) to give the title compound in 70% yield.

[0722] Step C: 1,3-Dioxoisoindolin-2-yl 4,4,4-trifluoro-2-methoxybutanoate. A round-bottom flask was charged with 4,4,4-trifluoro-2-methoxybutanoic acid (1.0 g, 5.8 mmol, Step B) and diluted with EtOAc (5 mL). DIPEA (1.2 mL, 6.8 mmol) and T3P (3.5 mL, 5.8 mmol, 50% solution in THF) were added and stirred at room temperature for 2 minutes. 2-Hydroxyisoindoline-1,3-dione (0.79 g, 4.8 mmol) was then added, and the reaction was stirred at room temperature overnight. The solution was then diluted with EtOAc and washed sequentially with 1N aqueous HCl, saturated aqueous NaHCO3, water, and brine. The organic layer was then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound in 85% yield.

[0723] Intermediate 127: (S)-2,4,6-trimethyl-N-((E)-(5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methylene)benzenesulfinamide

[0724] [ka]

[0725] Step A: (S)-5-((2-Oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbaldehyde. (S)-4-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)imidazolidin-2-one (1.5 g, 3.6 mmol, Intermediate 65) was dissolved in THF (50 mL) and cooled to −40° C. Next, n-BuLi (4.3 mL, 11 mmol, 2.5 M in hexanes) was added dropwise over 5 min and stirred at −40° C. for 1 h. DMF (1.4 mL, 18 mmol) was then added dropwise, and the resulting mixture was allowed to warm to room temperature for 1 h. The reaction was quenched with MeOH, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to afford the title compound in 62% yield.

[0726] Step B: (S)-2,4,6-trimethyl-N-((E)-(5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methylene)benzenesulfinamide. A vial was charged with (S)-5-((2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbaldehyde (1.0 g, 2.3 mmol, Step A), (S)-2,4,6-trimethylbenzenesulfinamide (500 mg, 2.7 mmol), CsCO (884 mg, 2.7 mmol), and DCM (10 mL). The resulting mixture was stirred at room temperature overnight. After this time, the reaction was diluted with DCM and washed sequentially with water and brine. The organic layer was then dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0–70% EtOAc / petroleum ether) to afford the title compound in 44% yield.

[0727] Intermediate 128: (4S)-1-((2-(1-amino-4,4,4-trifluoro-2-methoxybutyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one

[0728] [ka]

[0729] Step A: (S)-2,4,6-trimethyl-N-(4,4,4-trifluoro-2-methoxy-1-(5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)butyl)benzenesulfinamide. A vial was charged with (S)-2,4,6-trimethyl-N-((E)-(5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methylene)benzenesulfinamide (600 mg, 0.99 mmol, Intermediate 127), 1,3-dioxoisoindolin-2-yl 4,4,4-trifluoro-2-methoxybutanoate (940 mg, 3.0 mmol, Intermediate 126), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (750 mg, 3.0 mmol), and DIPEA (0.34 mL, 2.0 mmol) in DMSO (12 mL). The solution was sparged with Ar for 10 minutes, sealed, and irradiated with a blue LED (450 nm, 40% intensity) for 2 hours. After this time, the reaction was diluted with water and extracted with EtOAc (50 mL × 4). The combined organic layers were washed sequentially with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0–100% EtOAc / petroleum ether) to afford the title compound in 55% yield.

[0730] Step B: (4S)-1-((2-(1-amino-4,4,4-trifluoro-2-methoxybutyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one. (S)-2,4,6-Trimethyl-N-(4,4,4-trifluoro-2-methoxy-1-(5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)butyl)benzenesulfinamide (400 mg, 0.54 mmol, Step A) was dissolved in DCM (3 mL). TFA (3 mL) was added in one portion and the reaction was heated at 40° C. for 3 h. After this time, the reaction was concentrated under reduced pressure, and the resulting residue was diluted with water and extracted with DCM. The aqueous layer was basified with NH4OH to pH > 10. The basified aqueous layer was extracted with DCM, and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and DIPEA (2 mL), heated to 80 °C, and stirred for 3 h. After this time, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM and washed with 1 N aqueous HCl. The aqueous washes were basified with NH4OH to pH > 10 and then extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound in 29% yield.

[0731] Intermediate 129: (R)-N-((R,E)-2-cyclopropoxypropylidene)-2-methylpropane-2-sulfinamide

[0732] [ka]

[0733] Step A: (R)-2-Cyclopropoxy-N-methoxy-N-methylpropanamide. The title compound was prepared in 43% yield as described for the synthesis of Intermediate 3, using (R)-2-cyclopropoxypropanoic acid instead of (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanoic acid.

[0734] Step B: (R)-2-Cyclopropoxypropanal. The title compound was prepared in 100% yield as described for the synthesis of Intermediate 4, using (R)-2-cyclopropoxy-N-methoxy-N-methylpropanamide (Step A) instead of (R)-N-methoxy-N-methyl-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanamide.

