Imidazopyrimidines as IL-17 modulators

Abstract

The present application discloses a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 and R 5 Defined in this specification, as well as methods of making and using the compounds disclosed herein for treating or ameliorating IL-17 mediated syndromes, disorders and / or diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 63 / 017,679, filed on April 30, 2020, under 35 U.S.C. 119(e), the disclosure of which is hereby incorporated by reference in its entirety.

[0003] Reference sequence listing submitted electronically

[0004] This application contains a sequence listing, which is submitted electronically via EFS-Web as an ASCII formatted sequence listing, with the file name "JBI6283WOPCT1SeqListing4-22-20.txt", the creation date is April 22, 2020, and the size is 5KB. This sequence listing submitted via EFS-Web is part of the present specification and is incorporated herein by reference in its entirety. Technical Field

[0005] Disclosed herein are imidazopyrimidine compounds that modulate interleukin-17A and pharmaceutical compositions thereof. Also disclosed herein are therapeutic uses of such compounds, for example, to treat and / or ameliorate IL-17A-mediated inflammatory syndromes, disorders or diseases. Background Art

[0006] Interleukin-17 ("IL-17"), also known as IL-17A and CTLA-8, is produced primarily by CD4+Th17 cells and also by other immune cells such as CD8+T cells, γδT cells, NK cells, NKT cells, and innate lymphoid cells (ILCs). IL-17A exists as a homodimer (A / A) or as a heterodimer (A / F) with IL-17F and signals by binding to the dimeric receptor complexes IL-17RA and IL-17RC. IL-17RA is ubiquitously expressed at particularly high levels in hematopoietic cell types, while IL-17RC is preferentially expressed in non-hematopoietic 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 new gene transcription through ACT1–TRAF6–TRAF4 triggering NF-kB, C / EBP and MAPK pathways. 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 proinflammatory state.

[0007] As discussed below, preclinical and clinical data have demonstrated a significant pathological role for IL-17A in a variety of autoimmune and inflammatory diseases.

[0008] For psoriasis: IL-17A mRNA and / or protein levels are elevated in the lesion skin and blood of patients with psoriasis and are associated with disease severity. IL-17A directly synergizes with other cytokines on keratinocytes (such as TNFα, IFNγ or IL-22), triggering a self-amplifying inflammatory response in the skin and leading to the formation of psoriasis plaques. Blocking IL-17A by antibodies to IL-17A or IL-23 leads to a complete reversal of molecular and clinical disease features in most psoriasis patients, indicating a significant role for IL-17A and IL-17-producing T cells in the immune pathogenesis 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 in psoriasis have demonstrated that IL-17A is an effective target for psoriasis treatment. (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).

[0009] For psoriatic arthritis (PsA): IL-17A is mechanistically associated with PsA through NFκB activation, which triggers the transcription of several PsA-related genes including receptor activator of nuclear factor κB ligand (RANKL). RANKL triggers osteoclast precursor cells to differentiate into activated osteoclasts, leading to bone resorption and subsequent joint deformity in PsA (Adamopoulos IE and Mellins ED., Nature reviews Rheumatology 2015; 11: 189-94). PsA joints are rich in IL-17+CD8+T cells, and the level of this T cell subset is associated 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 and secrete increased IL-6, CXCL8 and MMP3 in vitro compared to osteoarthritis patients. Secukinumab and ixekizumab are both FDA-approved PsA medications. In a matched-adjusted indirect comparison analysis, secukinumab was associated with higher ACR 20 / 50 / 70 response rates compared with anti-TNFα antibodies in patients with active PsA (Mease P. et al., Eur. J. Rheumatol. 20019 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 who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (Mease, PJ et al., Ann Rheum Diss 2020;79:123-131). Considering that small molecules generally have better tissue penetration, IL-17A small molecule inhibitor compounds may exert similar or better efficacy than biologics by approaching the same target.

[0010] For rheumatoid arthritis (RA): IL-17A has been recognized to be essential for the progression of rheumatoid arthritis. "The recognition of IL-17as a pro-inflammatory T cell derived cytokine,and its abundance within rheumatoid joints,provides the strongest candidate mechanism to date through which T cells can capture and localize macrophageeffector functions in rheumatoid arthritis",Stamp,LK,MJJames et al.,Immunol.Cell Biol.2004,82(1):1-9. In addition, in rheumatoid arthritis, IL-17A acts locally on synovial cells and osteoclasts, leading to synovitis and joint destruction. Robert and Miossec have proposed the use of synovial biopsy tissue and / or biomarkers to accurately identify patients who respond to IL-17A inhibition. Their work concluded that IL-17 inhibitors should now be considered in the development of precision medicine for RA. (Robert M and Miossec P, Front.Med.,2019,5:364)

[0011] For ankylosing spondylitis (AS): Various studies have reported elevated IL-17A and Th17 and other IL-17-producing cells in AS blood samples (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 DT et al., Rheumatology (Oxford). 2015 Apr, 54(4): 728–735). In situ analysis of AS spines revealed an increase in IL-17A-producing cells in facet joint bones (Appel H. et al., Arthritis Res Ther. 2011; 13(3): R95). Two advanced IL-17A neutralizing antibodies, secukinumab and ixekizumab, which are FDA-approved for AS, have demonstrated efficacy superior to placebo even in anti-TNF inadequate responders. In contrast, anti-IL-23p40 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 a mechanism underlying differentiation along the IL-23 / IL-17 pathway in AS and providing strong evidence to support continued development of IL-17A inhibitors.

[0012] For hidradenitis suppurativa (HS): IL-17 and IL-17-producing T helper cells have been reported to be increased in skin lesions of HS patients, and molecular proteomic and gene expression data suggest that the IL-23 / Th17 pathway is upregulated in HS lesions (Schlapbach et al., J. Am. Acad. Dermatol. 2011;65(4):790; Kelly G. et al., British J. Dermatol. 2015 Dec;173(6):1431-9; Moran et al., J. Invest. Dermatol. 2017;137(11):2389; Thomi et al., JAMA Dermatol. 2018;154(5):592). Seven of nine patients (78%) with moderate to severe HS achieved HiSCR in an open-label pilot trial with secukinumab (Prussick L. et al. British J. Dermatol. 2019 Sep;181(3):609-611.), and more clinical trials of anti-IL-17 mAbs in HS are ongoing.

[0013] For bullous pemphigoid (BP): IL-17 is elevated in blister fluid and perilesional skin of BP patients. (LeJan S. et al., J. Invest. Dermatol. 2014; 134(12): 2908-2917.; Chakievska L. J Autoimmun. 2019, 96: 104-112). Exome sequencing of BP patients revealed mutations in twelve IL-17-related genes in one-third of patients, providing a genetic connection between the IL-17 pathway and BP (Chakievska L. J 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 trial of ixekizumab in patients with treatment-naïve and refractory BP is ongoing (NCT03099538).

[0014] For atopic dermatitis (AD): IL-17 was found to be elevated in the peripheral blood and lesions of AD patients, and the infiltration of Th17 cells in acute lesions was more obvious than in chronic lesions, indicating that it plays a role in the acute phase of AD (Koga C. et al., Journal of Investigative Dermatology 2008, 128, 2625-2630). Molecular profiling analysis from ustekinumab phase II showed that the IL-23 / Th17 / IL-17 pathway may play a role in AD (Khattri S. et al., Exp. Dermatol. January 2017, 26(1): 28-35).

[0015] For vitiligo: Many studies on vitiligo patients have demonstrated that increased frequency of Th17 cells in both circulation and lesions and elevated IL-17 levels are positively correlated with disease duration, extent, and activity (Singh RK et al., Autoimm. Rev, April 2016, 15(4):397-404). Mouse studies have demonstrated that depigmentation is associated with increased IL-17 expression / secretion, which regulates vitiligo development (Eby JM et al., Pigment Cell Melanoma Res. November 2014, 27(6):1075-85).

[0016] For multiple sclerosis (MS): IL-17 expression is increased in PBMC, cerebrospinal fluid (CSF), and in brain lesions and cells from MS patients (Lock, CG et al., Nat. Med. 2002, 8: 500–508; Matusevicius, D et al., Mult. Scler. 1999, 5: 101–104; Tzartos, JS et al., Am. J. Pathol. 2008, 172: 146–155). IL-17-producing T cells are enriched in active MS lesions (Tzartos, JS 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 correlate with the CSF / serum albumin quotient (a measure of blood-brain barrier (BBB) ​​dysfunction) and in vitro data showing that IL-17A in combination with IL-6 reduced the expression of tight junction-related genes and disrupted monolayer integrity in BBB cell lines, highlighting the potential importance of targeting IL-17A to maintain BBB integrity in RRMS (Setiadi AF et al., J Neuroimmunol. 2019, 332: 147-154). Secukinumab first achieved promising results in a proof-of-concept study in MS patients (Havrdová, EA et al., J. Neurol. 2016, 263: 1287–1295).

[0017] For 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). It is reported that IL-17 increases in asthmatic airways and induces 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 chronic mouse asthma models (Camargo LDN et al., Front Immunol. 2018; 8: 1835; dos Santos TM et al., Front Physiol. 2018, 9: 1183).

[0018] For chronic obstructive pulmonary disease (COPD): Increased Th17 cells were observed in patients with COPD compared to current smokers and healthy subjects without COPD, and a negative correlation was found between Th17 cells and lung function (Vargas-Rojas et al., Respir. Med. 2011 Nov;105(11):1648-54). In three recent human COPD studies, gene expression profiling in the bronchial epithelium showed that higher IL-17 signature expression was associated with a lack of response to inhaled corticosteroids, suggesting the existence of a COPD subgroup that may benefit from IL-17 inhibitor therapy (Christenson SA et al., J. Clin. Invest. 2019;129(1):169–181).

[0019] For uveitis: IL-17 promotes the release of inflammatory mediators from retinal pigment epithelial cell lines, destroying the retinal pigment epithelial barrier function (Chen Y. et al., PLoS One. 2011; 6: e18139). IL-17 levels are elevated in the serum or aqueous humor of patients with uveitis (El-Asrar AMA et al., Clin. Immunol. 2011; 139 (2): 177-84; Jawad S et al., Ocul. Immunol. Inflamm. 2013; 21 (6): 434-9; Kuiper JJW. Am. J. Ophthalmol. 2011; 152 (2): 177-182.). Anti-IL-17 antibodies delay the onset of ocular inflammation in rats and significantly inhibit the development of experimental autoimmune uveitis (Zhang R. et al., Curr. Eye Res. 2009 April; 34 (4): 297-303). Analysis of secondary efficacy data from a Phase 3 trial of subcutaneous (sc) secukinumab in uveitis showed that secukinumab had a beneficial effect in reducing the use of concomitant immunosuppressive medications (Dick AD et al., Ophthalmology. 2013, 120(4):777-87). Subsequent studies of intravenous secukinumab in uveitis demonstrated that the efficacy of intravenous secukinumab was superior to sc administration, suggesting that optimal exposure is required for efficacy and 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 severe concomitant psoriasis and PsA who were unable to respond to conventional immunosuppressants (Mugheddu C. et al., Dermatol. Ther. 2017 Sep; 30(5); e12527.).

[0020] For multiple myeloma (MM): IL-17A serum levels are significantly elevated in MM patients compared to healthy subjects, and are also significantly elevated in advanced patients (Lemancewicz D. et al., Med. Sci. Monit. 2012; 18(1): BR54–BR59). After tumors were first detected in mice, weekly administration of secukinumab for 4 weeks in the SCIDhu model of human myeloma resulted in significant inhibition of tumor growth and reduced bone damage compared to isotype control mice (Prabhala R. et al., Leukemia. 2016 Feb, 30(2): 379–389).

[0021] For systemic lupus erythematosus (SLE): elevated IL-17 levels in serum or plasma, expansion of IL-17-producing T cells in peripheral blood, and infiltration of Th17 cells in target organs such as the kidneys have been observed in SLE patients (Wong CK et al., Lupus. 2000; 9(8):589–593; Wong CK et al., Clinical Immunology. 2008; 127(3):385–393; Zhao XF et al., Mol. Biol. Rep. 2010 Jan; 37(1):81-5; Chen XQ 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 is observed in SLE patients, including those in the quiescent phase ((Ma J. et al., Clinical Rheumatology. 2010; 29(11): 1251–1258; Dolff S. et al., Clinical Immunology 2011, 141(2): 197-204). Overexpression of IL-17A using adenovirus enhanced the severity of lupus nephritis, while blocking IL-17A using neutralizing antibodies resulted in reduced 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, has been shown to be effective in SLE patients (van Vollenhoven RF 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).

[0022] In summary, animal and human studies have shown that IL-17A plays a key role in the pathogenesis of the above-mentioned multiple diseases and / or conditions. The significance of targeting IL-17A has been demonstrated by the conversion efficacy of IL-17A neutralizing antibodies in patients. Although oral small molecule IL-17 inhibitors have not yet entered late-stage clinical trials, they are in an attractive area of ​​discovery because their development may broaden treatment options for many patients who cannot obtain biologics. In addition, safe and effective small molecule IL-17A inhibitors can provide significant benefits to patients, such as convenient dosing regimens and cost savings, which in turn can provide effective long-term disease management. Therefore, there is a need for new small molecule IL-17A regulators (e.g., inhibitors). Summary of the invention

[0023] The present application discloses a compound of formula I:

[0024]

[0025] or a pharmaceutically acceptable salt thereof, wherein:

[0026] R 1 For -C (1-6) Alkyl or -C (0-3) Alkyl C (3-6) Cycloalkyl;

[0027] Among them, the -C (1-6) Alkyl and the -C (0-3) Alkyl C (3-6) Cycloalkyl is unsubstituted or substituted with one to six fluorine atoms;

[0028] R 2 For -C (3-5) Cycloalkyl;

[0029] R 3 For -C (0-1) Alkyl C (3-6) Cycloalkyl, wherein the -C (0-1) Alkyl C (3-6) Cycloalkyl is unsubstituted or substituted with one to five fluorine atoms;

[0030] R 4 For -C (3-4) cycloalkyl or 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O and S;

[0031] Among them, C (3-4) The cycloalkyl group is unsubstituted or substituted with one to three R 4a group substitution; and

[0032] The 5- to 6-membered heteroaryl group is unsubstituted or substituted with one or two R 4b Group substitution;

[0033] Each R 4a The groups are independently selected from -C (1-4) Alkyl; and

[0034] Each R 4b The groups are independently selected from -C (0-2) Alkyl C (3-4) Cycloalkyl or -C (1-5) Alkyl, wherein the -C (0-2) Alkyl C (3-4) Cycloalkyl and -C (1-5) The alkyl group is unsubstituted or substituted with one to six fluorine atoms;

[0035] R 5 is H or F;

[0036] in

[0037] When R 4 For -C (3-4) When is cycloalkyl, the compound of formula I is a compound of formula Ia:

[0038]

[0039] 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.

[0040] Also described herein is a method for treating and / or ameliorating IL-17A-mediated inflammatory syndromes, disorders or diseases (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.), which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0041] 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 IL-17A-mediated inflammatory syndromes, disorders or diseases (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0042] In some embodiments, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or ameliorating IL-17A-mediated inflammatory syndromes, disorders or diseases (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0043] In some embodiments, provided herein are methods and intermediates disclosed herein that are useful for preparing compounds of Formula I or pharmaceutically acceptable salts thereof.

[0044] The present disclosure also provides compounds or methods as described herein. DETAILED DESCRIPTION

[0045] definition

[0046] Various publications, articles, and patents are cited or described in the background and throughout the specification; each of these references is incorporated herein by reference in its entirety. The discussion of documents, acts, materials, devices, articles, etc. included in this specification is intended to provide context for the present invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any invention disclosed or claimed.

[0047] 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 the invention belongs. Otherwise, certain terms used herein have the meanings described in this specification. All patents, published patent applications, and publications cited herein are incorporated herein by reference as if fully set forth herein.

[0048] It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0049] In order to help the reader of the application, the specification is divided into each paragraph or chapter, or relates to each embodiment of the application. These divisions should not be considered as the essence of a paragraph or chapter or embodiment being separated from the essence of another paragraph or chapter or embodiment. On the contrary, it will be appreciated by those skilled in the art that this specification has a wide range of applications, and encompasses all combinations of conceivable chapters, paragraphs and sentences. The discussion of any embodiment is intended to be exemplary only, and is not intended to indicate that the scope of the present disclosure (including claims) is limited to these examples.

[0050] In terms of the methods of the present invention, the term "administering" means a method of therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof or a medicament thereof. Such methods include administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof or a medicament thereof at different times during the course of treatment, or administering simultaneously or sequentially as a combination therapy.

[0051] 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, etc., more preferably humans.

[0052] The term "therapeutically effective amount" or "effective amount" means the amount of an active compound or agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, including prevention, treatment or amelioration of the symptoms of the syndrome, disorder or disease being treated.

[0053] As used herein, "IL-17" or "IL-17A" refers to interleukin 17A. It is also named IL17, CTLA8, CTLA-8. Interleukin 17A is a proinflammatory cytokine. The cytokine is produced by a group of immune cells in response to stimulation of the group of immune cells. An exemplary amino acid sequence of human IL-17 is represented in GenBank Accession No. NP_002181.1, which can be encoded by a nucleic acid sequence (such as the nucleic acid sequence in GenBank Accession No. NM_002190.3).

[0054] As used herein, the term "modulator" refers to any agent or molecule capable of binding to IL-17, including small molecule compounds.

[0055] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0056] As used herein, in one embodiment, the term "treatment" of any disease, disorder, syndrome or disorder refers to improving the disease, disorder, syndrome or disorder (i.e., slowing down or preventing or slowing down the development of at least one of the disease or its clinical symptoms). In another embodiment, "treatment" refers to alleviating or improving at least one physiological or biochemical parameter associated with or causing a disease, disorder, syndrome or disorder, including parameters that the patient may not be able to discern. In another embodiment, "treatment" refers to regulating a disease, disorder, syndrome or disorder physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, "treatment" refers to preventing or delaying the onset or development or progression of a disease, disorder, syndrome or disorder.

[0057] As used herein, the term "QD" means once daily.

[0058] As used herein, the term "BID" means twice daily.

[0059] The term "alkyl" is a straight or branched chain saturated hydrocarbon. For example, an alkyl group may have 1 to 12 carbon atoms (i.e., (C1-C 12 )alkyl) or 1 to 6 carbon atoms (i.e., (C1-C6)alkyl). Examples of alkyl include, but are not limited to, 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, -CH2CH2C H2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 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 CH3). Any alkyl group may be unsubstituted or substituted.

[0060] The term "C (a-b) "(where a and b are integers, referring to the specified number of carbon atoms) refers to alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl, or to the alkyl portion of a group, where alkyl appears as a prefix root and contains a to b (including a and b) carbon atoms. For example, C (1-4) denotes a group containing 1, 2, 3 or 4 carbon atoms.

[0061] The term "heterocycle" or "heterocyclyl" refers to a single saturated or partially unsaturated ring having at least one atom other than the carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur. Exemplary heterocycles include, but are not limited to, oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl and thiomorpholinyl.

[0062] The term "cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms (i.e., C (3-8) cycloalkyl) and preferably 3 to 6 carbon atoms (ie, C (3-6)All saturated or partially unsaturated carbocyclic ring systems of cycloalkyl (cycloalkyl), wherein the cycloalkyl ring system has a single ring or multiple rings in the form of a spirocyclic or bicyclic ring. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specifically stated in this specification, cycloalkyls may be unsubstituted or substituted. Some cycloalkyls may exist as spirocycloalkyls, in which two cycloalkyl rings are fused through a single carbon atom; for example, but not limited to, spiropentyl is exemplified by For example, but not limited to, examples of spirohexyl groups include For example, but not limited to, examples of cycloheptyl groups include For example, but not limited to, examples of cyclooctyl groups include Unless otherwise specifically stated in the specification, a spirocycloalkyl group may be unsubstituted or substituted.

[0063] The term "heteroaryl" refers to a single aromatic ring having at least one atom other than a carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. The term "heteroaryl" includes single aromatic rings having from 1 to 6 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, Azolyl, Oxazolyl, iso oxazolyl, triazolyl, imidazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl or furanyl.

[0064] The term "halogen" refers to bromo (-Br), chloro (-Cl), fluoro (-F) or iodo (-I).

[0065] When the compounds according to Formula I disclosed herein have at least one stereocenter, these compounds may exist as enantiomers or diastereomers, respectively. It should be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0066] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of one another.

[0067] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A "racemic" mixture is a 1:1 mixture of a pair of enantiomers. A "non-racemic" mixture of enantiomers is a mixture of enantiomers in a ratio other than 1:1.