[0735] Step C: The title compound was prepared in 47% yield as described for the synthesis of (R)-N-((R,E)-2-cyclopropoxypropylidene)-2-methylpropane-2-sulfinamide intermediate 5, using (R)-2-cyclopropoxypropanal (Step B) instead of (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanal.

[0736] Intermediate 130: (S)-1-((S)-1-(2-((1R,2R)-1-amino-2-cyclopropoxypropyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one

[0737] [ka]

[0738] Step A: (R)—N-((1R,2R)-2-Cyclopropoxy-1-(5-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)propyl)-2-methylpropane-2-sulfinamide. (S)-2-(2-Methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)isoindoline-1,3-dione (1.55 g, 3.42 mmol, Intermediate 76) and THF (80 mL) were combined and cooled to −78° C. under a nitrogen atmosphere. LDA (5.2 mL, 5.2 mmol, 1 M in THF / hexane) was then added dropwise and the contents were stirred at −78° C. for 10 minutes. (R)—N—((R,E)-2-cyclopropoxypropylidene)-2-methylpropane-2-sulfinamide (1.32 g, 6.07 mmol, Intermediate 129) in THF (3 mL) was then added and the contents were stirred at −78° C. for 30 minutes. Additional LDA (1.7 mL, 1.7 mmol, 1 M in THF / hexane) was then added three times at 30 minute intervals and stirred at −78° C. for 15 minutes after the final addition of LDA. The reaction was then quenched at −78° C. by the addition of acetic acid (2 mL) in THF (10 mL). The reaction solution was stirred at −78° C. for 2 minutes, and then the contents were allowed to warm to room temperature. The reaction solution was then transferred to a separatory funnel with ethyl acetate and extracted twice with deionized water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was purified in batches by preparative HPLC (XBridge Phenyl Prep 5 μm C18 50 × 250 mm, 40–100% MeCN with 0.05% TFA / water with 0.05% TFA) to give the title compound in 13% yield after lyophilization.

[0739] Step B: (R)—N—((1R,2R)-1-(5-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-cyclopropoxypropyl)-2-methylpropane-2-sulfinamide. (R)—N—((R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide was prepared as described for the synthesis of intermediate 32. The title compound was prepared in 95% yield using (R)—N-((1R,2R)-2-cyclopropoxy-1-(5-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)propyl)-2-methylpropane-2-sulfinamide (Step A) instead of the amide.

[0740] Step C: (R)—N-((1R,2R)-2-cyclopropoxy-1-(5-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)propyl)-2-methylpropane-2-sulfinamide. Benzyl((S)-3-(((R)-(2-((R)-1-(((R)-tert-butylsulfinyl)amino)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)amino)-1,1,1-trifluoromethyl-2-methylpropan-2-yloxy)ethyl ... The title compound was prepared in 39% yield over three steps using (R)—N-((1R,2R)-1-(5-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-cyclopropoxypropyl)-2-methylpropane-2-sulfinamide (Step B) instead of (fluoropropan-2-yl)carbamate.

[0741] Step D: (S)-1-((S)-1-(2-((1R,2R)-1-amino-2-cyclopropoxypropyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one. (R)-N-((R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfine as described for the synthesis of Intermediate 34. The title compound was prepared in 53% yield using (R)—N-((1R,2R)-2-cyclopropoxy-1-(5-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)propyl)-2-methylpropane-2-sulfinamide (Step C) instead of the amide.

[0742] Intermediate 131: 1-((S)-1-(2-((1R,2R)-1-amino-2-cyclopropoxypropyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0743] [ka]

[0744] Step A: (R)—N-((1R,2R)-2-cyclopropoxy-1-(5-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)propyl)-2-methylpropane-2-sulfinamide. (R)-N-((R)-1-(5-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methyl- The title compound was prepared in 70% yield over three steps using (R)—N-((1R,2R)-1-(5-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-cyclopropoxypropyl)-2-methylpropane-2-sulfinamide (Intermediate 130 Step B) in place of methylpropane-2-sulfinamide.

[0745] Step B. 1-((S)-1-(2-((1R,2R)-1-amino-2-cyclopropoxypropyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. (R)-N-((R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfine can be prepared as described for the synthesis of intermediate 37. The title compound was prepared in 68% yield using (R)—N-((1R,2R)-2-cyclopropoxy-1-(5-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)propyl)-2-methylpropane-2-sulfinamide (Step A) instead of the amide.

[0746] Intermediate 132: 5-Bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

[0747] [ka]

[0748] A solution of 5-bromo-4-fluoro-1H-benzo[d]imidazole (1.00 g, 4.65 mmol) in THF (20 mL) was cooled to 0 °C, then NaH (179 mg, 7.44 mmol, 60% dispersion in mineral oil) was added portionwise over 20 min. The mixture was stirred at 0 °C for 1 h, then (2-(chloromethoxy)ethyl)trimethylsilane (0.99 mL, 5.6 mmol) was added over 5 min. The resulting mixture was warmed to room temperature and stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4Cl (40 mL) and water (60 mL). The mixture was then extracted with EtOAc (2 × 30 mL), and the organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to afford the title compound as a black oil (88% yield).