[0068] If the method for preparing the compounds according to the invention produces a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. These compounds can be prepared in racemic form, non-racemic mixtures, or individual enantiomers can be prepared by enantiospecific synthesis or by splitting. For example, diastereomeric pairs can be formed by standard techniques, such as by forming salts 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, thereby splitting these compounds into their component enantiomers. These compounds can also be split by forming diastereomeric esters or amides, followed by chromatographic separation and removal of chiral auxiliary agents. Alternatively, these compounds can be split using chiral column bottles HPLC or SFC. In some cases, there may be rotational isomers of the compound, which can be separated by 1 H NMR observations, leading to 1 Complex multiplets and peak integration in H NMR spectra.

[0069] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. Chiral centers of known absolute configuration are marked by prefixes R and S specified using standard order rule procedures, and by appropriate positional priority when necessary (Pure & Appl. Chem. 45, 1976, 11–30). Certain examples contain chemical structures depicted or labeled as (R*) or (S*). When (R*) or (S*) is used in the name of a compound or in the chemical representation of a compound, it is intended to indicate that the compound is a pure single isomer at the stereocenter; however, the absolute configuration of the stereocenter has not yet been determined. Therefore, a compound designated as (R*) refers to a compound of a pure single isomer at the stereocenter with an absolute configuration (R) or (S), and a compound designated as (S*) refers to a compound of a pure single isomer at the stereocenter with an absolute configuration (R) or (S). For example, N-((S)-(7-((R)-cyclopropyl((S*)-4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-1,2,4-triazole-5-carboxamide:

[0070] Refers to the following compounds:

[0071]

[0072] Although pseudoasymmetric stereogenic centers are treated in the same manner as chiral centers, the former are given lower case letter symbols, r or s (Angew. Chem. Int. Ed. Engl. 1982, 21, 567-583).

[0073] In any of the processes for preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules concerned. This can be achieved by conventional protecting groups such as those described in: Protective Groups in Organic Chemistry ”, JFW McOmie, ed., Plenum Press, 1973; and TW Greene and PGM Wuts, “ Protective Groups in Organic Synthesis ”, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.

[0074] Furthermore, within the scope of the present invention, any element, particularly when referred to in relation to a compound of Formula I or a pharmaceutically acceptable salt thereof, is intended to include all isotopes or isotopic mixtures (naturally occurring or synthetically produced) of said element in its natural abundance or in its isotopically enriched form. For example, a reference to hydrogen includes within its scope 1 H. 2 H (i.e. deuterium or D) and 3 H (ie, tritium or T). In some embodiments, the compounds described herein include 2 H (i.e. deuterium) isotopes. For example, -C (1-6) Alkyl groups include not only -CH3 but also CD3; not only CH2CH3 but also CD2CD3, etc. Similarly, references to carbon and oxygen include within their scope, respectively 12 C. 13 C and 14 C, and 15 O and 16 O and 17 O and 18 O. The isotope may be radioactive or non-radioactive. The radiolabeled compound of Formula I may include a radioactive isotope selected from the group consisting of: 3 H. 11 C. 18 F. 35 S. 122 I. 123 I. 125 I. 131 I. 75 Br, 76 Br, 77Br and 82 Preferably, the radioisotope is selected from the group consisting of 3 H. 11 C and 18 F's group.

[0075] Compounds of formula I

[0076] The present application discloses a compound of formula I:

[0077]

[0078] or a pharmaceutically acceptable salt thereof, wherein:

[0079] R 1 For -C (1-6) Alkyl or -C (0-3) Alkyl C (3-6) Cycloalkyl;

[0080] Among them, the -C (1-6) Alkyl and the -C (0-3) Alkyl C (3-6) Cycloalkyl is unsubstituted or substituted with one to six fluorine atoms;

[0081] R 2 For -C (3-5) Cycloalkyl;

[0082] R 3 For -C (0-1) Alkyl C (3-6) Cycloalkyl, wherein the -C (0-1) Alkyl C (3-6) Cycloalkyl is unsubstituted or substituted with one to five fluorine atoms;

[0083] R 4 For -C (3-4) cycloalkyl or 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O and S;

[0084] Among them, C (3-4) The cycloalkyl group is unsubstituted or substituted with one to three R 4a group substitution; and

[0085] The 5- to 6-membered heteroaryl group is unsubstituted or substituted with one or two R 4b group substitution;

[0086] Each R 4a The groups are independently selected from -C (1-4) Alkyl; and

[0087] Each R 4b The groups are independently selected from -C (0-2)Alkyl C (3-4) Cycloalkyl or -C (1-5) Alkyl, wherein the -C (0-2) Alkyl C (3-4) Cycloalkyl and -C (1-5) The alkyl group is unsubstituted or substituted with one to six fluorine atoms;

[0088] R 5 is H or F;

[0089] in

[0090] When R 4 For -C (3-4) When is cycloalkyl, the compound of formula I is a compound of formula Ia:

[0091]

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

[0093] R 1 For -C (1-6) Alkyl or -C (0-3) Alkyl C (3-6) Cycloalkyl;

[0094] Among them, the -C (1-6) Alkyl and the -C (0-3) Alkyl C (3-6) Cycloalkyl is unsubstituted or substituted with one to six fluorine atoms;

[0095] R 2 For -C (3-5) Cycloalkyl;

[0096] R 3 For -C (0-1) Alkyl C (3-6) Cycloalkyl, wherein the -C (0-1) Alkyl C (3-6) Cycloalkyl is unsubstituted or substituted with one to five fluorine atoms;

[0097] R 4 is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O and S;

[0098] The 5- to 6-membered heteroaryl group is unsubstituted or substituted with one or two R 4b group substitution; and

[0099] Each R 4b The groups are independently selected from -C (0-2) Alkyl C (3-4) Cycloalkyl or -C (1-5) Alkyl, wherein the -C (0-2) Alkyl C(3-4) Cycloalkyl and -C (1-5) The alkyl group is unsubstituted or substituted with one to six fluorine atoms;

[0100] R 5 It is H or F.

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

[0102] R 5 For H.

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

[0104] R 1 For -C (1-4) Alkyl or -C (0-3) Alkyl C (3-5) Cycloalkyl;

[0105] Among them, the -C (1-4) Alkyl and the -C (0-3) Alkyl C (3-5) The cycloalkyl group is unsubstituted or substituted with one to six fluorine atoms.

[0106] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0107] R 1 For -C (1-3) Alkyl or -C (0-3) Alkyl C (3-5) Cycloalkyl;

[0108] Among them, the -C (1-3) Alkyl and the -C (0-3) Alkyl C (3-5) The cycloalkyl group is unsubstituted or substituted with one to six fluorine atoms.

[0109] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0110] R 1 For -C (1-3) Alkyl, wherein the -C (1-3) The alkyl group is unsubstituted or substituted with one to three fluorine atoms.

[0111] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0112] R 1 For -C (0-3) Alkyl C (3-5) Cycloalkyl, wherein the -C(0-3) Alkyl C (3-5) The cycloalkyl group is unsubstituted or substituted with one to six fluorine atoms.

[0113] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0114] R 1 C (1-2) Alkyl C (3-5) Cycloalkyl, wherein the -C (1-2) Alkyl C (3-5) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms.

[0115] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0116]

[0117] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0118]

[0119] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0120]

[0121] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0122] R 2 For -C (3-4) Cycloalkyl.

[0123] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0124] R 2 It is cyclopropyl.

[0125] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0126] R 3 For -C (0) Alkyl C (5-6) Cycloalkyl, wherein the -C (0) Alkyl C (5-6) The cycloalkyl group is unsubstituted or substituted with one to five fluorine atoms.

[0127] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0128] R 3 For -C (0) Alkyl C (5-6) Cycloalkyl, wherein the -C (0) Alkyl C (5-6) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms.

[0129] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0130] R 3 For -C (0) Alkyl C (6) Cycloalkyl, wherein the -C (0) Alkyl C (6) The cycloalkyl group is unsubstituted or substituted with one to two fluorine atoms.

[0131] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0132] R 3 for

[0133] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0134] R 4 is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from N and O;

[0135] The 5- to 6-membered heteroaryl group is unsubstituted or substituted with one or two R 4b Group substitution;

[0136] Each R 4b The groups are independently selected from -C (0-1) Alkyl C (3) Cycloalkyl or -C (1-3) Alkyl, where

[0137] The-C (0-1) Alkyl C (3) Cycloalkyl and -C (1-3) The alkyl group is unsubstituted or substituted with one to four fluorine atoms;

[0138] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0139] R 4 Not replaced or replaced by C (1-2) Alkyl-substituted pyridyl, the C(1-2) The alkyl group is unsubstituted or substituted with one to three fluorine atoms.

[0140] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0141] R 4 for

[0142] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0143] R 4 is unsubstituted or replaced by one or two R 4b substituted pyrazolyl, triazolyl, isocyanate Azolyl or Oxazolyl,

[0144] Each R 4b The groups are independently selected from -C (0-1) Alkyl C (3) Cycloalkyl or -C (1-3) Alkyl, where

[0145] The-C (0-1) Alkyl C (3) Cycloalkyl and -C (1-3) The alkyl group is unsubstituted or substituted with one to four fluorine atoms.

[0146] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0147] R 4 is unsubstituted or replaced by one or two R 4b substituted pyrazolyl, triazolyl, isocyanate Azolyl or Oxazolyl,

[0148] Each R 4b The groups are independently selected from -C (1) Alkyl C (3) Cycloalkyl or -C (1-3) Alkyl, wherein the -C (1) Alkyl C (3) Cycloalkyl and -C (1-3) The alkyl group is unsubstituted or substituted with one to three fluorine atoms.

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

[0150] R 4 is unsubstituted or replaced by one or two R 4b substituted pyrazolyl, triazolyl, isocyanate Azolyl or Oxazolyl,

[0151] Each R 4b The groups are independently -C (1-3) Alkyl, wherein the -C (1-3) The alkyl group is unsubstituted or substituted with one to three fluorine atoms.

[0152] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0153] R 4 is unsubstituted or replaced by one or two R 4b 1H-pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, isocyanate Azol-4-yl or 1,2,5- Oxazolyl.

[0154] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0155] R 4 is unsubstituted or replaced by one or two R 4b 1H-pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, isocyanate Oxazol-4-yl, iso Azol-3-yl or 1,2,5- Oxazolyl.

[0156] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0157] R 4 is unsubstituted or replaced by one or two R 4b 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-5-yl, isocyanate Azol-4-yl or 1,2,5- Oxadiazole-3-yl.

[0158] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0159] R 4 is unsubstituted or replaced by one or two R 4b1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-5-yl, isocyanate Oxazol-4-yl, iso Azol-3-yl or 1,2,5- Oxadiazole-3-yl.

[0160] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0161] R 4 for:

[0162]

[0163]

[0164] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0165] R 4 for:

[0166]

[0167] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0168] R 4 for:

[0169]

[0170] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0171] R 4 for:

[0172]

[0173] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0174] R 4 for:

[0175]

[0176] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0177] R 4 for:

[0178]

[0179] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0180] R 4 For -C (3) Cycloalkyl;

[0181] Among them, C (3) The cycloalkyl group is unsubstituted or substituted with one to three R 4a group substitution; and

[0182] Each R 4a The groups are independently selected from -C (1-2) Alkyl; and

[0183] Wherein the compound of formula I is a compound of formula Ia:

[0184]

[0185] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0186] R 4 is unsubstituted or substituted with one -CF3 -C (3) cycloalkyl, and

[0187] Wherein the compound of formula I is a compound of formula Ia:

[0188]

[0189] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0190] R 4 for

[0191]

[0192] And wherein the compound of formula I is a compound of formula Ia:

[0193]

[0194] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ia:

[0195]

[0196] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table 1A below.

[0197] Table 1A

[0198]

[0199]

[0200]

[0201]

[0202]

[0203] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table 1AA below.

[0204] Table 1AA

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table 1B below.

[0213] Table 1B

[0214]

[0215] In some embodiments, disclosed herein are compounds of Formula I, wherein the compound is

[0216] or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, disclosed herein are compounds of Formula I, wherein the compound is

[0218] or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, disclosed herein are compounds of Formula I, wherein the compound is

[0220] or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, disclosed herein are compounds of Formula I, wherein the compound is

[0222] or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, disclosed herein are compounds of Formula I, wherein the compound is

[0224] or a pharmaceutically acceptable salt thereof.

[0225] 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., tablets or capsules).

[0226] In some embodiments, disclosed herein is a pharmaceutical composition prepared by mixing a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0227] In some embodiments, disclosed herein is a method for preparing a pharmaceutical composition, the method comprising mixing a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0228] III. Therapeutic Uses

[0229] The present application also relates to a method for treating and / or improving IL-17-mediated inflammatory syndromes, disorders or diseases, which comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof or a medicament thereof to a subject in need thereof.

[0230] In some embodiments, disclosed herein is a method for treating or ameliorating an IL-17A-mediated inflammatory syndrome, disorder or disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder or disease, the method 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 disease, multiple myeloma and systemic lupus erythematosus.

[0232] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 psoriasis.

[0233] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 psoriatic arthritis.

[0234] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 rheumatoid arthritis.

[0235] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 ankylosing spondylitis.

[0236] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 hidradenitis suppurativa.

[0237] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 bullous pemphigoid.

[0238] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 atopic dermatitis.

[0239] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 vitiligo.

[0240] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 multiple sclerosis.

[0241] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder or disease, the method 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 systemic lupus erythematosus.

[0242] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 asthma.

[0243] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 uveitis.

[0244] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 chronic obstructive pulmonary disease.

[0245] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, the method 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 multiple myeloma.

[0246] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder or disease, the method 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 systemic lupus erythematosus.

[0247] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder or disease, the method 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 disease, multiple myeloma and systemic lupus erythematosus, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).

[0248] In some embodiments, disclosed herein is a method 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, suppurative hidradenitis, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma and systemic lupus erythematosus, 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.

[0249] In some embodiments, disclosed herein is a method 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 disease, multiple myeloma, and systemic lupus erythematosus, wherein 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. In some embodiments, the therapeutically effective amount is a dose of about 5 mg to 150 mg BID.

[0250] 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 disease, multiple myeloma and systemic lupus erythematosus.

[0251] In some embodiments, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation 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 disease, multiple myeloma and systemic lupus erythematosus.

[0252] In some embodiments, disclosed herein is a method for treating and / or ameliorating IL-17-mediated inflammatory syndromes, disorders or diseases, the method 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.

[0253] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder or disease, 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, hormone-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma and systemic lupus erythematosus, the method 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.

[0254] In some embodiments, disclosed herein is a method for treating or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, and ankylosing spondylitis, the method 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.

[0255] 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.

[0256] Also disclosed herein is a method of 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.

[0257] IV. Combination Therapy

[0258] The compound of formula I or a pharmaceutically acceptable salt thereof, a composition thereof or a medicament thereof may also be used in combination with one or more additional therapeutic agents.

[0259] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of anti-inflammatory agents, immunomodulators, and immunosuppressants.

[0260] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of:

[0261] (a) Anti-TNFα agents, such as infliximab Adalimumab Certolizumab Golimumab Etanercept Thalidomide Lenalidomide and pomalidomide

[0262] (b) Anti-p40 antibody agents, such as Ustekinumab and

[0263] (c) Anti-p19 antibody agents, such as guselkumab Ilumya TM / Ilumetri), Risanzumab (Skyrizi TM ) and migizone.

[0264] In some embodiments, disclosed herein is a method of treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder or disease in a subject in need thereof, the method 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 combination therapy thereof with one or more additional therapeutic agents (such as an anti-inflammatory agent, an immunomodulator 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, hormone-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma and systemic lupus erythematosus.

[0265] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17-mediated inflammatory syndrome, disorder or disease in a subject in need thereof, the method 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 drug thereof and a combination therapy with one or more additional therapeutic agents (such as an anti-inflammatory agent or an immunosuppressant), wherein the syndrome, disorder or disease is psoriasis, psoriatic arthritis, ankylosing spondylitis. In some embodiments, an IL-17-mediated inflammatory syndrome, disorder or disease is psoriasis. In some embodiments, an IL-17-mediated inflammatory syndrome, disorder or disease is psoriatic arthritis. In some embodiments, an IL-17-mediated inflammatory syndrome, disorder or disease is ankylosing spondylitis.

[0266] V. Dosage Regimen

[0267] When used as an IL-17A modulator, the compounds disclosed herein can be administered in an effective amount within a dosage range of about 0.5 mg to about 1 g, preferably about 0.5 mg to about 500 mg, in a single dose or divided daily 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 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 300 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, or 400 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, or 500 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt can 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 its pharmaceutically acceptable salt can 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 its pharmaceutically acceptable salt can be administered in an effective amount within a dosage range of about 50 mg to 100 mg QD.

[0269] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof can 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 can be administered in an effective amount within a dosage range of about 50 mg to 100 mg QD.

[0270] The dosage administered will be influenced by factors such as the route of administration, the health, weight, and age of the recipient, the frequency of treatment, and the presence of concurrent and unrelated treatments.

[0271] It will also be apparent to those skilled in the art that the therapeutically effective dose of the compound of the present invention or its pharmaceutical composition will vary according to the desired effect. Therefore, the optimal dose to be administered can be easily determined by those skilled in the art, and the optimal dose will vary with the specific compound used, the mode of administration, the strength of the formulation, and the progression of the disease condition. In addition, factors associated with the specific subject receiving treatment, including the subject's age, weight, diet, and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. Therefore, the above-mentioned doses are examples of general conditions. Of course, there may be individual cases where a higher or lower dosage range should be used, and such cases are also within the scope of the present invention.

[0272] VI. Pharmaceutically Acceptable Salts

[0273] Pharmaceutically acceptable acid salts / anionic salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, etopate, esylate, fumarate, glucoheptonate, gluconate, glutamate, p-hydroxyacetamidophenylarsonic acid salt, hexylresorcinol salt, hydrazine, hydrobromide, hydrochloride, The organic or inorganic acid also includes, but is not limited to, hydroiodic acid, perchloric acid, sulfuric acid, phosphoric acid, propionic acid, glycolic acid, methanesulfonic acid, oxalic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, saccharinic acid or trifluoroacetic acid.

[0274] 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, tromethamine, 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, NH3, NH4OH, N-methyl-D-glucamine, piperidine, potassium, potassium t-butoxide, potassium hydroxide (aqueous solution), procaine, quinine, sodium, sodium carbonate, sodium 2-ethylhexanoate, sodium hydroxide, triethanolamine, or zinc.

[0275] VII. Pharmaceutical Compositions

[0276] The compound of formula I or a pharmaceutically acceptable salt can be formulated into a pharmaceutical composition comprising any known pharmaceutically acceptable carrier. Exemplary carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antibacterial and antifungal agent, and isotonic agent. Exemplary excipients that can also be used as formulation components include fillers, binders, disintegrants, and lubricants.

[0277] The pharmaceutically acceptable salt of the compound of formula I, or its pharmaceutically acceptable salt comprises conventional non-toxic salt or quaternary ammonium salt formed by inorganic or organic acid or base.The example of such acid addition salt comprises acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecyl sulfate, hydrochloride, hydrobromide, lactate, maleate, mesylate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate.Alkali salt comprises ammonium salt, alkali metal salt such as sodium salt and potassium salt, alkaline earth metal salt such as calcium salt and magnesium salt, organic alkali salt such as dicyclohexylamine salt and amino acid such as arginine salt.In addition, basic nitrogen-containing group can be quaternized with for example alkyl halide.

[0278] The pharmaceutical composition of the present invention can be administered in any manner that can achieve its intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, oral or ocular routes. Alternatively or simultaneously, administration can be by oral routes. Preparations suitable for parenteral administration include aqueous solutions of water-soluble forms of the active compound (e.g., water-soluble salts), acidic solutions, alkaline solutions, dextrose aqueous solutions, isotonic carbohydrate solutions, and cyclodextrin inclusion complexes.

[0279] Also disclosed herein is a method for preparing a pharmaceutical composition, comprising mixing a pharmaceutically acceptable carrier with any one of the compounds of Formula I or a pharmaceutically acceptable salt thereof. In addition, the present application includes a pharmaceutical composition prepared by mixing a pharmaceutically acceptable carrier with any one of the compounds of the present invention.

[0280] Example

[0281] abbreviation

[0282] Herein and throughout this application, the following abbreviations may be used.

[0283] Ac Acetyl

[0284] ACN Acetonitrile

[0285] Boc tert-Butyloxycarbonyl

[0286] br Broad Peak

[0287] Bu Butyl

[0288] Cbz benzyloxycarbonyl

[0289] CbzCl Benzyl chloroformate

[0290] cod cyclooctadiene

[0291] δ NMR chemical shift (parts per million downfield relative to standard)

[0292] d Twin Peaks

[0293] d day

[0294] DCM Dichloromethane

[0295] DCE Dichloroethane

[0296] DEA Diethylamine

[0297] DIPEA N,N-Diisopropylethylamine (Hünig's base)

[0298] DMF N,N-Dimethylformamide

[0299] DMSO Dimethyl sulfoxide

[0300] EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0301] ESI Electrospray ionization

[0302] Et Ethyl

[0303] EtOAc Ethyl acetate

[0304] FCC Flash Column Chromatography

[0305] Fmoc Fluorenylmethoxycarbonyl

[0306] g

[0307] h hour

[0308] HATU N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethylammonium hexafluorophosphate N-oxide

[0309] HOBt 1-Hydroxybenzotriazole

[0310] HPLC High Pressure Liquid Chromatography

[0311] Hz Hertz

[0312] i different

[0313] IPA Isopropyl Alcohol

[0314] J coupling constant (NMR spectrum)

[0315] L Liter

[0316] LC Liquid Chromatography

[0317] m Milli- or multiplet

[0318] m / z mass-to-charge ratio

[0319] M + Parent molecular ion

[0320] M moles per liter (mol / L)

[0321] Me Methyl

[0322] mCPBA 3-Chloroperbenzoic acid

[0323] MeCN Acetonitrile

[0324] min

[0325] μ micro

[0326] MS or molecular sieve

[0327] MTBE tert-butyl methyl ether

[0328] NCS N-Chlorosuccinimide

[0329] Normal

[0330] n Na

[0331] N standard (equivalent concentration)

[0332] NMR Nuclear Magnetic Resonance

[0333] Pd / C Palladium on Carbon

[0334] PPTS Pyridine p-Toluenesulfonate

[0335] Pr Propyl

[0336] q quartet

[0337] rt room temperature

[0338] s Single peak

[0339] Selectfluor TM 1-Chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate)

[0340] SFC Supercritical Fluid Chromatography

[0341] Uncle T

[0342] t Triplet

[0343] TCFH Chloro-N,N,N',N'-tetramethylformamidine hexafluorophosphate

[0344] Tf trifluoromethanesulfonate (trifluoromethanesulfonate)

[0345] TFA Trifluoroacetic acid

[0346] THF Tetrahydrofuran

[0347] TMS Trimethylsilyl

[0348] wt% weight percentage

[0349] In some embodiments, provided herein are methods and intermediates disclosed herein that are useful for preparing compounds of Formula I or pharmaceutically acceptable salts thereof.

[0350] General approach :

[0351] The compounds of formula I are synthesized according to the synthetic methods described herein, which are intended to represent synthetic examples only and are not intended to be limiting in any way. Unless otherwise indicated, the substituent groups in schemes 1 to 11 are defined as above with reference to formula I. If no temperature or temperature range is indicated, it should be understood that the reaction is carried out at room temperature.

[0352] Solution 1

[0353]

[0354] Compounds of Formula I can be prepared according to Scheme 1. The Boc group of A-Ia is removed under acidic conditions (such as aqueous hydrochloric acid or TFA (neat) or TFA in DCM) to produce the corresponding amine A-Ib. The above conditions for removing the Boc group are referred to as "Boc deprotection conditions". The amine A-Ib is then reacted with a carboxylic acid (R) by amide bond formation techniques. 4 -CO2H(A-Ic)) to produce a compound of Formula I. Examples of amide bond formation techniques include: (i) reaction of an amine A-Ib with a carboxylic acid A-Ic, wherein the carboxylic acid is activated with a suitable activating agent, e.g., a carbodiimide (such as DCC or EDCI), optionally in the presence of: HOBt and / or a catalyst such as DMAP; a halogenated triamino salts such as BOP, PyBOP or PyBroP; suitable pyridine Salts (such as 2-chloro-1-methylpyridine chloride); or another suitable coupling agent such as HBTU, HATU or 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphine-2,4,6-trioxide These coupling reactions are optionally carried out in the presence of a tertiary amine such as N-methylmorpholine, diisopropylethylamine or triethylamine in a suitable solvent such as DCM, THF, DMF and mixtures thereof to produce compounds of Formula I; (ii) alternatively, amine A-Ib is reacted with a carboxylic acid chloride (R) in the presence of a base such as TEA, DIPEA, pyridine or NMO in a solvent such as THF or DCM. 4 -COCl(A-Id)) or anhydride ((R 4 -C(O))2O(A-Ie)) to produce a compound of formula I.

[0355] Solution 2

[0356]

[0357] Alternatively, compounds of Formula I can be prepared according to Scheme 2. The amine A-If is then reacted with a carboxylic acid (R 1 -CO2H(A-Ig)) to produce a compound of Formula I. Examples of amide bond formation techniques include: (i) reaction of an amine A-If with a carboxylic acid A-Ig, wherein the carboxylic acid is activated with a suitable activating agent, e.g., a carbodiimide (such as DCC or EDCI), optionally in the presence of: HOBt and / or a catalyst such as DMAP; a halogenated triamino salts such as BOP, PyBOP or PyBroP; suitable pyridine Salts (such as 2-chloro-1-methylpyridine chloride); or another suitable coupling agent such as HBTU, HATU or 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphine-2,4,6-trioxide These coupling reactions are optionally carried out in the presence of a tertiary amine such as N-methylmorpholine, diisopropylethylamine or triethylamine in a suitable solvent such as DCM, THF, DMF and mixtures thereof to produce compounds of Formula I; (ii) alternatively, the amine A-If is reacted with a carboxylic acid chloride (R) in the presence of a base such as TEA, DIPEA, pyridine or NMO in a solvent such as THF or DCM. 1 -COCl(A-Ih)) or anhydride ((R 1 -C(O))2O(A-Ii)) to produce a compound of formula I.

[0358] Solution 3

[0359]

[0360] Compounds of formula A-Ia can be prepared according to the sequence shown in Scheme 3. Condensation of 2-(methylthio)pyrimidine-4-carboxaldehyde with (S)-(-)-2-methyl-2-propanesulfinamide produces the corresponding sulfinyl imide compound A-III. A nucleophilic carbon-containing reagent such as an alkyl magnesium halide (R 2 The sulfenyl imine compound A-III is added with MgBr) to produce the corresponding sulfenamide (structure not shown), and the sulfenamide is hydrolyzed under acidic conditions (such as hydrochloric acid in dioxane solution) to produce compound A-IVa. Subsequent protection of the amine in A-IVa using a reagent such as CbzCl in the presence of a base such as DIPEA in a solvent such as DCM produces the carbamate compound A-Va. The above conditions for protecting the amine as a CBz group are referred to as "Cbz protection conditions". In a solvent such as aqueous acetonitrile or mCPBA, an oxidizing agent such as The methyl sulfide in compound A-Va is oxidized to produce the corresponding sulfone (structure not shown), which, when treated with ammonia in a solvent such as isopropanol, produces compound A-VIa. Compound A-VIa is cyclocondensed with ylide compound B-Ia in the presence of a catalyst such as di-μ-chlorobis[(1,2,5,6-η)-1,5-cyclooctadiene]diiridium, wherein R 5 The Cbz group is deprotected with a reagent such as ammonium formate in the presence of a palladium catalyst in a solvent such as aqueous methanol to produce the corresponding amine, which is separated into diastereomers using SFC to produce compound A-VIIIa. The above conditions for removing the Cbz group are referred to as "Cbz deprotection conditions". Subsequent amide bond formation is performed using the conditions described in Scheme 2 to produce compounds of general structure A-Ia.

[0361] Solution 4

[0362]

[0363] Alternatively, compound A-Ia can be prepared as shown in Scheme 4. Using the amide bond coupling conditions described in Scheme 2, amine compound A-IVa is reacted with a carboxylic acid R 1 CO2H (compound A-Ig) coupling produces compound A-IXa. The methyl sulfide compound A-IXa is oxidized using an oxidant such as mCPBA to produce the corresponding sulfone (structure not shown), which, when treated with ammonia in a solvent such as isopropanol, produces compound A-Xa. In the presence of a catalyst such as di-μ-chlorobis[(1,2,5,6-η)-1,5-cyclooctadiene]diiridium, compound A-Xa is cyclocondensed with ylide compound B-1a, wherein R 5 is H, yielding compound A-Ia.

[0364] Solution 5

[0365]

[0366] Compound B-Ia can be prepared as shown in scheme 5. In the presence of a dehydrating agent such as copper sulfate II, in a solvent such as DCM, aldehyde B-IIa is treated with (S)-(-)-2-methyl-2-propane sulfinamide to produce sulfinimide B-IIb. In the presence of a catalyst such as Sc(OTf) 3, in a solvent such as DCM, TMSCN is used to cyanate compound B-IIb to produce nitrile compound B-IIIc. Nitrile and sulfinamide groups of compound B-IIIc are hydrolyzed simultaneously under acidic conditions (such as aqueous hydrochloric acid) to produce corresponding amino acids (structure not shown). In solvents such as DCM, THF or their mixtures, by making the free NH of the corresponding amino acid with di-tert-butyl dicarbonate ((Boc) 2O) reaction to produce compound B-IVd, thereby the corresponding amino acid is protected as tert-butyl carbamate (Boc group). Compound B-IVd is treated with isobutyl chloroformate in the presence of a base such as Et3N in a solvent such as THF to give the corresponding mixed anhydride (structure not shown). 6 The mixed anhydride is treated with methane to produce an ylide compound B-Ia, the (dimethyl (oxy) -λ 6 -sulfinyl)methane is prepared in situ by mixing trimethylsulfoxide iodide with a base such as sodium tert-butoxide.

[0367] Solution 6

[0368]

[0369] Indole salt compound B-Ia can be prepared as shown in scheme 6. In the presence of a dehydrating agent such as copper sulfate II, in a solvent such as DCM, 4,4-difluorocyclohexanecarboxaldehyde is treated with (S)-(-)-2-methyl-2-propanesulfinamide to produce sulfinimide B-II. In the presence of a catalyst such as Sc(OTf), in a solvent such as DCM, TMSCN is used to cyanate compound B-II to produce nitrile compound B-III. Nitrile and sulfinamide groups in compound B-III are hydrolyzed simultaneously under acidic conditions (such as aqueous hydrochloric acid) to produce corresponding amino acids (structure not shown). In solvents such as DCM, THF or their mixtures, by making the free NH of the corresponding amino acid with di-tert-butyl dicarbonate ((Boc) O) reaction to produce compound B-IV, so that the corresponding amino acid is protected as tert-butyl carbamate (Boc group). Compound B-IV is treated with isobutyl chloroformate in the presence of a base such as Et3N in a solvent such as THF to give the corresponding mixed anhydride (structure not shown). 6 -sulfylidene)methane treatment of the mixed anhydride to produce an ylide compound BI, the (dimethyl (oxy) -λ 6 -sulfinyl)methane is prepared in situ by mixing trimethylsulfoxide iodide with a base such as sodium tert-butoxide.

[0370] Solution 7

[0371]

[0372] Where R 5 The compound of formula A-Ib wherein R 5 The Boc protecting group in compound A-Ia is removed using Boc deprotection conditions, followed by fluorination with a fluorinating agent such as Treatment yields compound A-Ib.

[0373] Solution 8

[0374]

[0375] Substituted 1,2,3-triazole-5-carboxylic acid compounds C-II can be prepared as shown in Scheme 8. In a solvent such as DMF, the 1,2,3-triazole-5-carboxylic acid compounds C-II are reacted with a base such as potassium carbonate and an alkylating agent such as an alkyl bromide (R 4bBr) treatment to alkylate 1H-1,2,3-triazole-5-carboxylate to produce a mixture of N1, N2 or N3-1,2,3-triazole-5-carboxylate compounds CI. These N1, N2 or N3-1,2,3-triazole-5-carboxylate compounds CI are separated by FCC. The ester is hydrolyzed with an aqueous base such as sodium hydroxide in a solvent such as THF to produce a carboxylic acid C-II.

[0376] Solution 9

[0377]

[0378] Heteroaromatic carboxylic acid chlorides D-Ib and D-IIb can be prepared as shown in Scheme 9. Treatment of the isoaromatic carboxylic acid with excess thionyl chloride Oxazole-4-carboxylic acid D-Ia produces the acid chloride D-Ib. 4-Methyl-1,2,5- Oxadiazole-3-carboxylic acid D-IIa, yields the acid chloride D-IIb.

[0379] Solution 10

[0380]

[0381] 3-substituted iso Oxazole-4-carboxylic acid E-III can be prepared as shown in Scheme 10. Condensation of 4,4,4-trifluorobutyraldehyde with hydroxylamine hydrochloride in a solvent such as ethanol produces the corresponding oxime EI. Subsequent treatment with NCS and cycloaddition with ethyl 3-(diethylamino)acrylate in a solvent such as chloroform produces ester E-II. Saponification of the ester with sodium hydroxide in aqueous ethanol produces isocyanate. Oxazole 4-carboxylic acid E-III.

[0382] Solution 11

[0383]

[0384] Compound A-If can be prepared as shown in Scheme 11. Compound A-VIIIa is protected as a carbamate such as benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (Fmoc) to produce compound A-Ij. Compound A-Ij wherein PG is Cbz is prepared by subjecting A-VIIIa to Cbz protection conditions. Compound A-Ij wherein PG is Fmoc is prepared by treating A-VIIIa with Fmoc-Cl in the presence of a base such as N-methylmorpholine, diisopropylethylamine or triethylamine in a solvent such as DCM or THF. Compound A-Ij is subjected to Boc deprotection conditions to produce compound A-Ik. Compound A-Ik is subjected to amide bond forming conditions such as those described in Scheme 1 for preparing compounds of Formula I from compound A-Ib to produce compound A-Im. When the carbamate compound A-Im is a Cbz group, it is removed using Cbz protecting group removal conditions to produce A-If. When the carbamate compound A-Im is an Fmoc group, it is removed by treatment with a base such as piperidine in a solvent such as DMF to yield A-If.

[0385] In obtaining the compounds and corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

[0386] Unless otherwise specified, the reaction solutions were kept at room temperature and N 2(g) or Ar (g) When solutions are "concentrated to dryness", they are concentrated under reduced pressure using a rotary evaporator, and when solutions are dried, they are usually dried over a desiccant such as MgSO4 or Na2SO4.

[0387] Unless otherwise indicated, normal phase flash column chromatography (FCC) was performed using ethyl acetate (EtOAc) / hexanes, CH2Cl2 / MeOH, or CH2Cl2 / 10% 2N NH3 in MeOH as eluents with a prepacked silica gel column such as Performed on silica gel.

[0388] Merck silica gel 60F was used for thin layer chromatography 254 2.5 cm × 7.5 cm 250 μm or 5.0 cm × 10.0 cm 250 μm pre-coated silica gel plates were used for preparative thin layer chromatography. EM Science silica gel 60F 25420 cm x 20 cm 0.5 mm pre-coated plate with a 20 cm x 4 cm concentrating area. Unless otherwise indicated, mass spectra were obtained on an Agilent series 1100MSD using electrospray ionization (ESI) in positive ion mode. The calculated masses correspond to the exact masses. NMR spectra were obtained on any of the Bruker model DPX400 (400 MHz), DPX500 (500 MHz), DRX600 (600 MHz) spectrometers. The following 1 The format of H NMR data is as follows: chemical shift (ppm) downfield from a tetramethylsilane reference (multiplicity, coupling constant J (Hz), integration).

[0389] When the yield is given as a percentage, such yield refers to the ratio of the mass of the entity for which the yield is given to the maximum amount of the same entity obtainable under the specified stoichiometric conditions. Unless otherwise indicated, reagent concentrations given as percentages refer to mass ratios.

[0390] Generally, chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0391] Intermediates

[0392] Intermediate 1

[0393] (S,E)-2-Methyl-N-((2-(methylthio)pyrimidin-4-yl)methylene)propane-2-sulfenamide

[0394]

[0395] 2-(Methylthio)pyrimidine-4-carboxaldehyde (30 g, 194.7 mmol), (S)-t-BuSONH2 (26.4 g, 214 mmol), Ti(OEt)4 (8.9 g, 38.9 mmol) and THF (300 mL) were loaded into a 500 mL three-necked flask equipped with an overhead stirrer at 20 ° C-30 ° C under nitrogen. The mixture was concentrated in vacuo. Saturated NaHCO3 aqueous solution (60 mL), H2O (400 mL) and EtOAc (300 mL) were loaded into the residue and stirred for 15 min. The resulting mixture was filtered, and the filter cake was washed with EtOAc (60 mL). After phase separation, the aqueous phase was extracted with EtOAc (300 mL). The combined organic phase was concentrated in vacuo. The residue was purified by FCC (10: 1 petroleum ether / ethyl acetate) to obtain the title compound as a yellow solid.

[0396] Intermediate 2

[0397] (S)-N-(Cyclopropyl(2-(methylthio)pyrimidin-4-yl)methyl)-2-methylpropane-2-sulfenamide

[0398]

[0399] Under nitrogen, (S)-2-methyl-N-((2-(methylthio)pyrimidin-4-yl)methylene)propane-2-sulfinamide (47.3 g, 183.8 mmol, intermediate 1) and THF (710 mL) were charged into a 2L three-necked flask equipped with an overhead stirrer. The resulting solution was cooled to -78 ° C, and cyclopropylmagnesium bromide (341 mL, 183.8 mmol, 0.6 M THF solution) was added dropwise at -78 ° C within 30 min. The resulting reaction mixture was stirred at -78 ° C for 1 h. After the reaction was completed, the mixture was quenched with 20wt% aqueous citric acid solution (100 mL). Then, H2O (2 L) was added, and the mixture was extracted with EtOAc (2 × 1 L). The combined organic phases were concentrated in vacuo to give the title compound as a brown oil.

[0400] Intermediate 3

[0401] Cyclopropyl(2-(methylthio)pyrimidin-4-yl)methanamine

[0402]

[0403] A 2L three-necked flask equipped with an overhead stirrer was charged with (S)-N-(cyclopropyl(2-(methylthio)pyrimidin-4-yl)methyl)-2-methylpropane-2-sulfinamide (115 g, 295.7 mmol, Intermediate 2) and 1,4-dioxane (1150 mL) under nitrogen. After cooling to 15°C-20°C, HCl solution (380 mL, 1520 mmol, 4 M solution in 1,4-dioxane) was added dropwise over 30 min. The resulting mixture was stirred at 15°C-20°C for 1 h. After completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was dissolved in H2O (1150 mL) and then extracted with MTBE (3×600 mL). After phase separation, the pH of the aqueous phase was adjusted to pH 8-9 by adding 0.1N K2CO3 aqueous solution. The resulting solution was extracted with EtOAc (6×600 mL). The combined EtOAc layers were concentrated in vacuo to give the title compound as a yellow solid.

[0404] Intermediate 4

[0405] N-(Cyclopropyl(2-(methylthio)pyrimidin-4-yl)methyl)-4,4,4-trifluorobutyramide

[0406]

[0407] To a mixture of cyclopropyl (2- (methylthio) pyrimidine -4-yl) methylamine (7.1g, 36.4mmol, intermediate 3), 4,4,4- trifluorobutyric acid (5.86g, 40mmol), HOBt (5.16g, 38.2mmol) and ACN (150mL) was added DIPEA (7.52mL, 43.6mmol), and the mixture was stirred for 10min. Then, EDCI (7.32g, 38.2mmol) was added, and the resulting mixture was stirred at room temperature for 1h, then stirred at 60°C for 1min, and then allowed to cool to room temperature. The reactant was quenched by adding water (800mL). A precipitate was formed and the suspension was stirred at room temperature for 30min. The solid was collected by filtration, washed with water and lyophilized to give the title compound as a white solid.

[0408] Intermediate 5

[0409] N-(Cyclopropyl(2-(methylsulfonyl)pyrimidin-4-yl)methyl)-4,4,4-trifluorobutyramide

[0410]

[0411] A mixture of N-(cyclopropyl(2-(methylthio)pyrimidin-4-yl)methyl)-4,4,4-trifluorobutanamide (150 mg, 0.47 mmol, Intermediate 4) in DCM (5 mL) was cooled to 0 °C. Then, mCPBA (243 mg, 1.41 mmol) was added and the resulting mixture was stirred at 0 °C for 1 h before warming to room temperature over an additional hour. The mixture was partitioned between saturated aqueous bicarbonate solution and DCM. The layers were separated and the organic layer was washed with water, then brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by FCC (0-100% EtOAc / hexanes) to give the title compound as a white solid.

[0412] Intermediate 6

[0413] N-((2-aminopyrimidin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutyramide

[0414]

[0415] N-(cyclopropyl(2-(methylsulfonyl)pyrimidin-4-yl)methyl)-4,4,4-trifluorobutyramide (600 mg, 1.71 mmol, intermediate 5) and ammonia solution (10 mL, 20 mmol, 2 M in 2-propanol) were added to a sealed tube. The tube was sealed and the mixture was stirred at 75 °C for 18 h. The mixture was cooled to room temperature and then concentrated to dryness. The residue was purified by FCC (0-100% (10% MeOH in EtOAc) / hexane) to give the title compound as a white solid.