[0749] Intermediate 133: 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-benzo[d]imidazole

[0750] [ka]

[0751] 5-Bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (7.00 g, 20.3 mmol, Intermediate 132), potassium trifluoro(vinyl)borate (5.43 g, 40.5 mmol), KPO (12.9 g, 60.8 mmol), Pd(dppf)Cl·CHCl (828 mg, 1.01 mmol), 1,4-dioxane (70 mL), and HO (20 mL) were added to a three-necked round-bottom flask. The reaction mixture was purged with N three times and then heated at 95 °C for 16 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 2). The combined extracts were dried over anhydrous NaSO, filtered, and concentrated to dryness to give a brown oil. The oil was subjected to silica gel chromatography (0-30% EtOAc / petroleum ether) to afford the title compound as a yellow oil, which was used without further purification.

[0752] Intermediate 134: 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbaldehyde

[0753] [ka]

[0754] 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-benzo[d]imidazole (17.8 g, 60.9 mmol, Intermediate 133), potassium osmate(VI) dihydrate (1.12 g, 3.04 mmol), THF (200 mL), and HO (50 mL) were added to a round-bottom flask and then cooled to 0° C. The mixture was stirred at 0° C. for 30 minutes, and then sodium periodate (39.1 g, 183 mmol) was added in small portions over 2 minutes at 0° C. The mixture was stirred at 0° C. for 30 minutes, and then the reaction vessel was removed from the cooling bath and stirred at room temperature for 16 hours. The mixture was filtered through diatomaceous earth (e.g., Celite®), and HO (150 mL) was added to the filtrate. The mixture was extracted with EtOAc (150 mL x 2), and the organic layers were combined, washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound as a black oil, which was used without further purification.

[0755] Intermediate 135: (R,E)-N-((4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)-2-methylpropane-2-sulfinamide

[0756] [ka]

[0757] 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbaldehyde (17.8 g, 60.5 mmol, Intermediate 134), (R)-2-methylpropane-2-sulfinamide (11.0 g, 90.7 mmol), CsCO (39.4 g, 121 mmol), and DCM (250 mL) were added to a three-necked round-bottom flask. The resulting mixture was heated at 40 °C for 16 h. The reaction mixture was filtered and diluted with HO (200 mL). The mixture was extracted with CHCl (150 mL × 3), and the combined organic layers were washed with brine (150 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to dryness to give a black oil. The oil was subjected to silica gel chromatography (0-50% EtOAc / petroleum ether) to afford the title compound in 61% yield.

[0758] Intermediate 136: (R)-N-((S)-1-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-2-methylpropane-2-sulfinamide

[0759] [ka]

[0760] Tributyl(methoxymethyl)stannane (4.21 g, 12.6 mmol) and THF (40 mL) were added to an oven-dried and nitrogen-purged three-neck round-bottom flask, which was then cooled to −65° C. (dry ice / EtOH). Next, n-BuLi (12.6 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at −65° C. for 1 hour. Then, a solution of (R,E)-N-((4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methylene)-2-methylpropane-2-sulfinamide (1.00 g, 2.52 mmol, Intermediate 135) in THF (10 mL) was added dropwise over 40 minutes. The resulting mixture was stirred at −65° C. for 1 hour. The reaction mixture was treated with saturated aqueous NH4Cl (10 mL) and then diluted with EtOAc (30 mL). The mixture was washed with HO (30 mL × 2) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give a yellow oil. The oil was then subjected to silica gel chromatography (0-30% MeOH / DCM) to give the title compound as a yellow oil (68% yield).

[0761] Intermediate 137: (S)-1-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethanamine

[0762] [ka]

[0763] To a solution of (R)-N-((S)-1-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-2-methylpropane-2-sulfinamide (588 mg, 1.33 mmol, Intermediate 136) in EtOAc (5 mL) was added 4 M HCl in 1,4-dioxane (1.04 mL, 4.15 mmol) dropwise over 1 minute. The resulting mixture was stirred at room temperature for 0.5 h. The reaction was diluted with HO (10 mL) and the aqueous phase was washed with EtOAc (10 mL × 3). The combined organic phase was extracted with 2 M aqueous HCl (5 mL × 2), and the pH of the combined aqueous phase was adjusted to pH 8 by the addition of saturated aqueous NaHCO3. The mixture was extracted with EtOAc (20 mL × 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to dryness to give the title compound as a yellow oil (79% yield), which was used without further purification.

[0764] Intermediate 138: (S)-2-(1-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)isoindoline-1,3-dione

[0765] [ka]

[0766] A mixture of (S)-1-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethanamine (408 mg, 1.20 mmol, Intermediate 137), ethyl 1,3-dioxoisoindoline-2-carboxylate (294 mg, 1.34 mmol), and DIPEA (0.70 mL, 4.0 mmol) in THF (7 mL) was heated at 75 °C for 48 h. The reaction mixture was then treated with HO (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness to give a yellow oil. The oil was then subjected to silica gel chromatography (0-50% EtOAc / petroleum ether) to give the title compound as a yellow oil (80% yield).

[0767] Intermediate 139: (S)—N-((1R,2R)-1-(5-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0768] [ka]

[0769] (S)-2-(1-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)isoindoline-1,3-dione (500 mg, 1.07 mmol, Intermediate 138), (R,E)-2-methyl-N-((R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide (466 mg, 1.70 mmol, Intermediate 5), and dry THF (35 mL) were added to an oven-dried and nitrogen-purged three-neck round-bottom flask, which was then cooled to −70° C. LDA (3.2 mL, 3.2 mmol, 1.0 M in THF) was then added dropwise over 25 minutes. The resulting mixture was stirred at -70°C for 1 hour and then quenched by the addition of a solution of HOAc / THF (3 mL; a solution of 0.5 mL of acetic acid in 25 mL of THF). The mixture was stirred at -78°C for 2 minutes, then the ice bath was removed and the contents were allowed to warm to room temperature. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous MgSO, filtered, and concentrated to dryness to give a yellow oil. The oil was subjected to silica gel chromatography (0-0.5% MeOH / DCM) to afford the title compound as a yellow oil (27% yield).

[0770] Intermediate 140: (S)—N-((1R,2R)-1-(5-((S)-1-amino-2-methoxyethyl)-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0771] [ka]

[0772] (S)—N-((1R,2R)-1-(5-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (244 mg, 0.328 mmol, Intermediate 139), EtOH (2 mL), and N2H4·H2O (194 mg, 3.28 mmol) were combined and stirred at room temperature for 4 hours. Then EtOAc (20 mL) was added, and the mixture was washed with HO (20 mL × 2) and brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound as a pale yellow oil, which was used without further purification.

[0773] Intermediate 141: benzyl ((S)-3-(((S)-1-(2-((1R,2R)-1-(((S)-tert-butylsulfinyl)amino)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)amino)-1,1,1-trifluoropropan-2-yl)carbamate

[0774] [ka]

[0775] (S)—N-((1R,2R)-1-(5-((S)-1-amino-2-methoxyethyl)-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (620 mg, 1.01 mmol, Intermediate 140), NaCO (322 mg, 3.04 mmol), (S)-benzyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (987 mg, 3.04 mmol, Intermediate 24), and THF / MeCN (1:1, 10 mL) were added to the vial. The reaction mixture was heated at 35° C. for 16 hours. The reaction was diluted with EtOAc (50 mL), washed with HO (50 mL × 2) and brine (70 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness to give a pale yellow oil, which was then subjected to silica gel chromatography (0-10% MeOH / DCM) to give the title compound as a colorless oil (80% yield).

[0776] Intermediate 142: (S)—N-((1R,2R)-1-(5-((S)-1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-methoxyethyl)-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0777] [ka]

[0778] Benzyl ((S)-3-(((S)-1-(2-((1R,2R)-1-(((S)-tert-butylsulfinyl)amino)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)amino)-1,1,1-trifluoropropan-2-yl)carbamate (820 mg, 0.956 mmol, Intermediate 141), MeOH (10 mL), and 10% wet Pd / C (820 mg, 10% Pd and 50% water) were added to a hydrogenation bottle. The resulting mixture was stirred under H (45 psi) at 25 °C for 2 h. The mixture was filtered, and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated to dryness to give the title compound as a white solid, which was used without further purification.

[0779] Intermediate 143: (S)-1-((S)-1-(2-((1R,2R)-1-amino-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one

[0780] [ka]

[0781] (S)—N-((1R,2R)-1-(5-((S)-1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-methoxyethyl)-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (740 mg, 1.02 mmol, Intermediate 142), DIPEA (0.7 mL, 4 mmol), and DCM (12 mL) were added to a vial cooled to 0° C. Next, bis(trichloromethyl)carbonate (160 mg, 0.539 mmol) was added in one portion, and the resulting mixture was stirred at 0° C. for 0.5 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (100 mL × 2). The combined organic extracts were washed with saturated aqueous NaHCO (50 mL) and brine (50 mL), dried over anhydrous MgSO, filtered, and concentrated to dryness to give a yellow oil. The oil was subjected to silica gel chromatography (0–10% MeOH / DCM) to give a mixture of the title compound and the desilylated product, ((S)-1-((S)-1-(2-((1R,2R)-1-amino-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-7-fluoro-1H-benzo[d]imidazol-6-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one) as a pale yellow oil, which was used without further purification.