[0416] Intermediate 7

[0417] (S,E)-N-((4,4-difluorocyclohexyl)methylene)-2-methylpropane-2-sulfenamide

[0418]

[0419] To a mixture of 4,4-difluorocyclohexanecarboxaldehyde (3 mL, 21.6 mmol), (S)-(-)-2-methyl-2-propanesulfenamide (2.62 g, 21.6 mmol), copper (II) sulfate (10.75 g, 67.4 mmol) and DCM (65 mL) was added PPTS (574 mg, 2.29 mmol), and the resulting mixture was stirred at room temperature for 48 h. The mixture was filtered. The filter cake was rinsed with EtOAc and the combined filtrates were concentrated. The residue was purified by FCC (0-40% EtOAc / hexanes) to give the title compound as a clear colorless oil.

[0420] Intermediate 8

[0421] (S)-N-((S)-Cyano(4,4-difluorocyclohexyl)methyl)-2-methylpropane-2-sulfenamide

[0422]

[0423] Scandium trifluoromethanesulfonate (727mg, 1.48mmol) was added to a DCM (85mL) solution of (S, E)-N-((4,4-difluorocyclohexyl) methylene)-2-methylpropane-2-sulfinamide (3.22g, 12.8mmol, intermediate 7) and TMSCN (3.21mL, 25.6mmol), and the resulting suspension was stirred at room temperature for 72h. Afterwards, the mixture was filtered through a silica gel pad, rinsed with EtOAc, and the filtrate was concentrated to dryness. The residue was purified twice by FCC (30%-80% EtOAc / hexanes, followed by 45%-70% EtOAc / hexanes) to obtain the title compound as a colorless crystalline solid.

[0424] Intermediate 9

[0425] (S)-2-((tert-Butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid

[0426]

[0427] A mixture of (S)-N-((S)-cyano(4,4-difluorocyclohexyl)methyl)-2-methylpropane-2-sulfinamide (1 g, 3.6 mmol, intermediate 8) in HCl (9 mL, 107.5 mmol, 37% aqueous solution) was stirred at 80 ° C for 24 h and then cooled to room temperature. Then, water was added to dissolve the solid formed after cooling, and the mixture was washed twice with EtOAc and concentrated to dryness. The residue was diluted with 1N NaOH aqueous solution (10 mL) and washed twice with EtOAc. Then, THF (10 mL) was added, followed by di-tert-butyl dicarbonate (0.8 mL, 3.7 mmol), and the mixture was stirred at room temperature for 45 h. Afterwards, the mixture was washed with Et2O, and the water layer was made acidic by adding 1N HCl aqueous solution. The water layer was then extracted with EtOAc, and the organics were combined, dried over anhydrous MgSO4, filtered and concentrated to dryness to give the title compound as a colorless foam.

[0428] Intermediate 10

[0429] (S)-(1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-λ 6 -sulfonylidene)-2-oxopropyl)carbamic acid tert-butyl ester

[0430]

[0431] Trimethylsulfoxide iodide (2.64 g, 12 mmol) was added to a solution of potassium tert-butoxide (1.31 g, 11.7 mmol) in THF (42 mL), and the resulting mixture was stirred at reflux for 2 h. Afterwards, the solution was cooled to 0 ° C. (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid (2.4 g, 6.96 mmol, intermediate 9), Et3N (0.96 mL, 6.96 mmol) and THF (9 mL) were added to a separate flask, and the solution was then added dropwise to a solution of isobutyl chloroformate (0.9 mL, 6.96 mmol) in THF (21 mL) at 0 ° C. The resulting mixture was stirred at 0 ° C for 30 min. The suspension was then filtered, and the solid was washed with THF (2 mL) at 0 ° C. The washings and filtrate were combined, cooled to 0 ° C, and then added dropwise to the ylide solution. The resulting mixture was stirred at 0 ° C for 2 h. Afterwards, the mixture was partitioned between water and EtOAc. The aqueous solution was further extracted with EtOAc (2×), and the organic layers were then combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated to dryness. The residue was purified by FCC (50%-100% (10% MeOH in EtOAc) / hexanes) to give the title compound as a colorless solid.

[0432] Intermediate 11

[0433] tert-Butyl ((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0434]

[0435] A 50 mL three-necked flask equipped with a magnetic stirrer was charged with N-((2-aminopyrimidin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutyramide (1.0 g, 3.47 mmol, intermediate 6), (S)-(1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-λ 6 -sulfonyl)-2-oxopropyl)carbamic acid tert-butyl ester (1.66 g, 4.51 mmol, intermediate 10), [Ir(COD)Cl]2 (47 mg, 0.07 mmol), 1,10-phenanthroline (40 mg, 0.14 mmol), NaOTf (40 mg, 0.14 mmol), MS (3.0 g, 300% w / w) and DCE (15 mL). The resulting mixture was warmed to 80-85° C. and maintained at this temperature for 20 h. Thereafter, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by FCC (50% petroleum ether / EtOAc) to give the title compound as a yellow solid.

[0436] Intermediate 12

[0437] tert-Butyl ((S)-(7-((S)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0438]

[0439] Intermediate 13

[0440] tert-Butyl ((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0441]

[0442] Tert-butyl ((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Intermediate 11) was purified by SFC using a chiral stationary phase (CHIRALPAK IH, 50 mm×250 mm; 20% i-PrOH (2 mM NH3 in MeOH) / CO2) to give a pair of diastereomers. The first eluting isomer was Intermediate 12, and the second eluting isomer was Intermediate 13.

[0443] Intermediate 14

[0444] N-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutyramide

[0445]

[0446] To a solution of tert-butyl ((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (215 mg, 0.38 mmol, intermediate 11) in DCM (0.92 mL) was added HCl (0.38 mL, 1.54 mmol, 4 M in 1,4-dioxane) and the resulting suspension was stirred at room temperature for 4 h. The mixture was concentrated to dryness and the residue was partitioned between water and EtOAc. The aqueous layer was further washed with EtOAc and the organic layer was discarded. The aqueous layer was made basic by the addition of 15% aqueous NaOH and then extracted with EtOAc (3×). The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated to dryness to give the title compound as a yellow film.

[0447] Intermediate 15

[0448] 2-(3,3,3-Trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid methyl ester

[0449]

[0450] To a mixture of 1H-1,2,3-triazole-4-carboxylic acid methyl ester (5 g, 38.2 mmol), K2CO3 (5.27 g, 38.2 mmol) and DMF (49 mL) was added 3-bromo-1,1,1-trifluoropropane (4.07 mL, 38.2 mmol), and the resulting mixture was stirred at room temperature for 17 h. The product was filtered through a pad of 4% paraformaldehyde (50 mL), rinsed with EtOAc and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous solution was further extracted with EtOAc (2 × 50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC (0 to 75% EtOAc / hexane; second eluting isomer) to give the title compound as a white solid.

[0451] Intermediate 16

[0452] 1-(3,3,3-Trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid methyl ester

[0453]

[0454] The title compound was prepared as described for the synthesis of intermediate 15 and was the first eluting isomer isolated as a clear, colorless oil.

[0455] Intermediate 17

[0456] 2-(3,3,3-Trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid

[0457]

[0458] To a mixture of methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate (4.28 g, 19.2 mmol, intermediate 15) in THF (58 mL) was added 2M NaOH aqueous solution (58 mL, 115 mmol), and the mixture was stirred at room temperature for 15 h. Afterwards, the mixture was concentrated to remove THF and then washed with EtOAc (2×50 mL). The aqueous layer was then acidified to pH 3 by adding 1N HCl aqueous solution and extracted with 2-MeTHF (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the title compound as a white solid.

[0459] Intermediate 18

[0460] 1-(3,3,3-Trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid

[0461]

[0462] The title compound was prepared as described for the synthesis of Intermediate 17 using methyl 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylate (Intermediate 16) instead of methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate to give the title compound as a white solid.

[0463] Intermediate 19

[0464] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxamide

[0465]

[0466] A mixture of N-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutyramide (80 mg, 0.16 mmol, Intermediate 14), 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid (35 mg, 0.17 mmol, Intermediate 18) and HOBt (23 mg, 0.17 mmol) was diluted with MeCN (0.75 mL). DIPEA (0.069 mL, 0.4 mmol) was added followed by EDCI (32.5 mg, 0.17 mmol) and the resulting solution was heated to 45 °C for 18 h. Afterwards, the solution was cooled to room temperature and water and EtOAc were added. The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by FCC (30%-100% acetone / hexanes) to give the title compound as a diastereomeric mixture as a pale yellow film.

[0467] Intermediate 20

[0468] Benzyl (cyclopropyl(2-(methylthio)pyrimidin-4-yl)methyl)carbamate

[0469]

[0470] A 1L three-necked flask equipped with an overhead stirrer was charged with cyclopropyl(2-(methylthio)pyrimidin-4-yl)methanamine (50 g, 256 mmol, intermediate 3), DIPEA (49.6 g, 385 mmol) and DCM (500 mL). The resulting mixture was cooled to -5°C to 5°C, and CbzCl (48 g, 282 mmol) was added dropwise over 30 min. The resulting mixture was stirred at -5°C to 5°C for 1 h. Afterwards, the reactant was quenched with H2O (100 mL) and the phases were separated. The organic phase was concentrated in vacuo to give the title compound as a yellow solid.

[0471] Intermediate 21

[0472] Benzyl (cyclopropyl(2-(methylsulfonyl)pyrimidin-4-yl)methyl)carbamate

[0473]

[0474] Under nitrogen, a 3L three-necked flask equipped with an overhead stirrer was charged with benzyl (cyclopropyl(2-(methylthio)pyrimidin-4-yl)methyl)carbamate (95 g, 231 mmol, intermediate 20), ACN (950 mL) and H2O (950 mL). After cooling to 0°C-10°C, 2-(methylthio)pyrimidin-4-yl)methyl)carbamate was added in portions at 0°C-10°C. The mixture was stirred at the same temperature for 3 hours. Afterwards, the mixture was filtered and the filter cake was washed with EtOAc (470 mL). The filtrate was collected and the pH was adjusted to about 5 to 6 by adding 0.1N Na2CO3 aqueous solution. Each phase was separated and the organic layer was concentrated to dryness. The residue was purified by FCC (15%-50% EtOAc / petroleum ether) to obtain the title compound as a brown oil.

[0475] Intermediate 22

[0476] Benzyl ((2-aminopyrimidin-4-yl)(cyclopropyl)methyl)carbamate

[0477]

[0478] The title compound was prepared using benzyl (cyclopropyl(2-(methylsulfonyl)pyrimidin-4-yl)methyl)carbamate (Intermediate 21) instead of N-(cyclopropyl(2-(methylsulfonyl)pyrimidin-4-yl)methyl)-4,4,4-trifluorobutanamide as described for the synthesis of Intermediate 6. The crude material was purified by FCC (35% EtOAc / petroleum ether) to give the title compound as an off-white solid.

[0479] Intermediate 23

[0480] tert-Butyl ((1S)-(7-((((benzyloxy)carbonyl)amino)(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0481]

[0482] Under nitrogen, a 500 mL three-necked flask equipped with an overhead stirrer was charged with benzyl ((2-aminopyrimidin-4-yl)(cyclopropyl)methyl)carbamate (11.0 g, 36.9 mmol, intermediate 22), (S)-(1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-λ 6-sulfonyl)-2-oxopropyl)carbamic acid tert-butyl ester (20.0 g, 55.3 mmol, intermediate 10), [Ir(COD)Cl]2 (1.37 g, 1.84 mmol), 1,10-phenanthroline (0.73 g, 3.69 mmol), NaOTf (0.73 g, 3.69 mmol), MS (22.0 g, 200% w / w) and toluene (165 mL). The resulting mixture was stirred at 80 ° C -85 ° C for 40 h. Afterwards, the reaction mixture was cooled to room temperature and concentrated to dryness. The residue was purified by FCC (25% -50% EtOAc / petroleum ether) to give the title compound as a yellow solid.

[0483] Intermediate 24

[0484] tert-Butyl ((1S)-(7-(amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0485]

[0486] Under nitrogen, a 500 mL three-necked flask equipped with an overhead stirrer was charged with tert-butyl ((1S)-(7-((((benzyloxy)carbonyl)amino)(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (11.0 g, 19.3 mmol, intermediate 23), Pd / C (2.2 g, 20% w / w), HCO2NH4 (9.7 g, 154 mmol), MeOH (196 mL) and H2O (26.5 mL), respectively. After stirring at 25°C-35°C for 3 h, the mixture was filtered and the filtrate was concentrated in vacuo to remove MeOH. The resulting aqueous solution was extracted with 2-MeTHF (2×300 mL). The combined organic phases were concentrated to dryness to give the title compound as an off-white solid.

[0487] Intermediate 25

[0488] tert-Butyl ((S)-(7-((S)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0489]

[0490] Intermediate 26

[0491] tert-Butyl ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0492]

[0493] Tert-butyl ((1S)-(7-(amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Intermediate 24) was purified by SFC using a chiral stationary phase (CHIRALPAK IH, 50 mm×250 mm; 30% MeOH (0.1% i-PrNH2) / CO2) to give a pair of diastereomers. The first eluting isomer was Intermediate 25, and the second eluting isomer was Intermediate 26.

[0494] Intermediate 27

[0495] tert-Butyl ((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0496]

[0497] A mixture of tert-butyl ((S)-(7-((S)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (1.0 g, 2.3 mmol, intermediate 25), 3-trifluoromethylbutanoic acid (376 mg, 2.41 mmol), DIPEA (0.59 mL, 3.44 mmol) and HOBt (0.33 g, 2.41 mmol) was diluted with MeCN (50 mL). The mixture was stirred at 40 °C for 10 min, and then EDCI (0.46 g, 2.41 mmol) was added. The resulting mixture was stirred at 40 °C for 1 h. Afterwards, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated to dryness to give the title compound as off-white foam.

[0498] Intermediate 28

[0499] N-((S)-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluoro-3-methylbutanamide

[0500] A mixture of tert-butyl ((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (1.3 g, 2.27 mmol, Intermediate 27) in TFA (10 mL, 131 mmol) was stirred at room temperature for 5 min and then concentrated to dryness. The residue was diluted with water and made basic by adding saturated aqueous NaHCO3. The mixture was then extracted three times with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated to dryness to give the title compound as a tan foam.

[0501] Intermediate 29

[0502] N-((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)isonicotinamide

[0503]

[0504] A mixture of N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluoro-3-methylbutanamide (100 mg, 0.21 mmol, Intermediate 28), 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (45.5 mg, 0.22 mmol), DIPEA (0.055 mL, 0.32 mmol) and HOBt (30 mg, 0.22 mmol) was diluted with MeCN (5 mL). The mixture was stirred at 40 °C for 10 min, and then EDCI (43 mg, 0.22 mmol) was added. The resulting mixture was stirred at 40 °C for 30 min. Thereafter, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, and concentrated to dryness. The residue was purified by FCC (0-100% (10% MeOH in EtOAc) / hexanes) to give the title compound as a foam.

[0505] Intermediate 30

[0506] 2-(Cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid methyl ester

[0507]

[0508] The title compound was prepared as described for the synthesis of intermediate 15 using (bromomethyl)cyclopropane instead of 3-bromo-1,1,1-trifluoropropane to afford the title compound as a clear colorless oil.

[0509] Intermediate 31

[0510] 2-(Cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid

[0511]

[0512] The title compound was prepared as described for the synthesis of Intermediate 17 using methyl 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylate (Intermediate 30) in place of methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate to afford the title compound as a white solid.

[0513] Intermediate 32

[0514] (EZ)-4,4,4-Trifluorobutyraldehyde oxime

[0515]

[0516] Potassium carbonate (3.29 g, 23.8 mmol) was added to a mixture of 4,4,4-trifluorobutyraldehyde (2 g, 15.9 mmol), hydroxylamine hydrochloride (1.21 g, 17.5 mmol) and EtOH (20 mL), and the resulting mixture was stirred at room temperature for 16 h. Afterwards, the mixture was concentrated to dryness, diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the title compound as a colorless oil.

[0517] Intermediate 33

[0518] 3-(3,3,3-trifluoropropyl)iso Ethyl oxadiazole-4-carboxylate

[0519]

[0520] NCS (392mg, 2.93mmol) is added to a solution of (EZ)-4,4,4-trifluorobutyraldehyde oxime (394mg, 2.79mmol, intermediate 32) and chloroform (2mL). The reaction mixture is stirred at room temperature for 3h. 3-(diethylamino)ethyl acrylate (400mg, 2.79mmol) is added, and the reaction mixture is stirred at room temperature for 16h. Meanwhile, the mixture is concentrated under reduced pressure. Then, the residue is dissolved in EtOAc (10mL), and washed with water (10mL), then washed with brine (10mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. Purify by preparative HPLC (Boston Green column, ODS 150 mm×30 mm×5 μm) (eluent: 50% to 80% (v / v) water / (0.2% formic acid)-ACN), and the resulting product is suspended in water (10 mL), frozen using dry ice / acetone, and then lyophilized to dryness to give the title compound.

[0521] Intermediate 34

[0522] 3-(3,3,3-trifluoropropyl)iso Oxazole-4-carboxylic acid

[0523]

[0524] Sodium hydroxide (84 mg, 2.1 mmol) was added to the 3-(3,3,3-trifluoropropyl)isothiazolyl chloride solution. In the mixture of 4-nitro-4-oxadiazole-4-carboxylic acid ethyl ester (100mg, 0.42mmol, intermediate 33), H2O (0.5mL) and EtOH (2.5mL). The obtained mixture was stirred at room temperature for 3h, then concentrated under reduced pressure, and the residue was diluted with water (10mL). The obtained mixture was acidified to pH 3 with 1N HCl aqueous solution, frozen with dry ice / acetone, and then lyophilized to dryness to obtain the title compound as a white solid.

[0525] Intermediate 35

[0526] tert-Butyl ((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0527]

[0528] A mixture of tert-butyl ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (750 mg, 1.72 mmol, Intermediate 26), 2-(3,3-difluorocyclobutyl)acetic acid (280 mg, 1.81 mmol) and HOBt (244 mg, 1.81 mmol) was diluted with MeCN (19 mL). Hünig's base (0.45 mL, 2.58 mmol) was added followed by EDCI (347 mg, 1.81 mmol) and the resulting solution was heated to 40 °C for 2 h. Afterwards, the solution was cooled to room temperature and water and EtOAc were added. The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as a yellow foam.

[0529] Intermediate 36

[0530] N-((R)-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide

[0531]

[0532] The title compound was prepared as described in the synthesis of Intermediate 28 using tert-butyl ((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Intermediate 35) instead of tert-butyl ((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.

[0533] Intermediate 37

[0534] trans-(1,2)-N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-1-carboxamide

[0535]

[0536] A mixture of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (125 mg, 0.26 mmol, Intermediate 36), trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid (46 mg, 0.3 mmol) and HOBt (37 mg, 0.28 mmol) was diluted with MeCN (2.9 mL). Hünig's base (0.054 mL, 0.31 mmol) was added followed by EDCI (53 mg, 0.28 mmol) and the resulting solution was heated to 40 °C for 2 h. Afterwards, the solution was cooled to room temperature and water and EtOAc were added. The layers were separated and the aqueous layer was extracted once more with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was further purified by preparative HPLC (XBridge C18, 40% to 100% MeCN / NH4OH in water (20 mM)) to give the title compound as a white solid.

[0537] Intermediate 38

[0538] tert-Butyl ((S)-(7-((S)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0539]

[0540] The title compound was prepared as described for the synthesis of Intermediate 35 using tert-butyl ((S)-(7-((S)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Intermediate 25) instead of tert-butyl ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate to give the title compound as a light orange-brown foam.

[0541] Intermediate 39

[0542] N-((S)-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide

[0543] The title compound was prepared as described in the synthesis of Intermediate 28 using tert-butyl ((S)-(7-((S)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Intermediate 38) instead of tert-butyl ((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.

[0544] Intermediate 40

[0545] 4-methyl-1,2,5- oxadiazole-3-carbonyl chloride

[0546]

[0547] 4-Methyl-1,2,5- A mixture of oxadiazole-3-carboxylic acid (135 mg, 1.05 mmol) and thionyl chloride (6.4 mL, 88 mmol) was stirred at 80 °C for 2 h and then concentrated to dryness.

[0548] Intermediate 41

[0549] N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutyramide

[0550]

[0551] The title compound was prepared using tert-butyl ((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Intermediate 13) instead of tert-butyl ((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate as described in the synthesis of Intermediate 28. The crude residue was lyophilized to afford the title compound as an off-white solid.

[0552] Intermediate 42

[0553] trans-(1,2)-N-((S)-(7-((S)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-1-carboxamide

[0554]

[0555] The title compound was prepared as described in the synthesis of Intermediate 37 using N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (Intermediate 39) instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide.

[0556] Intermediate 43

[0557] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0558]

[0559] The title compound was prepared as described for the synthesis of Intermediate 19 using 1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxylic acid instead of 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid.

[0560] Intermediate 44

[0561] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0562]

[0563] The title compound was prepared as described for the synthesis of Intermediate 19 using 1-isopropyl-1H-pyrazole-5-carboxylic acid in place of 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid.