[0782] Intermediate 144: (S)-1-((S)-1-(2-((1R,2R)-1-amino-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-4-fluoro-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one

[0783] [ka]

[0784] To a solution of (S)-1-((S)-1-(2-((1R,2R)-1-amino-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (250 mg, 0.387 mmol, Intermediate 143) in 1,4-dioxane (1.5 mL) was added HCl (4 M in 1,4-dioxane, 3.0 mL, 12 mmol) dropwise over 1 minute. The resulting mixture was heated at 55° C. for 1 hour. The reaction mixture was then concentrated to dryness, dissolved in HO (20 mL), washed with DCM (20 mL × 2), and the combined organic phase was extracted with 2 M aqueous HCl (20 mL × 2). The pH of the combined aqueous phase was adjusted to pH 7–8 by adding saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (25 mL × 3). The EtOAc extracts were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give a mixture of partially and fully deprotected products as a yellow solid. To this mixture was added DIPEA (1.0 mL, 5.7 mmol) and MeOH (1.0 mL). The resulting mixture was heated at 80 °C for 2 h. The reaction mixture was then concentrated to dryness, dissolved in DCM (5 mL), and washed with HO (10 mL). The organic phase was extracted with 2 M aqueous HCl (10 mL × 2), and then the pH of the combined aqueous phase was adjusted to pH 7-8 with saturated aqueous NaHCO3. The resulting mixture was then extracted with EtOAc (15 mL × 3), and the combined EtOAc layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound as a pale yellow solid, which was used without further purification.

[0785] Intermediate 145: tert-butyl (R)-(1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl (R)-(1-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0786] [ka]

[0787] (R)-N-((R)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide and ((R)-N-((R)-1-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazo To a solution of (1,1,1-trifluoro-2-methylpropan-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (6.95 g, 11.6 mmol, Intermediate 68) in THF:HO (4:1 ratio, 192 mL) was added iodine (587 mg, 2.32 mmol) and the resulting mixture was heated at 50° C. for 2 h. After this time, additional iodine (587 mg, 2.32 mmol) was added. was added, and the mixture was stirred at 50 °C for an additional 3.5 h. The reaction mixture was then allowed to cool to room temperature, quenched with sodium thiosulfate pentahydrate (25.4 mL, 5.07 mmol), and extracted with EtOAc (3 × 60 mL). The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated to dryness. This material was dissolved in DCM (58 mL). EtN (3.54 mL, 25.5 mmol) was added, followed by di-tert-butyl dicarbonate (3.06 g, 14.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was then diluted with saturated aqueous NHCl and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0–60% EtOAc / hexanes) to give the mixture of title compounds in 92% yield.

[0788] Intermediate 146: tert-butyl (R)-(1-(5-(3-methoxyprop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl (R)-(1-(6-(3-methoxyprop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0789] [ka]

[0790] tert-Butyl (R)-(1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl (R)-(1-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate in 1,4-dioxane (15 mL) To a suspension of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (905 mg, 1.52 mmol, Intermediate 145), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (404 mg, 1.59 mmol), and potassium acetate (449 mg, 4.58 mmol) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (114 mg, 0.145 mmol). The mixture was purged with N for 10 min and heated at 100 °C in a microwave reactor for 1 h. The reaction mixture was cooled to room temperature, and then 2-bromo-3-methoxyprop-1-ene (0.33 mL, 3.04 mmol), KPO (1.02 g, 4.55 mmol), mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (79.3 mg, 0.107 mmol), and HO (1.5 mL) were added. The resulting mixture was stirred and purged with N for 10 minutes. The reaction mixture was heated at 100 °C using a heating block for 18 hours. The reaction was cooled to room temperature, filtered through diatomaceous earth (e.g., Celite®), and the filtrate was diluted with HO (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. Purification by silica gel chromatography (0-100% EtOAc (10% MeOH) / hexanes) afforded a mixture of the title compounds in 49% yield.

[0791] Intermediate 147: tert-butyl (R)-(1-(5-(2-methoxyacetyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl (R)-(1-(6-(2-methoxyacetyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0792] [ka]

[0793] tert-Butyl (R)-(1-(5-(3-methoxyprop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl (R)-(1-(6-(3-methoxypropan-2-yl)oxy)ethyl)carbamate in 1,4-dioxane (1 mL) To (per-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (439 mg, 0.747 mmol, Intermediate 146) was added a suspension of sodium metaperiodate (959 mg, 4.48 mmol) in HO (1 mL). The mixture was stirred vigorously, and then potassium osmate(VI) dihydrate (11 mg, 0.030 mmol) was added. The resulting mixture was stirred at room temperature for 1 h, and then the reaction was diluted with HO (5 mL) and EtOAc (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. Purification by silica gel chromatography (10-100% EtOAc / hexanes) afforded the mixture of title compounds in 37% yield.

[0794] Intermediate 148: tert-butyl ((1R)-1-(5-(1-((2-amino-2-methylpropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl ((1R)-1-(6-(1-((2-amino-2-methylpropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0795] [ka]

[0796] tert-Butyl (R)-(1-(5-(2-methoxyacetyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl (R)-(1-(6-(2-methoxyacetyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate in DCM (3.3 mL) To (1,1,1-trifluoro-2-methylpropan-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)methyl)carbamate (200 mg, 0.339 mmol, Intermediate 147) were added 2-methylpropane-1,2-diamine (0.092 mL, 0.848 mmol) and TEA (0.19 mL, 1.36 mmol), and the resulting mixture was stirred at room temperature for 45 minutes. Acetic acid (0.116 mL, 2.04 mmol) and MeOH (1.2 mL) were then added. After stirring the mixture at room temperature for 30 minutes, sodium cyanoborohydride (74.6 mg, 1.19 mmol) was added, and the mixture was stirred at room temperature for 45 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness to give a mixture of the title compounds which were used without further purification.