[0564] Intermediate 45

[0565] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[0566]

[0567] The title compound was prepared as described for the synthesis of Intermediate 19 using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid.

[0568] Intermediate 46

[0569] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide

[0570]

[0571] The title compound was prepared as described for the synthesis of Intermediate 19 using 1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxylic acid instead of 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid.

[0572] Intermediate 47

[0573] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[0574]

[0575] The title compound was prepared as described for the synthesis of Intermediate 19 using 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid instead of 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid.

[0576] Intermediate 48

[0577] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0578]

[0579] The title compound was prepared as described for the synthesis of Intermediate 19 using 5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxylic acid instead of 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid.

[0580] Intermediate 49

[0581] N-((S)-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutyramide

[0582]

[0583] The title compound was prepared using tert-butyl ((S)-(7-((S)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Intermediate 12) instead of tert-butyl ((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate as described in the synthesis of Intermediate 28. The crude residue was lyophilized to afford the title compound as an off-white solid.

[0584] Intermediate 50

[0585] 3-Cyclopropyl-N-((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)iso Azole-4-carboxamide

[0586]

[0587] As described for the synthesis of intermediate 29, 3-cyclopropylisothiazolinone was used. The title compound was prepared by substituting oxadiazole-4-carboxylic acid for 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid.

[0588] Intermediate 51

[0589] N-((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isothiazolyl Azole-4-carboxamide

[0590]

[0591] As described for the synthesis of intermediate 29, 3-(3,3,3-trifluoropropyl)isothiazolyl was used. The title compound was prepared using oxadiazole-4-carboxylic acid (Intermediate 34) instead of 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid.

[0592] Intermediate 52

[0593] tert-Butyl ((1S)-(7-((1R)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0594]

[0595] The title compound was prepared as described for Intermediate 27 using tert-butyl ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Intermediate 26) instead of tert-butyl ((S)-(7-((S)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.

[0596] Intermediate 53

[0597] N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluoro-3-methylbutanamide

[0598]

[0599] The title compound was prepared as described for Intermediate 28 using tert-butyl ((1S)-(7-((1R)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Intermediate 52) instead of tert-butyl ((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.

[0600] Intermediate 54

[0601] N-((1S)-(7-((1R)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide

[0602]

[0603] The title compound was prepared as described for the synthesis of Intermediate 29 using N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluoro-3-methylbutanamide (Intermediate 53) instead of N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluoro-3-methylbutanamide and 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid instead of 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid.

[0604] Intermediate 55

[0605] N-((1S)-(7-((1R)-cyclopropyl(4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-1,2,4-triazole-5-carboxamide

[0606]

[0607] The title compound was prepared as described for the synthesis of Intermediate 29 using N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluoro-3-methylbutanamide (Intermediate 53) instead of N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluoro-3-methylbutanamide and 1-isopropyl-1H-1,2,4-triazole-5-carboxylic acid instead of 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid.

[0608] Intermediate 56

[0609] trans-(1,2)-N-((1S)-(7-((1R)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-1-carboxamide

[0610]

[0611] The title compound was prepared as described for the synthesis of Intermediate 29 using N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluoro-3-methylbutanamide (Intermediate 53) instead of N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluoro-3-methylbutanamide and trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid instead of 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid. The above method produced four diastereomers, which were separated into Examples 5 and 6.

[0612] Intermediate 57

[0613] N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)-3-fluoroimidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutyramide

[0614]

[0615] A stirring bar, N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutyramide (200 mg, 0.44 mmol, intermediate 41), Selectfluor TM (386 mg, 1.09 mmol) and MeCN (8 mL). The reaction was stirred for one hour and progressed to 60% conversion. The reaction was quenched by adding water and extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried over anhydrous MgSO4, filtered and condensed. By preparative HPLC ( Prep, 5 μM, C18OBD TM The crude material was purified by HPLC-MS / MS (50 mm x 100 mm), 0-100% acetonitrile / water (containing 20 mM NH4OH). The product containing fractions were lyophilized to give the title compound as a white solid.

[0616] Intermediate 58

[0617] tert-Butyl ((1S)-(7-((1R)-cyclopropyl(2-(2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0618]

[0619] The title compound was prepared as described in the synthesis of Intermediate 27 using tert-butyl ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)-(4,4-difluorocyclohexyl)methyl)carbamate (Intermediate 26) instead of tert-butyl ((S)-(7-((S)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate and (2,2-difluorocyclopropyl)acetic acid instead of 3-trifluoromethylbutyric acid. The crude material was purified by FCC (0-100% EtOAc / hexanes) to give the title compound as a yellow foam.

[0620] Intermediate 59

[0621] N-((R)-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(2,2-difluorocyclopropyl)acetamide

[0622]

[0623] The title compound was prepared as described in the synthesis of Intermediate 28 using tert-butyl ((1S)-(7-((1R)-cyclopropyl(2-(2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Intermediate 58) instead of tert-butyl ((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate to give the title compound as a yellow amorphous solid.

[0624] Intermediate 60

[0625] tert-Butyl ((S)-(7-((R)-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0626]

[0627] To a mixture of tert-butyl ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (2 g, 4.6 mmol, Intermediate 26) in DCM (20 mL) was added DIPEA (1.37 mL, 8.27 mmol) and Fmoc-Cl (1.31 g, 5.05 mmol), and the resulting mixture was stirred at room temperature for 2 h. The reactants were concentrated to dryness and then partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was further extracted with EtOAc (2×20 mL), and the organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC (0-50% EtOAc / petroleum ether) to give the title compound.

[0628] Intermediate 61

[0629] (9H-fluoren-9-yl)methyl((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)carbamate hydrochloride

[0630]

[0631] To a solution of tert-butyl ((S)-(7-((R)-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (3.0 g, 4.5 mmol, intermediate 60) in DCM (4 mL) was added HCl (11 mL, 11 mmol, 1 M in EtOAc) and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness to give the title compound as a white solid.

[0632] Intermediate 62

[0633] (9H-fluoren-9-yl)methyl((R)-cyclopropyl(2-((S)-(4,4-difluorocyclohexyl)(4-methyl-1,2,5- oxadiazole-3-carboxamido)methyl)imidazo[1,2-a]pyrimidin-7-yl)methyl)carbamate

[0634]

[0635] To a mixture of (9H-fluoren-9-yl)methyl((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)carbamate hydrochloride (2.0 g, 3.6 mmol, intermediate 61) and DIPEA (2.6 mL, 18 mmol) in DMF (5 mL) was added 4-methyl-1,2,5- To oxadiazole-3-carboxylic acid (550 mg, 4.3 mmol), HATU (1.6 g, 4.3 mmol) was subsequently added, and the resulting mixture was stirred at room temperature for 16 h. Afterwards, the reaction was quenched by adding saturated aqueous NaHCO3 and extracted with EtOAc (3×25 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC (0-50% EtOAc / petroleum ether) to give the title compound as a white solid.

[0636] Intermediate 63

[0637] N-((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide

[0638] Piperidine (0.58 g, 6.8 mmol) was added to the (9H-fluoren-9-yl)methyl((R)-cyclopropyl(2-((S)-(4,4-difluorocyclohexyl)(4-methyl-1,2,5- In a mixture of oxadiazole-3-formamido)methyl)imidazo[1,2-a]pyrimidin-7-yl)methyl)carbamate (1.6 g, 2.3 mmol, intermediate 62) in DCM (15 mL), the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness and purified twice by FCC (0-100% EtOAc / Et2O, then 0-15% MeOH / EtOAc), then purified by SFC (DAICEL CHIRALPAK AD, 30 mm × 250 mm, 10 μm, 60% EtOH (0.1% NH4OH) / CO2) to give the title compound as a white solid.

[0639] Intermediate 64

[0640] 3-Fluorobicyclo[1.1.1]pentane-1-carbonyl chloride

[0641]

[0642] To a solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (0.3 g, 2.30 mmol) in DCM (5 mL) and DMF (0.02 mL) was added a solution of oxalyl chloride (438 mg, 3.45 mmol) in DCM (1 mL), and the resulting solution was stirred at room temperature for 2 h. Afterwards, the solvent was removed under reduced pressure to give the title compound as a yellow oil.

[0643] Intermediate 65

[0644] 2-diazo-1-(3-fluorobicyclo[1.1.1]pentan-1-yl)ethan-1-one

[0645]

[0646] At 0 ° C, 3-fluorobicyclo [1.1.1] pentane -1- carbonyl chloride (330mg, 2.22mmol, intermediate 64) in ACN (2mL) and THF (2mL) solution was added (diazomethyl) trimethylsilane (2.22mL, 4.44mmol), and the resulting mixture was stirred at room temperature for 3h. The reactant was concentrated to dryness, then dissolved in Et2O, and washed with 0.5M citric acid aqueous solution, followed by saturated NaHCO3 aqueous solution (5mL). The organic layer was concentrated to dryness to give the title compound as a yellow oil.

[0647] Intermediate 66

[0648] 5-(Pyrrolidin-1-yl)-4-(2,2,2-trifluoroethyl)-4,5-dihydroiso Ethyl oxadiazole-3-carboxylate

[0649]

[0650] 4,4,4-trifluorobutyraldehyde (0.28 mL, 2.6 mmol) was added to a solution of pyrrolidine (0.12 mL, 1.5 mmol) and triethylamine (0.092 mL, 0.66 mmol) in DCM (1.3 mL) at 0 °C. A solution of ethyl 2-chloro-2-(hydroxyamino)acetate (100 mg, 0.66 mmol) in DCM (6.6 mL) was added in 5 portions over 5 min intervals. After 10 min, the ice bath was removed and the reaction was stirred at room temperature for 1.5 h. The solution was then concentrated under reduced pressure and the crude product was obtained without further purification.

[0651] Intermediate 67

[0652] 4-(2,2,2-Trifluoroethyl)isothiazolin Ethyl oxadiazole-3-carboxylate

[0653]

[0654] mCPBA (180 mg, 1.1 mmol) was added to 5-(pyrrolidin-1-yl)-4-(2,2,2-trifluoroethyl)-4,5-dihydroisocyanate at room temperature. In the DCM (2.5mL) solution of oxazole-3-carboxylic acid ethyl ester (190mg, 0.66mmol, intermediate 66).The reactant was stirred at room temperature for 2h, then quenched with saturated NaHCO3 aqueous solution.The biphasic mixture was transferred to a separatory funnel and extracted with EtOAc (3×20mL).The combined organic layers were washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure.Purified by FCC (0-45% EtOAc / hexane) to produce the title compound.

[0655] Intermediate 68

[0656] 4-(2,2,2-Trifluoroethyl)isothiazolin Oxazole-3-carboxylic acid

[0657]

[0658] 4-(2,2,2-trifluoroethyl) Ethyl oxadiazole-3-carboxylate (110 mg, 0.49 mmol, intermediate 67) was dissolved in THF (0.29 mL), and a solution of LiOH (24 mg, 0.99 mmol) in water (0.49 mL) was added dropwise. The mixture was stirred until the raw material was completely consumed (about 1 h), at which time the reactant was acidified with 1N HCl aqueous solution and diluted with water (10 mL). The mixture was extracted with 20% IPA in CHCl3 solution (15 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give the title compound as an off-white solid, which was used without further purification.

[0659] Example

[0660] Example 1

[0661] N-((S)-(7-((R*)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxamide

[0662]

[0663] Example 2

[0664] N-((S)-(7-((S*)-Cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxamide

[0665]

[0666] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxamide (Intermediate 19) was purified by SFC using a chiral stationary phase (Whelk-01 (S,S), 25:75 MeOH / CO2) to give a pair of diastereomers. The first eluting isomer was repurified by preparative HPLC (XBridge C18, 10%-100% MeCN / NH4OH in water (20 mM)) to give Example 1 as a colorless solid. The second eluting isomer was repurified by preparative HPLC (XBridge C18, 10% to 100% MeCN / NH4OH in water (20 mM)) to give Example 2 as a colorless solid. Embodiment 1: 1 H NMR(500MHz,DMSO-d6)δ9.20(d,J=9.0Hz,1H),8.87(d,J=6.9Hz,1H),8.72(d,J=7.5Hz,1H ),8.45(s,1H),7.83(s,1H),7.04(d,J=7.0Hz,1H),5.14(t,J=8.7Hz,1H),4.99-4.84(m,2 H),4.25(t,J=8.3Hz,1H),2.99-2.85(m,2H),2.52-2.38(m,4H),2.28-2.17(m,1H),2.11- 1.87(m,3H),1.87-1.68(m,2H),1.68-1.57(m,1H),1.45-1.14(m,3H),0.60-0.35(m,4H). MS(ESI)m / z:[M+H] + Measured value 651.3. Example 2: 1H NMR (400MHz, DMSO-d6) δ9.19(d,J=8.9Hz,1H),8.88(d,J=6.9Hz,1H),8.72(d,J =7.6Hz,1H),8.46(s,1H),7.84(s,1H),7.05(d,J=7.0Hz,1H),5.15(t,J=8.6Hz ,1H),4.98-4.86(m,2H),4.31-4.25(m,1H),3.00-2.86(m,2H),2.55-2.39(m,4 H),2.29-2.16(m,1H),2.13-1.60(m,6H),1.47-1.17(m,3H),0.59-0.37(m,4H). MS (ESI) m / z: [M+H] + The measured value is 651.3.

[0667] Example 3

[0668] N-((S)-(7-((S)-cyclopropyl((R*)-4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)isonicotinamide

[0669]

[0670] Example 4

[0671] N-((S)-(7-((S)-cyclopropyl((S*)-4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)isonicotinamide

[0672]

[0673] N-((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)isonicotinamide (Intermediate 29) was purified twice by SFC using a chiral stationary phase (Whelk-O1 (S,S), 21.2 mm×250 mm, 30:70 i-PrOH / CO2; followed by CHIRALCEL OD-H, 30 mm×250 mm, 9:91 i-PrOH (0.3% i-PrNH2) / CO2) to give a pair of diastereomers. The first eluting isomer is Example 3, and the second eluting isomer is Example 4. Example 3: 11H NMR (600 MHz, DMSO-d6) δ 9.09 (d, J = 9.0 Hz, 1H), 8.87 (d, J = 6.9 Hz, 1H), 8.76 (d, J = 7.6 Hz, 1H), 8.74 - 8.70 (m, 1H), 7.85 (s, 1H), 7.83 (s, 1H), 7.81 (dd, J = 1.5, 5.1 Hz, 1H), 7.04 (d, J = 6.9 Hz, 1H), 5.17 (t, J = 8.6 Hz, 1H), 4.36 - 4.18 (m, 1H), 3.89 (q, J = 11.4 Hz, 2H), 2.85 - 2.68 (m, 1H), 2.49 - 2.45 (m, 1H), 2.35 - 2.27 (m, 1H), 2.27 - 2.18 (m, 1H), 2.10 - 1.96 (m, 2H), 1.95 - 1.88 (m, 1H), 1.86 - 1.72 (m, 2H), 1.71 - 1.64 (m, 1H), 1.46 - 1.36 (m, 1H), 1.34 - 1.27 (m, 1H), 1.26 - 1.21 (m, 1H), 1.07 (d, J = 6.9 Hz, 3H), 0.58 - 0.45 (m, 3H), 0.44 - 0.37 (m, 1H). MS (ESI) m / z: [M+H] + Measured value 661.3. Example 4: 1 1H NMR (600 MHz, DMSO-d6) δ 9.09 (d, J = 8.8 Hz, 1H), 8.87 (d, J = 7.1 Hz, 1H), 8.77 (d, J = 7.6 Hz, 1H), 8.72 (d, J = 5.1 Hz, 1H), 7.85 (s, 1H), 7.83 (s, 1H), 7.81 (dd, J = 1.7, 5.1 Hz, 1H), 7.05 (d, J = 6.9 Hz, 1H), 5.17 (t, J = 8.6 Hz, 1H), 4.33 - 4.16 (m, 1H), 3.89 (q, J = 11.4 Hz, 2H), 2.82 - 2.68 (m, 1H), 2.56 - 2.52 (m, 1H), 2.32 - 2.25 (m, 1H), 2.25 - 2.18 (m, 1H), 2.10 - 1.96 (m, 2H), 1.94 - 1.87 (m, 1H), 1.86 - 1.72 (m, 2H), 1.71 - 1.64 (m, 1H), 1.47 - 1.37 (m, 1H), 1.34 - 1.26 (m, 1H), 1.25 - 1.19 (m, 1H), 1.02 (d, J = 6.9 Hz, 3H), 0.58 - 0.52 (m, 1H), 0.52 - 0.44 (m, 2H), 0.43 - 0.35 (m, 1H). MS (ESI) m / z: [M+H] + Measured value 661.2.

[0674] Example 5

[0675] trans-(1,2)-N-((S)-(7-((R)-cyclopropyl-4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-1-carboxamide

[0676]

[0677] Example 6

[0678] trans-(1,2)-N-((1S)-(7-((1R)-cyclopropyl-(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-1-carboxamide

[0679]

[0680] Trans-(1,2)-N-((1S)-(7-((1R)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-1-carboxamide (Intermediate 56, four diastereomers) was purified by SFC using a chiral stationary phase (OD-H2 cm×25 cm / 15% (2:1) heptane:IPA / CO2, 100 bar 70 mL / min) to give two products (Examples 5 and 6), each of which was a 1:1 mixture of two diastereomers. The first eluting material was Example 5, and the second eluting material was Example 6. Example 5: 1HNMR(600MHz,DMSO-d6)δ8.89(dd,J=1.0,7.1Hz,1H),8.81(d,J=9.3Hz,1H),8.77(dd,J=5.2,7.7Hz, 1H),7.72(d,J=1.1Hz,1H),7.05(dd,J=1.2,7.0Hz,1H),5.07-4.82(m,1H),4.35-4.16(m,1H),2.80-2 .71(m,1H),2.57-2.52(m,1H),2.38-2.23(m,2H),2.11-1.91(m,4H),1.84-1.68(m,3H),1.62-1.53(m ,1H),1.39-1.28(m,1H),1.27-1.14(m,4H),1.11-0.98(m,3H),0.58-0.45(m,3H),0.44-0.35(m,1H). MS(ESI)m / z:[M+H] + Measured value 610.3. Example 6: 1 HNMR(600MHz,DMSO-d6)δ8.87(d,J=6.9Hz,1H),8.81-8.73(m,2H),7.71(d,J=0.8Hz,1H),7.05(dd,J=1.3 ,7.1Hz,1H),5.05-4.93(m,1H),4.33-4.22(m,1H),4.14-4.01(m,1H),2.82-2.69(m,1H),2.56-2.52(m,1H ),2.37-2.23(m,2H),2.17-2.10(m,1H),2.10-1.92(m,3H),1.86-1.69(m,3H),1.64-1.57(m,1H),1.43-1. 31(m,1H),1.27-1.17(m,2H),1.14-1.10(m,1H),1.09-0.98(m,3H),0.59-0.44(m,3H),0.44-0.36(m,1H). MS(ESI)m / z:[M+H] + The measured value is 610.3.

[0681] Example 7

[0682] N-((S)-(7-((S)-cyclopropyl((S*)-4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isothiazolyl Azole-4-carboxamide

[0683]

[0684] Example 8

[0685] N-((S)-(7-((S)-cyclopropyl((R*)-4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isothiazolyl Azole-4-carboxamide

[0686]

[0687] N-((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isothiazolyl Oxazole-4-carboxamide (Intermediate 51) was purified by SFC using a chiral stationary phase (CHIRALCEL OD-H, 5 μm, 250 mm×30 mm, 91% CO 2 , 9% IPA (containing 0.3% iPrNH 2 )) to give a pair of diastereomers. The first eluting isomer was Example 8, and the second eluting isomer was Example 7. The product was purified by preparative HPLC ( Prep, 5 μM, C18OBD TM , 50mm×100mm, 0-100% acetonitrile / water (containing 20mM NH4OH)) to further purify the two isomers. The fractions containing the product were lyophilized to a white powder. Example 7: 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.86(d,J=7.0Hz,1H),8.82-8.73(m,2H),7.80(s,1H),7.04(d,J=7.0Hz,1H),5.14(t,J=8.5Hz,1H), 4.33-4.16(m,1H),3.15-3.01(m,2H),2.80-2.61(m,3H),2.57-2.52( m,1H),2.33-2.22(m,1H),2.21-2.10(m,1H),2.10-1.94(m,2H),1.92

[0688] -1.70(m,3H),1.69-1.59(m,1H),1.45-1.17(m,3H),1.02(d,J=6.9Hz,3H),0.60-0.53(m,1H),0.51-0.44(m,2H),0.43-0.35(m,1H). MS(ESI)m / z:[M+H]+ Measured value 665.3. Example 8: 1 HNMR(500MHz,DMSO-d6)δ9.51(s,1H),8.87(d,J=6.9Hz,1H),8.82-8.72(m,2H),7.81(s,1H),7.0 4(d,J=6.9Hz,1H),5.21-5.07(m,1H),4.32-4.20(m,1H),3.13-2.97(m,2H),2.81-2.62(m,3H),2 .49-2.45(m,1H),2.35-2.27(m,1H),2.22-2.13(m,1H),2.10-1.94(m,2H),1.93-1.70(m,3H),1. 68-1.60(m,1H),1.47-1.18(m,3H),1.07(d,J=6.9Hz,3H),0.60-0.44(m,3H),0.44-0.34(m,1H). MS(ESI)m / z:[M+H] + The measured value is 665.3.