[0797] Intermediate 149: tert-butyl ((1R)-1-(5-(1-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl ((1R)-1-(6-(1-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0798] [ka]

[0799] tert-Butyl ((1R)-1-(5-(1-((2-amino-2-methylpropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl ((1R)-1-(6-(1-(( A solution of 2-amino-2-methylpropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (120 mg, 0.18 mmol, Intermediate 148) and DIPEA (96 mL, 0.55 mmol) was cooled to 0 °C under N. The resulting mixture was treated with triphosgene (18 mg, 0.060 mmol) and stirred at 0 °C for 20 min. The reaction mixture was then treated with water (2 mL), extracted with DCM (2 × 5 mL), and the combined organic extracts were concentrated to dryness. The isolated material was purified by silica gel chromatography (5–100% EtOAc (10% MeOH) / DCM) to afford the mixture of title compounds in 33% yield as a clear oil.

[0800] Intermediate 150: 1-(1-(2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-4,4-dimethylimidazolidin-2-one

[0801] [ka]

[0802] As described for the synthesis of intermediate 37, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide to tert-butyl ((1R)-1-(5-(1-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (Intermediate 149) to afford the title compound, which was used directly in the next step without further purification.

[0803] Intermediate 151: (R)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanal

[0804] [ka]

[0805] The title compound was prepared as described in Intermediate 4 using (R)-N-methoxy-N-methyl-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanamide (Intermediate 7) instead of (R)-N-methoxy-N-methyl-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanamide and used without further purification (98% yield).

[0806] Intermediate 152: (R)-N-((1R,2R)-1-(5-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfine amide and (R)-N-((1R,2R)-1-(6-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0807] [ka]

[0808] As described for the synthesis of Intermediate 31, (S)-2-(2-methoxy-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)isoindoline-1,3-dione (Intermediate 76) was used in place of (R)-cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methanamine. The title compound (27% yield) was prepared using (R)-2-methyl-N-((R,E)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide (Intermediate 9) instead of (R,E)-2-methyl-N-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2-sulfinamide.

[0809] Intermediate 153: (R)-N-((1R,2R)-1-(5-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide and (R)-N-((1R,2R)-1-(6-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0810] [ka]

[0811] As described for the synthesis of intermediate 32, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, ((R)-N-((1R,2R)-1-(5-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- The title compound (98% yield) was prepared using benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide and (R)—N-((1R,2R)-1-(6-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 152).

[0812] Intermediate 154: (R)-N-((1R,2R)-1-(5-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidine-1(2H)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfine amide and (R)-N-((1R,2R)-1-(6-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidine-1(2H)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide

[0813] [ka]

[0814] As described for the synthesis of intermediate 36, (R)-N-((1R,2R)-1-(5-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide was used instead of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide. The title compound (78% yield) was prepared using (R)—N-((1R,2R)-1-(6-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 153).

[0815] Intermediate 155:1-((S)-1-(2-((1R * ,2R)-1-amino-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0816] [ka]

[0817] Instead of (R)-N-((R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((1R,2R)-1-(5-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[ The title compound was prepared using (R)—N-((1R,2R)-1-(6-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Intermediate 154) and used without further purification (assuming theoretical yield).

[0818] Intermediate 156: tert-butyl ((1R)-1-(5-(1-(((S)-2-amino-3,3,3-trifluoro-2-methylpropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl ((1R)-1-(6-(1-(((S)-2-amino-3,3,3-trifluoro-2-methylpropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0819] [ka]

[0820] tert-Butyl (R)-(1-(5-(2-methoxyacetyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl (R)-(1-(6-(2-methoxyacetyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)- To 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (150 mg, 0.254 mmol, Intermediate 147) and (2S)-3,3,3-trifluoro-2-methylpropane-1,2-diamine dihydrochloride (65.6 mg, 0.305 mmol) was added DCE (2.5 mL), EtN (0.106 mL, 0.763 mmol), and tetraisopropoxytitanium (0.149 mL, 0.509 mmol). The resulting mixture was heated at 50° C. under N for 4.5 h. The reaction was cooled to room temperature, and AcOH (0.073 mL, 1.27 mmol), sodium cyanoborohydride (48.0 mg, 0.763 mmol), and MeOH (0.29 mL, 7.05 mmol) were added, and the resulting mixture was heated at 50° C. for 18 hours. The reaction was diluted with saturated aqueous NaHCO (5 mL) and EtOAc (5 mL) and filtered through diatomaceous earth (e.g., Celite®). The filtrate layers were separated, and the organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to provide a mixture of the title compounds, which was used without further purification.