[0689] Example 9

[0690] 3-Cyclopropyl-N-((S)-(7-((S)-cyclopropyl((S*)-4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)iso Azole-4-carboxamide

[0691]

[0692] Example 10

[0693] 3-Cyclopropyl-N-((S)-(7-((R)-cyclopropyl((R*)-4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)iso Azole-4-carboxamide

[0694]

[0695] 3-Cyclopropyl-N-((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)iso Oxazole-4-carboxamide (Intermediate 50) was purified by SFC using a chiral stationary phase (CHIRALCEL OD-H, 5 μm, 250 mm×30 mm, mobile phase: 91% CO 2 , 9% IPA (0.3% iPrNH 2 )) to give a pair of diastereomers. The first eluting isomer was Example 10, and the second eluting isomer was Example 9. Example 9: 1 H NMR (500MHz, DMSO-d6) δ9.36(s,1H),8.87(d,J=7.0Hz,1H),8.77(d,J=7.5Hz,1H),8.66(d,J=8.9Hz,1H),7.80(s,1H ),7.05(d,J=7.0Hz,1H),5.23-5.06(m,1H),4.37-4.15(m,1H),2.84-2.67(m,1H),2.56–2.54(m,1H),2.48–2.41(m,1 H),2.32-2.24(m,1H),2.21-2.13(m,1H),2.10-1.95(m,2H),1.93-1.71(m,3H),1.70-1.62(m,1H),1.47-1.35(m,1H ),1.35-1.18(m,2H),1.10-0.96(m,5H),0.94-0.81(m,2H),0.60-0.52(m,1H),0.52-0.43(m,2H),0.43-0.37(m,1H). MS(ESI)m / z:[M+H] + Measured value: 609.3. Example 10: 1 H NMR (500MHz, DMSO-d6) δ9.36(s,1H),8.87(d,J=6.9Hz,1H),8.76(d,J=7.8Hz,1H),8.66(d,J=9.0Hz,1H),7.81(s, 1H),7.04(d,J=7.0Hz,1H),5.15(t,J=8.4Hz,1H),4.35-4.22(m,1H),2.83–2.70(m,1H),2.49-2.42(m,2H),2.34- 2.27(m,1H),2.22-2.13(m,1H),2.10-1.94(m,2H),1.94-1.71(m,3H),1.69-1.62(m,1H),1.45-1.35(m,1H),1.34 -1.19(m,2H),1.08(d,J=6.9Hz,3H),1.04-0.95(m,2H),0.94-0.82(m,2H),0.59-0.44(m,3H),0.44-0.36(m,1H). MS(ESI)m / z:[M+H]+ The measured value is 609.3.

[0696] Embodiment 11

[0697] trans-(1S*,2S*)-N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-1-carboxamide

[0698]

[0699] Example 12

[0700] trans-(1R*,2R*)-N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-1-carboxamide

[0701]

[0702] Trans-(1,2)-N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-1-carboxamide (Intermediate 37) was purified by SFC using a chiral stationary phase (Whelk-O1 (S,S), 21.2 mm×250 mm, 5 μm, 20:80 i-PrOH / CO2) to give a pair of diastereomers. The first eluting isomer is Example 11, and the second eluting isomer is Example 12. Example 11: 1H NMR (500MHz, CDCl3) δ8.35(d,J=6.9Hz,1H),7.41(s,1H),6.90(d,J=6.9Hz,1H),6.85-6.78(m,2 H),5.09(dd,J=8.7,7.3Hz,1H),4.62(t,J=8.3Hz,1H),2.82-2.69(m,2H),2.61-2.50(m,1H),2. 47(d,J=7.5Hz,2H),2.34-2.22(m,2H),2.16-2.07(m,2H),2.04-2.01(m,1H),1.97-1.90(m,1H) ,1.83-1.79(m,1H),1.77-1.62(m,3H),1.49-1.17(m,6H),0.63-0.57(m,3H),0.53-0.47(m,1H). MS(ESI)m / z:[M+H] + Measured value 604.2. Example 12: 1 H NMR (500MHz, CDCl3) δ8.35(d,J=6.9Hz,1H),7.43(s,1H),7.30(d,J=8.8Hz,1H),7.04(d,J=7.9Hz,1 H),6.91(d,J=6.9Hz,1H),5.01(t,J=8.4Hz,1H),4.56(t,J=8.4Hz,1H),2.81-2.69(m,2H),2.60-2.4 5(m,3H),2.36-2.25(m,2H),2.19-2.11(m,2H),2.07-1.97(m,3H),1.92-1.84(m,1H),1.78-1.56(m, 3H),1.30-1.24(m,3H),1.21-1.17(m,1H),1.15-1.10(m,1H),0.63-0.56(m,3H),0.53-0.49(m,1H). MS(ESI)m / z:[M+H] + The measured value is 604.2.

[0703] Example 13

[0704] N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-1,2,4-triazole-5-carboxamide

[0705]

[0706] The title compound was prepared using 1-isopropyl-1H-1,2,4-triazole-5-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid as described in the synthesis of intermediate 37. The mixture was stirred at 40°C for 23h instead of 2h, and the crude residue was purified by preparative HPLC (XBridge C18, 40% to 100% MeCN / NH4OH in water (20mM)) followed by SFC using a chiral stationary phase (CHIRALCEL OD-H, 21.2mm×250mm, 5μm, 20:80MeOH / CO2) to give the title compound as a white solid. 1 H NMR (500MHz, CDCl3) δ8.33(d,J=6.9Hz,1H),8.14(d,J=9.3Hz,1H),7.85(s,1H),7.48(s,1H),6.91-6. 84(m,2H),5.78-5.68(m,1H),5.21-5.14(m,1H),4.62(t,J=8.3Hz,1H),2.79-2.70(m,2H),2.62-2.50( m,1H),2.50-2.46(m,2H),2.34-2.24(m,3H),2.17-1.99(m,3H),1.74-1.70(m,2H),1.52(d,J=6.6Hz,3 H), 1.46 (d, J = 6.7Hz, 3H), 1.43-1.39 (m, 1H), 1.26-1.16 (m, 3H), 0.63-0.56 (m, 3H), 0.52-0.46 (m, 1H). MS(ESI)m / z:[M+H] + The measured value is 605.2.

[0707] Embodiment 14

[0708] N-((S)-(7-((S)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-1,2,4-triazole-5-carboxamide

[0709]

[0710] The title compound was prepared as described in the synthesis of Intermediate 37 using N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (Intermediate 39) instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide and 1-isopropyl-1H-1,2,4-triazole-5-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. The mixture was stirred at 40°C for 21 h instead of 2 h, and the crude residue was purified by preparative HPLC (XBridge C18, 40% to 100% MeCN / NH4OH in water (20 mM)) followed by SFC using a chiral stationary phase (CHIRALCEL OD-H, 21.2 mm×250 mm, 5 μm, 15:85 MeOH / CO2) to give the title compound as a cream solid. 1 H NMR(500MHz, CDCl3)8.33(d,J=6.9Hz,1H),8.12(d,J=9.3Hz,1H),7.86-7.82(m,1H),7.48(s,1H),6.88(dd,J=7 .3,2.1Hz,2H),5.73(hept,J=6.7Hz,1H),5.21-5.14(m,1H),4.62(t,J=8.3Hz,1H),2.81-2.68(m,2H),2.62-2.5 1(m,1H),2.50-2.46(m,2H),2.35-2.25(m,3H),2.04-1.99(m,1H),1.81-1.67(m,4H),1.55-1.49(m,4H),1.46( d,J=6.7Hz,3H),1.44-1.38(m,1H),1.27-1.24(m,1H),1.18-1.12(m,1H),0.60-0.53(m,3H),0.49-0.43(m,1H). MS(ESI)m / z:[M+H] + The measured value is 605.3.

[0711] Embodiment 15

[0712] N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide

[0713]

[0714] The title compound was prepared using 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid as described for the synthesis of intermediate 37. The mixture was stirred at 40°C for 21 h instead of 2 h, and after 3 h additional aliquots of 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid (12 mg, 0.07 mmol), HOBt (9 mg, 0.07 mmol), DIPEA (13 μL, 0.08 mmol) and ACN (0.2 mL) pre-stirred with EDCI (13 mg, 0.07 mmol) were added. 1 HNMR(400MHz, CDCl3)δ8.33(d,J=6.9Hz,1H),8.14(d,J=9.3Hz,1H),7.86(s,1H),7.48(s, 1H),6.95-6.84(m,2H),5.17(dd,J=9.3,7.8Hz,1H),4.62(t,J=8.3Hz,1H),4.53(d,J=2.5 Hz,1H),2.82-2.69(m,2H),2.62-2.51(m,1H),2.51-2.45(m,2H),2.35-2.23(m,3H),2.20 -2.10(m,1H),2.08-1.98(m,2H),1.85-1.79(m,1H),1.60-1.13(m,7H),0.60-0.42(m,8H). MS(ESI)m / z:[M+H] + The measured value is 617.3.

[0715] Example 16

[0716] N-((S)-(7-((S)-Cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide

[0717]

[0718] The title compound was prepared as described in the synthesis of Intermediate 37, using N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (Intermediate 39) instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide, and using 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. The mixture was stirred at 40 °C for 21 h instead of 2 h, and after 3 h additional aliquots of 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid (12 mg, 0.07 mmol), HOBt (9 mg, 0.07 mmol), DIPEA (13 μL, 0.08 mmol) and ACN (0.2 mL) pre-stirred with EDCI (13 mg, 0.07 mmol) were added. 1 HNMR(400MHz, CDCl3)δ8.33(d,J=6.9Hz,1H),8.12(d,J=9.4Hz,1H),7.85(s,1H),7.48(s,1H),6 .92-6.83(m,2H),5.22-5.12(m,1H),4.62(t,J=8.3Hz,1H),4.56–4.49(m,2H),2.84-2.67(m,2H) ,2.62-2.51(m,1H),2.51-2.47(m,2H),2.38-2.22(m,3H),2.17-1.98(m,3H),1.82-1.70(m,2H) ,1.56-1.48(m,1H),1.43-1.34(m,2H),1.27-1.24(m,1H),1.18-1.12(m,1H),0.62-0.41(m,8H). MS(ESI)m / z:[M+H] + The measured value is 617.2.

[0719] Embodiment 17

[0720] N-((S)-(7-((R)-cyclopropyl((S*)-4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-1,2,4-triazole-5-carboxamide

[0721]

[0722] Embodiment 18

[0723] N-((S)-(7-((R)-cyclopropyl((R*)-4,4,4-trifluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-1,2,4-triazole-5-carboxamide

[0724]

[0725] N-((1S)-(7-((1R)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-1,2,4-triazole-5-carboxamide (Intermediate 55) was separated via SFC using a chiral stationary phase (IC 2cm×15cm, 12% IPA (containing 0.3% NPA) in CO2, 100 bar, 65 mL / min) to give a pair of diastereomers. The first eluting isomer was Example 18, and the second eluting isomer was Example 17. Example 17: 1 H NMR(400MHz, DMSO-d6)δ8.90(d,J=7.0Hz,1H),8.86-8.67(m,2H),8.10(s,1H),7.85(s,1H),7.06(d,J =6.9Hz,1H),5.68-5.42(m,1H),5.12(t,J=8.5Hz,1H),4.37-4.26(m,1H),2.84-2.68(m,1H),2.36-2.2 8(m,1H),2.21-2.10(m,1H),2.09-1.96(m,2H),1.96-1.87(m,1H),1.85-1.69(m,2H),1.68-1.60(m,1 H),1.47-1.34(m,7H),1.31-1.19(m,3H),1.08(d,J=6.9Hz,3H),0.59-0.45(m,3H),0.45-0.37(m,1H). MS(ESI)m / z:[M+H] + Measured value 611.3. Example 18: 1H NMR (400MHz, DMSO-d6) δ8.89(d,J=6.9Hz,1H),8.80(dd,J=8.4,16.0Hz,2H),8.09(d,J=0.6Hz,1H),7.85(s ,1H),7.06(d,J=7.0Hz,1H),5.63-5.44(m,1H),5.11(t,J=8.4Hz,1H),4.35-4.19(m,1H),2.81-2.69(m,1H) ,2.32-2.24(m,1H),2.20-2.10(m,1H),2.09-1.96(m,2H),1.95-1.87(m,1H),1.85-1.69(m,2H),1.68-1.60 (m,1H),1.45-1.35(m,7H),1.33-1.17(m,3H),1.02(d,J=6.9Hz,3H),0.58-0.45(m,3H),0.44-0.37(m,1H). MS(ESI)m / z:[M+H] + The measured value is 611.3.

[0726] Embodiment 19

[0727] N-((S)-(7-((R)-cyclopropyl((S*)-4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide

[0728]

[0729] Embodiment 20

[0730] N-((S)-(7-((R)-cyclopropyl((R*)-4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide

[0731]

[0732] N-((1S)-(7-((1R)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide (Intermediate 54) was purified by SFC using a chiral stationary phase (IC 2cm×15cm, 13% IPA in CO2, 100 bar, 65 mL / min) to give a pair of diastereomers. The first eluting isomer was Example 20, and the second eluting isomer was Example 19. Example 20: 1 H NMR (500MHz, DMSO-d6) δ8.90(d,J=7.0Hz,1H),8.87(d,J=9.1Hz,1H),8.78(d,J=7.6Hz,1H),8.10(s,1H),7.85(s, 1H),7.06(d,J=7.0Hz,1H),5.11(t,J=8.5Hz,1H),4.51-4.36(m,2H),4.33-4.21(m,1H),2.79-2.69(m,1H),2.33– 2.25(m,1H),2.22-2.12(m,1H),2.09-1.94(m,2H),1.93-1.87(m,1H),1.86-1.70(m,2H),1.69-1.61(m,1H),1.43 -1.31(m,1H),1.31-1.17(m,4H),1.02(d,J=6.9Hz,3H),0.59-0.52(m,1H),0.52-0.44(m,4H),0.44-0.33(m,3H). MS(ESI)m / z:[M+H] + Measured value 623.3. Example 19: 1H NMR (500MHz, DMSO-d6) δ8.90(d,J=7.0Hz,1H),8.87(d,J=9.1Hz,1H),8.78(d,J=7.8Hz,1H),8.11(s,1H),7.8 5(s,1H),7.06(d,J=7.0Hz,1H),5.11(t,J=8.5Hz,1H),4.50-4.39(m,2H),4.37-4.28(m,1H),2.82-2.71(m,1 H),2.36-2.28(m,1H),2.21-2.10(m,1H),2.09-1.94(m,2H),1.93-1.87(m,1H),1.86-1.69(m,2H),1.69-1.5 9(m,1H),1.42-1.31(m,1H),1.31-1.18(m,4H),1.08(d,J=6.9Hz,3H),0.58-0.44(m,5H),0.44-0.33(m,3H). MS(ESI)m / z:[M+H] + The measured value is 623.3.

[0733] Embodiment 21

[0734] N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide

[0735]

[0736] A solution of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (65 mg, 0.14 mmol, intermediate 36) in DCM (2.6 mL) was cooled to 0 °C in an ice bath, then DIPEA (84 μL, 0.49 mmol) was added, followed by 4-methyl-1,2,5- Oxadiazole-3-carbonyl chloride (51mg, 0.35mmol, intermediate 40). The resulting mixture was stirred at 0°C for 45min, then taken out from an ice bath and warmed to room temperature within 19h. Afterwards, the mixture was cooled to 0°C and quenched with water. Then, EtOAc (20mL) was added and the layers were separated. The aqueous layer was further extracted with EtOAc (25mL), and the organic layers were merged, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (XBridge C18, 40% to 100% MeCN / NH4OH aqueous solution (20mM)) to obtain the title compound as a cream solid. 1 H NMR (400MHz, CDCl3) δ8.35(d,J=6.9Hz,1H),7.70(d,J=8.9Hz,1H),7.47(s,1H),6.90(d,J=6.9 Hz,1H),6.84(d,J=8.0Hz,1H),5.22(dd,J=9.0,7.7Hz,1H),4.61(t,J=8.3Hz,1H),2.80-2.69(m ,2H),2.60(s,3H),2.58-2.51(m,1H),2.51-2.45(m,2H),2.35-2.12(m,4H),2.08-1.98(m,2H), 1.84-1.63(m,3H),1.54-1.35(m,2H),1.24-1.13(m,1H),0.65-0.56(m,3H),0.54-0.44(m,1H). MS(ESI)m / z:[M+H] + The measured value is 578.2.

[0737] Embodiment 22

[0738] N-((S)-(7-((S)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide

[0739]

[0740] The title compound was prepared as described in the synthesis of Example 21 using N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (Intermediate 39) instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide. 1 H NMR (400MHz, CDCl3) δ8.35(d,J=6.9Hz,1H),7.68(d,J=9.0Hz,1H),7.48(s,1H),6.90(d,J=6 .9Hz,1H),6.82(d,J=8.0Hz,1H),5.26-5.18(m,1H),4.62(t,J=8.3Hz,1H),2.82-2.67(m,2H) ,2.60(s,3H),2.59-2.52(m,1H),2.52-2.47(m,2H),2.38-2.11(m,4H),2.10-1.99(m,2H),1. 82-1.62(m,3H),1.55-1.33(m,2H),1.21-1.11(m,1H),0.61-0.53(m,3H),0.53-0.44(m,1H). MS(ESI)m / z:[M+H] + The measured value is 578.2.

[0741] Embodiment 23

[0742] N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide

[0743]

[0744] The title compound was prepared as described in the synthesis of Example 21 using N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (Intermediate 41) instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide. 1H NMR(400MHz, CDCl3) δ8.35(d,J=6.9Hz,1H),7.69(d,J=9.0Hz,1H),7.48(s,1H) ,6.94-6.87(m,2H),5.22(dd,J=9.0,7.7Hz,1H),4.62(t,J=8.3Hz,1H),2.60(s ,3H),2.57-2.43(m,4H),2.27-2.12(m,2H),2.09-1.99(m,2H),1.82-1.63(m,3 H),1.55-1.32(m,2H),1.25-1.16(m,1H),0.66-0.57(m,3H),0.55-0.47(m,1H). MS (ESI) m / z: [M+H] + Actual measured value: 570.1.

[0745] Embodiment 24

[0746] 3-Cyclopropyl-N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)iso Azole-4-carboxamide

[0747]

[0748] As described for the synthesis of intermediate 37, 3-cyclopropyl-1,2- The title compound was prepared by using oxadiazole-4-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. 1 H NMR (500MHz, CDCl3) δ8.76(s,1H),8.35(d,J=6.9Hz,1H),7.46(s,1H),7.18(d,J=8.5Hz,1H),6.91(d, J=6.9Hz,1H),6.79(d,J=7.9Hz,1H),5.28-5.23(m,1H),4.59(t,J=8.3Hz,1H),2.81-2.67(m,2H),2.60 -2.50(m,1H),2.49-2.46(m,2H),2.34-2.24(m,2H),2.23-2.12(m,3H),2.09-1.98(m,2H),1.81-1.64( m,3H),1.57-1.48(m,1H),1.42-1.34(m,1H),1.20-1.05(m,5H),0.63-0.58(m,3H),0.54-0.48(m,1H). MS(ESI)m / z:[M+H] +The measured value is 603.2.

[0749] Embodiment 25

[0750] N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)isonicotinamide

[0751]

[0752] The title compound was prepared as described in the synthesis of intermediate 37 using 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid and stirring the mixture at 40 °C for 23 h instead of 2 h. 1 HNMR(500MHz, CDCl3)δ8.73(dd,J=5.1,0.8Hz,1H),8.36(d,J=6.9Hz,1H),7.72-7.68(m,1H),7.60(dd,J=5.1,1.7Hz,1H ),7.48(s,1H),7.33(d,J=8.6Hz,1H),6.92(d,J=6.9Hz,1H),6.77(d,J=7.9Hz,1H),5.32-5.24(m,1H),4.59(t,J=8.3Hz ,1H),3.67(q,J=10.6Hz,2H),2.81-2.67(m,2H),2.61-2.49(m,1H),2.49-2.44(m,2H),2.34-2.24(m,2H),2.20-2.12(m ,2H),2.08-1.98(m,2H),1.79-1.60(m,3H),1.55-1.31(m,2H),1.22-1.16(m,1H),0.64-0.58(m,3H),0.54-0.48(m,1H). MS(ESI)m / z:[M+H] + The measured value is 655.2.