[0821] Intermediate 157: tert-butyl((1R)-1-(5-(2-methoxy-1-((S)-4-methyl-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carba mate and tert-butyl ((1R)-1-(6-(2-methoxy-1-((S)-4-methyl-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0822] [ka]

[0823] tert-Butyl ((1R)-1-(5-(1-(((S)-2-amino-3,3,3-trifluoro-2-methylpropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate and tert-butyl ((1R)-1-(6-(1- A solution of (((S)-2-amino-3,3,3-trifluoro-2-methylpropyl)amino)-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (182 mg, 0.254 mmol, Intermediate 156) and DIPEA (0.135 mL, 0.775 mmol) was cooled to 0° C. To the mixture was added a solution of bis(trichloromethyl)carbonate (30.2 mg, 0.102 mmol) in DCM (0.5 mL) dropwise. After stirring at 0° C. for 20 min, the reaction was quenched with MeOH (2 mL) and the mixture was concentrated to dryness. Purification by silica gel chromatography (10-100% EtOAc (10% MeOH) / DCM) afforded the mixture of title compounds in 24% yield.

[0824] Intermediate 158: (4S)-1-(1-(2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)-2-methoxyethyl)-4-methyl-4-(trifluoromethyl)imidazolidin-2-one

[0825] [ka]

[0826] As described in Intermediate 37, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, tert-butyl((1R)-1-(5-(2-methoxy-1-((S)-4-methyl-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide The title compound was prepared using tert-butyl ((1R)-1-(6-(2-methoxy-1-((S)-4-methyl-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (Intermediate 157) and used without further purification (97% yield).

[0827] Intermediate 159: (R,E)-2-methyl-N-(4,4,4-trifluoro-3,3-dimethylbutylidene)propane-2-sulfinamide

[0828] [ka]

[0829] To a solution of 3,3,3-trifluoropropanal (140.0 g, 908.3 mmol) in DCM (1500 mL) was added (R)-2-methylpropane-2-sulfinamide (132.1 g, 1.09 mol), PPTS (23.1 g, 91.7 mmol), and CuSO (430 g, 2.74 mol), and the resulting mixture was heated at 30 °C for 12 h. The reaction was filtered through diatomaceous earth (e.g., Celite®), and the filtrate was concentrated to give a yellow oil. The material was purified by silica gel chromatography (0-10% EtOAc / petroleum ether) to give the title compound as a yellow oil.

[0830] Intermediate 160: (R)-N-((S)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)-2-methylpropane-2-sulfinamide

[0831] [ka]

[0832] Step A: N-((S)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)-2-methylpropane-2-sulfinamide. A solution of (R)-2-(cyclopropyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)isoindoline-1,3-dione (10.7 g, 23.34 mmol, Intermediate 30) and (R,E)-2-methyl-N-(4,4,4-trifluoro-3,3-dimethylbutylidene)propane-2-sulfinamide (10.09 g, 35.29 mmol, Intermediate 159) in THF (150 mL) was cooled to −78° C. under a nitrogen atmosphere. LDA (48 mL, 1 M in hexanes, 48 ​​mmol) was then added dropwise over 10 minutes. The resulting mixture was stirred at −78° C. for approximately 1 hour. The reaction was then quenched with a solution of AcOH (4 mL, 69.94 mmol) in THF (50 mL, 617.14 mmol) at -78 °C and then allowed to warm gradually to room temperature under nitrogen. The contents were then transferred to a separatory funnel with ethyl acetate and extracted twice with deionized water. The organic phase was then separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford an off-white foam. Purification was achieved by silica gel chromatography (25-40% DCM / EtOAc) to afford the title compound (50% yield).

[0833] Step B: (R)—N—((S)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)-2-methylpropane-2-sulfinamide. To a solution of N-((S)-1-(5-((R)-cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)-2-methylpropane-2-sulfinamide (1.18 g, 1.68 mmol, Step A) dissolved in EtOH (10 mL) was added hydrazine monohydrate (0.8 mL, 16.5 mmol) to produce a clear, colorless solution. The reaction was stirred at room temperature for 30 hours and then concentrated under reduced pressure. The residue was dissolved in EtOAc, the precipitate was removed by filtration, and the filtrate was concentrated to give the title compound (99% yield).

[0834] Intermediate 161: (R)-N-((S)-1-(5-((R)-cyclopropyl((S * )-2-Oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)-2-methylpropane-2-sulfinamide

[0835] [ka]

[0836] As described for the synthesis of intermediate 33, instead of (R)-N-((R)-1-(5-((R)-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((S)-1-(5-((R )-amino(cyclopropyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)-2-methylpropane-2-sulfinamide (Intermediate 160), and (S)-benzyl 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, instead of benzyl (S * The title compound was prepared using 4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22,2 dioxide (Intermediate 26) to give the title compound in three steps (26% yield).