[0753] Embodiment 26

[0754] N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isothiazolyl Azole-4-carboxamide

[0755]

[0756] As described for the synthesis of intermediate 37, 3-(3,3,3-trifluoropropyl)isothiazolyl was used. The title compound was prepared by using oxadiazole-4-carboxylic acid (Intermediate 34) instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. 1 H NMR (500MHz, CDCl3) δ8.76(s,1H),8.36(d,J=6.9Hz,1H),7.45(s,1H),6.99(d,J=8.4Hz,1H),6.92(d,J=6.9Hz ,1H),6.75(d,J=7.8Hz,1H),5.21(dd,J=8.5,7.3Hz,1H),4.58(dd,J=8.7,7.9Hz,1H),3.24-3.17(m,2H),2.81

[0757] -2.69(m,2H),2.67-2.53(m,3H),2.49-2.45(m,2H),2.33-2.24(m,2H),2.19

[0758] -1.97(m,4H),1.84-1.63(m,3H),1.55-1.47(m,1H),1.37-1.29(m,1H),1.22

[0759] -1.15(m,1H),0.64-0.58(m,3H),0.54-0.48(m,1H). MS(ESI)m / z:[M+H] + The measured value is 659.2.

[0760] Embodiment 27

[0761] 3-Cyclopropyl-N-((S)-(7-((S)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)iso Azole-4-carboxamide

[0762]

[0763] As described in the synthesis of Intermediate 37, N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (Intermediate 39) was used instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide and 3-cyclopropyl-1,2- The title compound was prepared by using oxadiazole-4-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. 1 H NMR (500MHz, CDCl3) δ8.75(s,1H),8.35(d,J=6.9Hz,1H),7.47(s,1H),7.13(d,J=8.6Hz,1H),6.9 0(d,J=6.9Hz,1H),6.77(d,J=7.9Hz,1H),5.29-5.23(m,1H),4.60(t,J=8.3Hz,1H),2.83-2.70(m, 2H),2.61-2.51(m,1H),2.50-2.46(m,2H),2.36-2.25(m,2H),2.25-2.19(m,1H),2.18-1.99(m,4H ),1.80-1.64(m,3H),1.56-1.34(m,2H),1.20-1.06(m,5H),0.61-0.54(m,3H),0.52-0.45(m,1H). MS(ESI)m / z:[M+H] + The measured value is 603.2.

[0764] Embodiment 28

[0765] N-((S)-(7-((S)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)isonicotinamide

[0766]

[0767] The title compound was prepared as described in the synthesis of Intermediate 37 using N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (Intermediate 39) instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide and 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. 1H NMR(500MHz, CDCl3)δ8.73(dd,J=5.1,0.9Hz,1H),8.36(d,J=6.9Hz,1H),7.72-7.67(m,1H),7.60(dd,J=5.1,1.6Hz,1H) ,7.48(s,1H),7.28(d,J=8.5Hz,1H),6.91(d,J=6.9Hz,1H),6.76(d,J=8.0Hz,1H),5.30-5.27(m,1H),4.61(t,J=8.3Hz, 1H),3.67(q,J=10.6Hz,2H),2.80-2.71(m,2H),2.61-2.51(m,1H),2.50-2.47(m,2H),2.36-2.24(m,2H),2.20-2.00(m, 4H),1.80-1.62(m,3H),1.56-1.49(m,1H),1.42-1.34(m,1H),1.21-1.13(m,1H),0.61-0.55(m,3H),0.51-0.44(m,1H). MS(ESI)m / z:[M+H] + The measured value is 655.2.

[0768] Embodiment 29

[0769] N-((S)-(7-((S)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isothiazolyl Azole-4-carboxamide

[0770]

[0771] As described in the synthesis of Intermediate 37, N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (Intermediate 39) was used instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclobutyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide and 3-(3,3,3-trifluoropropyl)isopropyl)isopropyl)-2-(3,3-difluorocyclobutyl)acetamide. The title compound was prepared by using oxadiazole-4-carboxylic acid (Intermediate 34) instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. 1H NMR (500MHz, CDCl3) δ8.76(s,1H),8.36(d,J=6.9Hz,1H),7.46(s,1H),6.96(d,J=8.6Hz,1H),6.92(d,J=6.9H z,1H),6.74(d,J=7.9Hz,1H),5.21(dd,J=8.6,7.5Hz,1H),4.60(t,J=8.3Hz,1H),3.24-3.16(m,2H),2.81-2.7 1(m,2H),2.65-2.55(m,3H),2.50-2.46(m,2H),2.36-2.25(m,2H),2.20-2.11(m,1H),2.10-1.97(m,3H),1.81 -1.64(m,3H),1.55-1.45(m,1H),1.39-1.29(m,1H),1.21-1.12(m,1H),0.61-0.54(m,3H),0.50-0.45(m,1H). MS(ESI)m / z:[M+H] + The measured value is 659.2.

[0772] Embodiment 30

[0773] N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isothiazolyl Azole-4-carboxamide

[0774]

[0775] As described in the synthesis of Intermediate 37, N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutyramide (Intermediate 41) was used instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide and 3-(3,3,3-trifluoropropyl)isothiocarboxylate was used. The title compound was prepared by replacing trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid with oxadiazole-4-carboxylic acid (Intermediate 34) and stirring the mixture at 40°C for 4.5 h instead of 2 h. 1H NMR (500MHz, CDCl3) δ8.77(s,1H),8.37(d,J=6.9Hz,1H),7.46(s,1H),7.05(d,J=8.4Hz,1H) ,6.93(d,J=7.0Hz,1H),6.82(d,J=7.8Hz,1H),5.21(dd,J=8.5,7.4Hz,1H),4.58(dd,J=8.8, 7.8Hz,1H),3.23-3.17(m,2H),2.65-2.42(m,6H),2.12-1.98(m,3H),1.79-1.62(m,4H),1.5 4-1.45(m,1H),1.37-1.28(m,1H),1.24-1.15(m,1H),0.65-0.59(m,3H),0.56-0.50(m,1H). MS(ESI)m / z:[M+H] + The measured value is 651.2.

[0776] Embodiment 31

[0777] N-((S)-(7-((S)-Cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxamide

[0778]

[0779] A vial was charged with a stir bar, N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (75 mg, 0.16 mmol, Intermediate 49), MeCN (2 mL), HOBt (23 mg, 0.17 mmol) and 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid (29 mg, 0.17 mmol, Intermediate 31). The reaction was stirred for 5 min, then EDCI (33 mg, 0.17 mmol) and Hünig's base (0.042 mL, 0.25 mmol) were added and the reaction was stirred at 40 °C for 30 min. The reaction was cooled to room temperature, poured into water and diluted with EtOAc. The layers were separated and the aqueous phase was further extracted with EtOAc (2 x 5 mL). The combined organics were washed with brine, dried over anhydrous MgSO4, filtered and condensed to a glassy solid. The crude material was purified by FCC (0-100% (10% MeOH in EtOAc) / hexanes). The fractions containing the product were condensed, taken up in minimal MeCN:water and lyophilized to give the title compound as a white powder.1 H NMR (500MHz, DMSO-d6) δ8.88(d,J=7.0Hz,1H),8.71(d,J=7.6Hz,1H),8.41(d,J=9.0Hz,1H),8.19(s,1 H),7.83(s,1H),7.05(d,J=7.0Hz,1H),5.15(t,J=8.6Hz,1H),4.36(d,J=7.4Hz,2H),4.28(dd,J=7.9, 8.8Hz,1H),2.49-2.41(m,4H),2.20-2.10(m,1H),2.09-1.93(m,2H),1.93–1.86(m,1H),1.85-1.67(m ,2H),1.67–1.56(m,1H),1.44-1.32(m,2H),1.31-1.18(m,2H),0.60-0.51(m,3H),0.51-0.37(m,5H). MS(ESI)m / z:[M+H] + The measured value is 609.3.

[0780] Embodiment 32

[0781] N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide

[0782]

[0783] The title compound was prepared as described in the synthesis of Example 31 using N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (Intermediate 41) instead of N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide and 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid instead of 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid. The title compound was prepared by preparative HPLC ( Prep, 5 μM, C18OBD TM The material was further purified by elution with 4% paraformaldehyde (50 mm x 100 mm), 0-100% acetonitrile / water (containing 20 mM NH 4 OH) to give the title compound. 1H NMR(400MHz,DMSO-d6)δ8.97-8.81(m,2H),8.72(d,J=7.8Hz,1H),8.10(s,1H),7.84(s,1 H),7.06(d,J=7.0Hz,1H),5.10(t,J=8.6Hz,1H),4.52-4.37(m,2H),4.28(dd,J=7.8,8.8H z,1H),2.48-2.39(m,4H),2.22-2.09(m,1H),2.09-1.94(m,2H),1.94-1.85(m,1H),1.85- 1.68(m,2H),1.68-1.59(m,1H),1.41-1.30(m,1H),1.29-1.15(m,3H),0.59-0.34(m,8H). MS(ESI)m / z:[M+H] + The measured value is 609.2.

[0784] Embodiment 33

[0785] N-((S)-(7-((S)-Cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide

[0786]

[0787] The title compound was prepared as described in the synthesis of Example 31 using 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid instead of 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid. Prep, 5 μM, C18OBD TM The material was further purified by elution with 4% paraformaldehyde (50 mm x 100 mm), 0-100% acetonitrile / water (containing 20 mM NH 4 OH) to give the title compound. 1H NMR(400MHz,DMSO-d6)δ8.94-8.83(m,2H),8.72(d,J=7.8Hz,1H),8.10(s,1H),7.84(s,1 H),7.06(d,J=7.0Hz,1H),5.10(t,J=8.5Hz,1H),4.51-4.36(m,2H),4.30(dd,J=8.0,8.6H z,1H),2.56–2.52(m,1H),2.48-2.40(m,3H),2.22-2.10(m,1H),2.09-1.93(m,2H),1.93- 1.68(m,3H),1.67–1.60(m,1H),1.44-1.30(m,1H),1.30-1.16(m,3H),0.57-0.32(m,8H). MS(ESI)m / z:[M+H] + The measured value is 609.3.

[0788] Embodiment 34

[0789] N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxamide

[0790]

[0791] The title compound was prepared as described in the synthesis of Example 31 using N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (Intermediate 41) instead of N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide. 1H NMR (500MHz, DMSO-d6) δ8.88(d,J=7.0Hz,1H),8.72(d,J=7.6Hz,1H),8.41(d,J=9.1Hz,1H),8.19(s,1 H),7.83(s,1H),7.05(d,J=6.9Hz,1H),5.15(t,J=8.6Hz,1H),4.35(d,J=7.3Hz,2H),4.27(dd,J=7.8, 8.8Hz,1H),2.49-2.40(m,4H),2.21-2.10(m,1H),2.08-1.94(m,2H),1.93–1.86(m,1H),1.86-1.66(m ,2H),1.66–1.58(m,1H),1.41-1.31(m,2H),1.31-1.17(m,2H),0.60-0.50(m,3H),0.50-0.36(m,5H). MS(ESI)m / z:[M+H] + The measured value is 609.3.

[0792] Embodiment 35

[0793] N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)-3-fluoroimidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0794]

[0795] The title compound was prepared as described in the synthesis of Example 31 using N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)-3-fluoroimidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (Intermediate 57) instead of N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide and 1-isopropyl-1H-pyrazole-5-carboxylic acid instead of 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid. 1H NMR(500MHz,DMSO-d6)δ8.81(d,J=8.5Hz,1H),8.75-8.67(m,2H),7.47(d,J=1.9Hz,1H),7.13(d,J=7.1Hz ,1H),6.92(d,J=2.0Hz,1H),5.38(spt,J=6.6Hz,1H),5.10(t,J=8.9Hz,1H),4.25(dd,J=7.6,8.9Hz,1H), 2.48-2.39(m,3H),2.30-2.18(m,1H),2.13-2.04(m,1H),2.04-1.92(m,2H),1.87-1.67(m,2H),1.65-1.5 7(m,1H),1.42-1.27(m,8H),1.27-1.13(m,2H),0.58-0.51(m,1H),0.50-0.43(m,2H),0.43-0.36(m,1H). MS(ESI)m / z:[M+H] + The measured value is 614.3.

[0796] Embodiment 36

[0797] 3-Cyclopropyl-N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)iso Azole-4-carboxamide

[0798]

[0799] As described in the synthesis of Example 31, N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (Intermediate 41) was used instead of N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide, and 3-cyclopropylisothiazolyl was used. The title compound was prepared by substituting 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid for 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid. 1H NMR(500MHz,DMSO-d6)δ9.36(s,1H),8.86(d,J=7.0Hz,1H),8.72(d,J=7.6Hz,1H),8.67(d,J=9.0Hz,1H),7.80 (s,1H),7.04(d,J=7.0Hz,1H),5.13(t,J=8.5Hz,1H),4.26(dd,J=7.7,8.8Hz,1H),2.49-2.40(m,5H),2.23-2. 11(m,1H),2.10-1.94(m,2H),1.94–1.86(m,1H),1.85-1.69(m,2H),1.86–1.56(m,1H),1.46-1.34(m,1H),1.3 4-1.24(m,1H),1.24-1.14(m,1H),1.04-0.94(m,2H),0.93-0.81(m,2H),0.59-0.43(m,3H),0.43-0.36(m,1H). MS(ESI)m / z:[M+H] + The measured value is 595.2.

[0800] Embodiment 37

[0801] 3-Cyclopropyl-N-((S)-(7-((S)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)iso Azole-4-carboxamide

[0802]

[0803] As described in the synthesis of Example 31, 3-cyclopropylisothiazolinone was used. The title compound was prepared by substituting 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid for 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid. 1H NMR (500MHz, DMSO-d6) δ9.35(s,1H),8.86(d,J=6.9Hz,1H),8.71(d,J=7.6Hz,1H),8.65(d,J=9.0Hz,1H),7.80(s,1 H),7.04(d,J=7.0Hz,1H),5.14(t,J=8.4Hz,1H),4.27(dd,J=7.8,8.7Hz,1H),2.48-2.39(m,5H),2.22–2.11(m,1H) ,2.10-1.94(m,2H),1.92–1.85(m,1H),1.85-1.70(m,2H),1.70–1.58(m,1H),1.47–1.35(m,1H),1.34-1.26(m,1H) ,1.26-1.19(m,1H),1.04-0.94(m,2H),0.93-0.82(m,2H),0.57-0.50(m,1H),0.50-0.42(m,2H),0.42-0.37(m,1H). MS(ESI)m / z:[M+H] + The measured value is 595.3.

[0804] Embodiment 38

[0805] N-((S)-(7-((S*)-Cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0806]

[0807] Embodiment 39

[0808] N-((S)-(7-((R*)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0809]

[0810] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (Intermediate 48) was purified by SFC using a chiral stationary phase (Whelk-01(R,R), 25cm×2cm; 25:75 EtOH(0.1%DEA) / CO2) to give a pair of diastereomers. The first eluting isomer was Example 39 and the second eluting isomer was Example 38. Example 38: 1 H NMR (400MHz, DMSO-d6) δ8.87(d,J=7.0Hz,1H),8.72(d,J=7.7Hz,1H),8.18(d,J =9.1Hz,1H),8.12(s,1H),7.77(s,1H),7.04(d,J=7.0Hz,1H),5.14(t,J=8.6Hz ,1H),4.37–4.21(m,3H),2.91–2.75(m,2H),2.53–2.39(m,7H),2.24–2.13(m,1 H),2.11–1.93(m,2H),1.92–1.60(m,4H),1.47–1.14(m,3H),0.61–0.35(m,4H). MS (ESI) m / z: [M+H] + Measured value 664.0. Example 39: 1 H NMR(500MHz,DMSO-d6)δ8.86(d,J=6.9Hz,1H),8.70(d,J=7.7Hz,1H),8.15(d,J=9.1Hz, 1H),8.11(s,1H),7.76(s,1H),7.02(d,J=7.0Hz,1H),5.14(t,J=8.5Hz,1H),4.32-4.25 (m,3H),2.88-2.76(m,2H),2.49(s,3H),2.49-2.39(m,4H),2.21-2.11(m,1H),2.09-1. 93(m,2H),1.89-1.62(m,4H),1.44-1.34(m,1H),1.32-1.17(m,2H),0.57-0.36(m,4H). MS(ESI)m / z:[M+H] + The measured value is 664.2.

[0811] Embodiment 40

[0812] N-((S)-(7-((S*)-Cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[0813]

[0814] Embodiment 41

[0815] N-((S)-(7-((R*)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[0816]

[0817] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide (Intermediate 47) was purified by SFC using a chiral stationary phase (CHIRALPAK IA, 25 cm×2 cm; 40:60 EtOH (0.1% DEA) / CO2) to give a pair of diastereomers. The first eluting isomer was Example 41, and the second eluting isomer was Example 40. Example 40: 1 HNMR(500MHz,DMSO-d6)δ8.88(d,J=6.9Hz,1H),8.72(d,J=7.6Hz,1H),8.47(d,J=9.0Hz,1H ),8.24(s,1H),7.83(s,1H),7.05(d,J=7.0Hz,1H),5.15(t,J=8.6Hz,1H),4.77(t,J=6.7Hz ,2H),4.27(t,J=8.2Hz,1H),3.12-2.98(m,2H),2.53-2.38(m,4H),2.22-2.10(m,1H),2.10 -1.86(m,3H),1.86-1.66(m,2H),1.66-1.56(m,1H),1.43-1.16(m,3H),0.60-0.35(m,4H). MS(ESI)m / z:[M+H] + Measured value 651.1. Example 41: 1H NMR (500MHz, DMSO-d6) δ8.87(d,J=6.9Hz,1H),8.71(d,J=7.5Hz,1H),8.46(d,J=9.0Hz,1H),8.24(s ,1H),7.82(s,1H),7.05(d,J=6.9Hz,1H),5.15(t,J=8.6Hz,1H),4.76(t,J=6.7Hz,2H),4.31-4.25( m,1H),3.10-2.99(m,2H),2.51-2.40(m,4H),2.20-2.10(m,1H),2.09-1.93(m,2H),1.93-1.85(m,1 H),1.85-1.67(m,2H),1.66-1.58(m,1H),1.42-1.31(m,1H),1.31-1.17(m,2H),0.57-0.37(m,4H). MS(ESI)m / z:[M+H] + The measured value is 651.1.

[0818] Embodiment 42

[0819] N-((S)-(7-((S*)-Cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide

[0820]

[0821] Embodiment 43

[0822] N-((S)-(7-((R*)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide

[0823]

[0824] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide (Intermediate 46) was purified by SFC using a chiral stationary phase (CHIRALPAK AD-H, 25 cm×2 cm; 15:85 MeOH (0.1% DEA) / CO2) to give a pair of diastereomers. The first eluting isomer was Example 43, and the second eluting isomer was Example 42. Example 42:1 H NMR (500MHz, DMSO-d6) δ8.88(d,J=6.9Hz,1H),8.73(d,J=7.6Hz,1H),7.99(d,J=9.2Hz,1H ),7.91(d,J=2.4Hz,1H),7.82(s,1H),7.06(d,J=7.0Hz,1H),6.67(d,J=2.3Hz,1H),5.16- 5.11(m,1H),4.47(t,J=7.0Hz,2H),4.28(dd,J=8.9,7.6Hz,1H),2.99-2.88(m,2H),2.52- 2.41(m,4H),2.15-1.66(m,6H),1.65-1.57(m,1H),1.39-1.18(m,3H),0.57-0.38(m,4H). MS(ESI)m / z:[M+H] + Measured value 650.3. Example 43: 1 H NMR (500MHz, DMSO-d6) δ8.88(d,J=6.9Hz,1H),8.71(d,J=7.7Hz,1H),7.99(d,J=9.2Hz,1H),7.90 (d,J=2.3Hz,1H),7.82(s,1H),7.05(d,J=7.0Hz,1H),6.67(d,J=2.4Hz,1H),5.13(t,J=8.5Hz,1H) ,4.46(t,J=7.0Hz,2H),4.32-4.27(m,1H),2.99-2.88(m,2H),2.55-2.40(m,4H),2.15-1.92(m,3H ),1.92-1.65(m,3H),1.65-1.57(m,1H),1.39-1.30(m,1H),1.30-1.17(m,2H),0.57-0.37(m,4H). MS(ESI)m / z:[M+H] + The measured value is 650.3.