[0837] Intermediate 162:(S)-1-((R)-(2-((S) * )-1-amino-4,4,4-trifluoro-3,3-dimethylbutyl)-1H-benzo[d]imidazol-5-yl)(cyclopropyl)methyl)-4-(trifluoromethyl)imidazolidin-2-one-5,5-d2

[0838] [ka]

[0839] As described for the synthesis of intermediate 34, instead of (R)-N-((R)-1-(5-((R)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2-sulfinamide, (R)-N-((S)-1-(5-((R)-cyclopropyl((S * The title compound (26% yield) was prepared using 2-oxo-4-(trifluoromethyl)imidazolidin-1-yl-5,5-d2)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)-2-methylpropane-2-sulfinamide (Intermediate 161).

[0840] Intermediate 163: (R)-N-((1R,2R)-1-(5-((S)-1-amino-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)...

Claims

1. Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ teeth, 【Chemistry 2】 and R １ａ is independently for each occurrence -C （１－３） Alkyl or -C （３－５） cycloalkyl, and the —C （１－３） alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R １ｂ is independently for each occurrence -C （１－３） Alkyl or C （３－５） cycloalkyl, and the —C （１－３） alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R １ｃ independently for each occurrence, halo, -C （１－３） Alkyl, or C （３－５） cycloalkyl, and the —C （１－３） alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; p is 0, 1, 2, 3, or 4; n is 1 or 2; m1, m2, and m3 each independently represent 0, 1, or 2; R ２ is H, -C （１－６） Alkyl, —C （３－５） Cycloalkyl, —C （１－３） Alkyl-O-C （１－３） Alkyl, or -C （１－３） Alkyl-O-C （３－５） cycloalkyl, and the —C （１－６） Alkyl, —C （３－５） Cycloalkyl, —C （１－３） Alkyl-O-C （１－３） Alkyl, and -C （１－３） Alkyl-O-C （３－５） The cycloalkyl group may be unsubstituted or may contain 1 to 6 R ２ａ is substituted with a group, R ２ａ is independently at each occurrence fluorine, —CN, or —O—C （１－３） is alkyl, R ３ is C （１－８） Alkyl, —C （１－６） Alkyl-O-C （１－６） Alkyl, or -C （１－６） Alkyl-O-C （３－５） cycloalkyl, （１－８） Alkyl and -C （１－６） Alkyl-O-C （１－６） The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and the —C （１－６） Alkyl-O-C （３－５） cycloalkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R ４ is unsubstituted or has 1 to 2 R ４ａ is a 5-membered heteroaryl substituted with a group; R ４ａ is halo, -C （１－６） Alkyl, —O—C （１－６） Alkyl, or -C （０－２） Alkyl-C （３－６） cycloalkyl, and the —C （１－６） Alkyl, —O—C （１－６） Alkyl, and -C （０－２） Alkyl-C （３－６） Cycloalkyl is unsubstituted or substituted with fluorine, CH ３ , C.H. ２ F, CHF ２ , C.F. ３ and -CN; X is CH, CF or N; A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein Y is CH or CF.

2. R １ teeth, 【Chemistry 3】 and R １ａ is independently calculated for each occurrence, ３ , C.H. ２ F, CHF ２ , C.F. ３ or cyclopropyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

3. R １ teeth, 【Chemistry 4】 and R １ｂ is independently calculated for each occurrence, ３ , C.H. ２ F, CHF ２ , C.F. ３ or cyclopropyl, R １ｃ is independently for each occurrence fluorine, CH ３ , C.H. ２ F, CHF ２ , C.F. ３ or cyclopropyl, n is 1 or 2; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m1, m2, and m3 are each independently 0, 1, or 2.

4. Formula (Ia): 【Chemistry 5】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable salt thereof.

5. R ３ But C （１－６） Alkyl, —C （１－４） Alkyl-O-C （１－４） Alkyl, or -C （１－４） Alkyl-O-C （３－４） cycloalkyl, （１－６） Alkyl and -C （１－４） Alkyl-O-C （１－４） alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and said -C （１－４） Alkyl-O-C （３－４） 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms.

6. Formula (Idd-1): 【Chemistry 6】 is a compound of In the formula, R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ are each independently H or CH ３ 2. The compound of claim 1, wherein:

7. R ４ is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from O and N, and said 5-membered heteroaryl is unsubstituted or contains 1 to 2 R ４ａ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted with a group.

8. below: 【Chemistry 7】 10. The compound of claim 1, having a structure selected from the group consisting of:

9. below: 【Chemistry 8】 10. The compound of claim 1, having a structure selected from the group consisting of:

10. below: 【Chemistry 9】 【Chemistry 10】 10. The compound of claim 1, having a structure selected from the group consisting of:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. 12. The pharmaceutical composition of claim 11, or a pharmaceutically acceptable salt thereof, which is administered orally.

13. 12. The pharmaceutical composition of claim 11, or a pharmaceutically acceptable salt thereof, administered as a tablet or capsule.

14. A method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of such treatment and / or amelioration a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

15. 15. The method of claim 14, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

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