[0825] Embodiment 44

[0826] N-((S)-(7-((S*)-Cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[0827]

[0828] Embodiment 45

[0829] N-((S)-(7-((R*)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[0830]

[0831] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-methyl-1H-pyrazole-5-carboxamide (Intermediate 45) was purified by SFC using a chiral stationary phase (CHIRALPAK AD-H, 25 cm×2 cm; 20:80 MeOH(0.1% DEA) / CO2) to give a pair of diastereomers. The first eluting isomer was Example 45, and the second eluting isomer was Example 44. Example 44: 1 H NMR (400MHz, DMSO-d6) δ8.86(d,J=6.9Hz,1H),8.77-8.66(m,2H),7.80(s,1H),7.45(d,J=2.1Hz,1H),7.08-6.99(m,2H),5.11(t,J=8.6 Hz,1H),4.30-4.22(m,1H),4.02(s,3H),2.57-2.37(m,4H),2.27-2.14(m,1H),2.12-1.59(m,6H),1.46-1.14(m,3H),0.59-0.35(m,4H). MS(ESI)m / z:[M+H] + Measured value 568.3. Example 45: 1 H NMR(500MHz,DMSO-d6)δ8.86(d,J=6.9Hz,1H),8.71(d,J=8.4Hz,2H),7.79(s,1H), 7.45(d,J=2.0Hz,1H),7.05-7.01(m,2H),5.11(t,J=8.6Hz,1H),4.29-4.24(m,1H), 4.01(s,3H),2.53-2.40(m,4H),2.24-2.15(m,1H),2.10-1.94(m,2H),1.92-1.85( m,1H),1.85-1.63(m,3H),1.44-1.34(m,1H),1.32-1.17(m,2H),0.57-0.37(m,4H). MS(ESI)m / z:[M+H] + The measured value is 568.3.

[0832] Embodiment 46

[0833] N-((S)-(7-((S*)-Cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0834]

[0835] Embodiment 47

[0836] N-((S)-(7-((R*)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0837]

[0838] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Intermediate 44) was purified by SFC using a chiral stationary phase (Whelk-01 (S,S), 25 cm×2 cm; 25:75 MeOH / CO2) to give a pair of diastereomers. The first eluting isomer was Example 47, and the second eluting isomer was Example 46. Example 46: 1 HNMR(600MHz,DMSO-d6)δ8.88(d,J=6.9Hz,1H),8.74-8.70(m,2H),7.81(s,1H),7.50(d,J=2.0 Hz,1H),7.05(d,J=7.0Hz,1H),6.93(d,J=2.0Hz,1H),5.43-5.36(m,1H),5.14(t,J=8.5Hz,1H), 4.31-4.26(m,1H),2.54-2.41(m,4H),2.24-2.16(m,1H),2.10-1.95(m,2H),1.92-1.85(m,1H), 1.84-1.64(m,3H),1.46-1.19(m,9H),0.57-0.51(m,1H),0.51-0.44(m,2H),0.43-0.38(m,1H). MS(ESI)m / z:[M+H] + Measured value 596.3. Example 47: 1H NMR(500MHz,DMSO-d6)δ8.87(d,J=6.9Hz,1H),8.78-8.67(m,2H),7.80(s,1H), 7.48(s,1H),7.04(d,J=6.9Hz,1H),6.93(d,J=2.0Hz,1H),5.44-5.34(m,1H),5 .12(t,J=8.7Hz,1H),4.27(t,J=8.3Hz,1H),2.56-2.40(m,4H),2.25-2.16(m,1 H),2.11-1.93(m,2H),1.93-1.61(m,4H),1.46-1.16(m,9H),0.57-0.36(m,4H). MS (ESI) m / z: [M+H] + The measured value is 596.3.

[0839] Embodiment 48

[0840] N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)isonicotinamide

[0841]

[0842] The title compound was prepared as described in the synthesis of Intermediate 37, using N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (Intermediate 41) instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide and 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid, and the mixture was stirred at 40°C for 21 h instead of 2 h. 1H NMR (500MHz, CDCl3) δ8.76-8.70(m,1H),8.37(d,J=6.9Hz,1H),7.71(s,1H),7.61(d,J=5.1Hz,1H),7.48(s,1H),7.34(br s,1H),6.93(d,J=6.9Hz,1H),6.84(d,J=7.8Hz,1H),5.29(t,J=8.0Hz,1 H),4.62-4.56(m,1H),3.67(q,J=10.6Hz,2H),2.57-2.42(m,4H),2.22-2 .11(m,2H),2.09-1.98(m,2H),1.82-1.63(m,3H),1.55-1.49(m,1H),1.4 1-1.32(m,1H),1.24-1.18(m,1H),0.65-0.59(m,3H),0.56-0.50(m,1H). MS(ESI)m / z:[M+H] + The measured value is 647.2.

[0843] Embodiment 49

[0844] N-((S)-(7-((S*)-Cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0845]

[0846] Embodiment 50

[0847] N-((S)-(7-((R*)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0848]

[0849] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (Intermediate 43) was purified by SFC using a chiral stationary phase (CHIRALPAK AD-H, 25 cm×3 cm; 45:55 EtOH / CO2) to give a pair of diastereomers. The first eluting isomer was Example 50, and the second eluting isomer was Example 49. Example 49: 1 H NMR(400MHz,DMSO-d6)δ8.86(d,J=6.8Hz,1H),8.73(d,J=7.7Hz,1H),8.40-8.28(m,2 H),8.01(s,1H),7.76(s,1H),7.03(d,J=6.8Hz,1H),5.12(t,J=8.5Hz,1H),4.39(t,J =6.7Hz,2H),4.25(t,J=8.3Hz,1H),2.97-2.80(m,2H),2.54-2.37(m,4H),2.24-2.11 (m,1H),2.11-1.92(m,2H),1.92-1.58(m,4H),1.45-1.13(m,3H),0.58-0.34(m,4H). MS(ESI)m / z:[M+H] + Measured value 650.3. Example 50: 1 H NMR(400MHz,DMSO-d6)δ8.86(d,J=6.7Hz,1H),8.72(d,J=7.7Hz,1H),8.40-8.27(m,2 H),8.02(s,1H),7.76(s,1H),7.03(d,J=6.9Hz,1H),5.13(t,J=8.5Hz,1H),4.39(t,J =6.8Hz,2H),4.27(t,J=8.3Hz,1H),2.96-2.81(m,2H),2.53-2.40(m,4H),2.23-2.11 (m,1H),2.11-1.93(m,2H),1.93-1.61(m,4H),1.49-1.15(m,3H),0.60-0.35(m,4H). MS(ESI)m / z:[M+H] + The measured value is 650.3.

[0850] Embodiment 51

[0851] N-((S)-(7-((R)-cyclopropyl(2-((S*)-2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide

[0852]

[0853] Embodiment 52

[0854] N-((S)-(7-((R)-cyclopropyl(2-((R*)-2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide

[0855]

[0856] To a solution of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(2,2-difluorocyclopropyl)acetamide (125 mg, 0.28 mmol, intermediate 59) in ACN (5.8 mL) were added TCFH (80 mg, 0.28 mmol), 4-methyl-1,2,5- Diazole-3-carboxylic acid (30 mg, 0.24 mmol) and 1-methylimidazole (0.1 mL, 1.25 mmol) were added and the resulting mixture was stirred at room temperature for 30 min. Afterwards, the mixture was poured into (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative basic HPLC followed by preparative HPLC (irregular bare silica, 0.2% / 98% / 2% NH4OH / DCM / MeOH). The material was further purified by achiral SFC (AMINO 6 μm, 250 mm×21.2 mm, 12:88 MeOH (0.3% i-PrNH2) / CO2) followed by SFC using a chiral stationary phase (Whelk-O1 (S,S), 21.2 mm×250 mm, 5 μm, 25:75 i-PrOH (0.3% i-PrNH2) / CO2) to give a pair of diastereomers. The first eluting isomer was Example 52 and the second eluting isomer was Example 51. Example 51: 1H NMR (500MHz, CDCl3) δ8.35(d,J=6.9Hz,1H),7.70(d,J=9.0Hz,1H),7.47(s,1H),6.91(d,J=6.9Hz,1H),6.87WO 2021 / 220183A1

[0857] (d,J=7.8Hz,1H),5.21(dd,J=9.0,7.8Hz,1H),4.62(t,J=8.2Hz,1H),2.6 0(s,3H),2.54–2.35(m,2H),2.26–2.12(m,2H),2.08–1.99(m,2H),1.94– 1.87(m,1H),1.82–1.65(m,3H),1.55–1.50(m,2H),1.46–1.35(m,1H),1. 27–1.22(m,1H),1.13–1.06(m,1H),0.65–0.58(m,3H),0.54–0.47(m,1H). MS(ESI)m / z:[M+H] + Measured value 564.2. Example 52: 1 H NMR (500MHz, CDCl3) δ8.34(d,J=6.9Hz,1H),7.70(d,J=9.0Hz,1H),7.47(s,1H),6.91(d,J=6.9 Hz,1H),6.84(d,J=7.9Hz,1H),5.21(dd,J=8.9,7.8Hz,1H),4.63(t,J=8.3Hz,1H),2.60(s,3H), 2.52–2.36(m,2H),2.26–2.13(m,2H),2.08–2.00(m,2H),1.95–1.86(m,1H),1.80–1.67(m,3H), 1.55–1.48(m,3H),1.41–1.35(m,1H),1.10–1.04(m,1H),0.64–0.58(m,3H),0.54–0.48(m,1H). MS(ESI)m / z:[M+H] + The measured value is 564.2.

[0858] Embodiment 53

[0859] N-((S)-(7-((R)-cyclopropyl(2-((S*)-2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methylisothiazolyl Azole-3-carboxamide

[0860]

[0861] Embodiment 54

[0862] N-((S)-(7-((R)-cyclopropyl(2-((R*)-2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methylisothiazolyl Azole-3-carboxamide

[0863]

[0864] As described in the synthesis of Intermediate 37, N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(2,2-difluorocyclopropyl)acetamide (Intermediate 59) was used instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide and 4-methylisothiazolyl was used. Examples 53 and 54 were prepared by replacing trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid with oxadiazole-3-carboxylic acid. Pure mixtures of diastereomers (Examples 53 and 54) were separated by SFC using a chiral stationary phase (Whelk-O1 (S,S), 21.2 mm×250 mm, 5 μm, 25:75 i-PrOH (0.3% i-PrNH2) / CO2). The first eluting isomer was Example 54, and the second eluting isomer was Example 53. Example 53: 1 H NMR(400MHz, CDCl3) δ8.33(d,J=6.9Hz,1H),8.24-8.20(m,1H),7.59(d,J=9.1Hz,1H),7.47(s,1H),6 .90(dd,J=16.5,7.4Hz,2H),5.23(dd,J=9.2,7.8Hz,1H),4.64(t,J=8.2Hz,1H),3.76-3.45(m,2H),2 .53(dd,J=15.8,6.8Hz,1H),2.41-2.32(m,1H),2.25-2.23(m,3H),2.18-2.11(m,1H),2.08-1.99(m, 2H),1.96-1.85(m,1H),1.78-1.65(m,3H),1.44-1.34(m,1H),1.26-1.07(m,3H),0.65-0.46(m,4H). MS(ESI)m / z:[M+H] + Measured value 563.2. Example 54: 1H NMR (400MHz, CDCl3) δ8.33(d,J=6.9Hz,1H),8.25-8.19(m,1H),7.60(d,J=9.1Hz,1H),7.47(s,1H),6 .89(d,J=6.9Hz,2H),5.23(dd,J=9.2,7.7Hz,1H),4.65(t,J=8.2Hz,1H),3.76-3.47(m,2H),2.54-2. 46(m,1H),2.42-2.35(m,1H),2.25-2.24(m,3H),2.07-1.98(m,2H),1.95-1.85(m,1H),1.75-1.67(m ,2H),1.55-1.47(m,2H),1.43-1.35(m,1H),1.26-1.19(m,2H),1.11-1.03(m,1H),0.65-0.45(m,4H). MS(ESI)m / z:[M+H] + The measured value is 563.2.

[0865] Embodiment 55

[0866] N-((S)-(7-((R)-cyclopropyl(2-((S*)-2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide

[0867]

[0868] Embodiment 56

[0869] N-((S)-(7-((R)-cyclopropyl(2-((R*)-2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide

[0870]

[0871] Examples 55 and 56 were prepared as described for the synthesis of Intermediate 37 using N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(2,2-difluorocyclopropyl)acetamide (Intermediate 59) instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide and 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. The mixture was stirred at 40°C for 24 h instead of 2 h, and an additional aliquot of EDCI (43 mg, 0.26 mmol) was added after 2 h. Examples 55 and 56 were separated by SFC using a chiral stationary phase (Whelk-O1 (S,S), 21.2 mm×250 mm, 5 μm, 25:75 i-PrOH (0.3% i-PrNH 2 ) / CO 2 ). The first eluting isomer was Example 56, and the second eluting isomer was Example 55. Example 55: 1 H NMR (400MHz, CDCl3) δ8.33(d,J=6.9Hz,1H),8.13(d,J=9.3Hz,1H),7.85(s,1H),7.47(s,1H),6.90(d d,J=15.5,7.4Hz,2H),5.17(dd,J=9.3,7.8Hz,1H),4.63(t,J=8.2Hz,1H),4.58-4.47(m,2H),2.57-2. 48(m,1H),2.41-2.33(m,1H),2.31-2.23(m,1H),2.20-2.10(m,1H),1.96-1.86(m,1H),1.81-1.62(m ,4H),1.59-1.50(m,2H),1.43-1.34(m,2H),1.26-1.19(m,2H),1.14-1.07(m,1H),0.66-0.41(m,8H). MS(ESI)m / z:[M+H] + Measured value 603.3. Example 56: 1H NMR (400MHz, CDCl3) δ8.33(d,J=6.9Hz,1H),8.12(d,J=9.3Hz,1H),7.85(s,1H),7.47(s,1H),6.89( d,J=6.9Hz,2H),5.17(dd,J=9.3,7.8Hz,1H),4.64(t,J=8.2Hz,1H),4.57-4.45(m,2H),2.55-2.46( m,1H),2.42-2.34(m,1H),2.32-2.22(m,1H),2.19-2.10(m,1H),1.96-1.87(m,1H),1.79-1.63(m,4 H),1.57-1.48(m,2H),1.43-1.33(m,2H),1.27-1.18(m,2H),1.11-1.04(m,1H),0.64-0.41(m,8H). MS(ESI)m / z:[M+H] + The measured value is 603.2.

[0872] Embodiment 57

[0873] N-((S)-(7-((R)-cyclopropyl(2-((S*)-2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(trifluoromethyl)isothiazolyl Azole-4-carboxamide

[0874]

[0875] Embodiment 58

[0876] N-((S)-(7-((R)-cyclopropyl(2-((R*)-2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(trifluoromethyl)iso Azole-4-carboxamide

[0877]

[0878] As described in the synthesis of Intermediate 37, N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(2,2-difluorocyclopropyl)acetamide (Intermediate 59) was used instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide and 3-(trifluoromethyl)isopropyl)-1,2-difluoro ... Examples 57 and 58 were prepared by replacing trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid with oxadiazole-4-carboxylic acid. Examples 57 and 58 were separated by SFC using a chiral stationary phase (Whelk-O1 (S,S), 21.2 mm×250 mm, 5 μm, 15:85 EtOH / CO2). The second eluting diastereomer (Example 57) was repurified by SFC using a chiral stationary phase (Whelk-O1 (S,S), 21.2 mm×250 mm, 5 μm, 15:85 EtOH / CO2). The first eluting isomer was Example 58, and the second eluting isomer was Example 57. Example 57: 1 H NMR (400MHz, CDCl3) δ9.03-8.96 (m, 1H), 8.36 (d, J = 6.9 Hz, 1H), 7.46 (s, 1H), 7.19 (d, J = 8. 4Hz,1H),6.92(d,J=6.9Hz,1H),6.85(d,J=7.7Hz,1H),5.22(t,J=8.0Hz,1H),4.58(t,J=8. 2Hz,1H),2.52-2.37(m,2H),2.18-2.11(m,2H),2.05-1.86(m,3H),1.70-1.64(m,2H),1.61 -1.50(m,2H),1.36-1.25(m,2H),1.23-1.17(m,1H),1.14-1.06(m,1H),0.64-0.48(m,4H). MS(ESI)m / z:[M+H] + Measured value 617.2. Example 58: 1 H NMR (400MHz, CDCl3) δ9.01-8.95 (m, 1H), 8.36 (d, J = 6.9 Hz, 1H), 7.46 (s, 1H), 7.17 (d, J = 8. 5Hz,1H),6.93(d,J=6.9Hz,1H),6.80(d,J=7.8Hz,1H),5.22(t,J=7.9Hz,1H),4.60(t,J=8. 2Hz,1H),2.53-2.36(m,2H),2.20-2.09(m,2H),2.06-1.86(m,3H),1.81-1.74(m,1H),1.67 -1.64(m,1H),1.58-1.47(m,2H),1.38-1.18(m,3H),1.12-1.04(m,1H),0.66-0.48(m,4H). MS(ESI)m / z:[M+H] + The measured value is 617.2.

[0879] Embodiment 59

[0880] N-((S)-(7-((R)-cyclopropyl(2-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide

[0881]

[0882] To 2-diazo-1-(3-fluorobicyclo[1.1.1]pentan-1-yl)ethan-1-one (50 mg, 0.32 mmol, intermediate 65), N-((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- To a solution of oxadiazole-3-carboxamide (75 mg, 0.16 mmol, intermediate 63) and DIPEA (0.17 mL, 0.98 mmol) in ACN (3 mL) was added silver (I) benzoate (7 mg, 0.03 mmol). The resulting mixture was stirred at 45 ° C for 2 h and then concentrated to dryness. The residue was purified by preparative HPLC (Phenomenex Gemini-NX C18, 30 mm×75 mm, 3 μm, 40%-70% ACN / water (0.05% NH4OH+10 mM NH4HCO3)) to give the title compound. 1 H NMR (400MHz, CDCl3) δ8.34(d,J=6.8Hz,1H),7.73(d,J=9.0Hz,1H),7.46(s,1H),6.89(d,J=6.8Hz,1H),6.83(d,J=8.1Hz,1H),5.20(t,J=8.4Hz,1 H),4.60(t,J=8.4Hz,1H),2.65-2.53(m,5H),2.04(d,J=2.4Hz,10H),1.8 3-1.66(m,3H),1.57-1.29(m,2H),1.23-1.10(m,1H),0.67-0.45(m,4H). MS(ESI)m / z:[M+H] + The measured value is 572.2.

[0883] Embodiment 60

[0884] N-((S)-(7-((R)-cyclopropyl((S)-4,4-difluoro-3-methylbutyramido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide

[0885]

[0886] As described in the synthesis of intermediate 37, N-((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- The title compound was prepared using oxadiazole-3-carboxamide (Intermediate 63) instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide, and (S)-4,4-difluoro-3-methylbutanamide instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. The reaction was carried out at room temperature for 30 min instead of 2 h at 40°C, after which the mixture was concentrated to dryness and purified by preparative HPLC (Phenomenex Gemini-NX C18, 30 mm×75 mm, 3 μm, 40%-70% ACN / water (0.05% NH4OH+10 mM NH4HCO3)) to give the title compound. 1 H NMR(400MHz, CDCl3) δ8.37(d,J=6.8Hz,1H),7.75(d,J=9.2Hz,1H),7.50(s,1H),6 .93(d,J=6.8Hz,2H),5.98-5.59(m,1H),5.23(t,J=8.4Hz,1H),4.64(t,J=8.4Hz, 1H),2.62(s,3H),2.58-2.46(m,2H),2.32-1.98(m,5H),1.87-1.67(m,3H),1.60- 1.33(m,2H),1.30-1.17(m,1H),1.07(dd,J=19.6,6.8Hz,3H),0.74-0.45(m,4H). MS (ESI) m / z: [M+H] + The measured value is 566.4.

[0887] Embodiment 61

[0888] N-((S)-(7-((R)-cyclopropyl(2-((1r,3S)-3-tetrafluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide

[0889]

[0890] As described in the synthesis of intermediate 37, N-((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- The title compound was prepared using oxadiazole-3-carboxamide (Intermediate 63) instead of N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide, and 2-((1r,3s)-3-tetrafluorocyclobutyl)acetic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. The reaction was carried out at room temperature for 30 min instead of 2 h at 40°C, after which the mixture was concentrated to dryness and purified by preparative HPLC (Phenomenex Gemini-NX C18, 30 mm×75 mm, 3 μm, 35%-65% ACN / water (0.05% NH4OH+10 mM NH4HCO3)) to give the title compound. 1 H NMR (400MHz, CDCl3) δ8.37(d,J=7.0Hz,1H),7.80(d,J=8.8Hz,1H),7.50(s,1H),6.96-6.82(m,2H),5.30-5.01(m,2H),4.64(t,J=8.3Hz,1 H),2.88-2.71(m,1H),2.67-2.56(m,3H),2.54-2.36(m,4H),2.32-2.00(m,6H),1.88-1.69(m,3H),1.60-1.15(m,3H),0.68-0.45(m,4H). MS(ESI)m / z:[M+H] + The measured value is 560.4.

[0891] Embodiment 62

[0892] 4-cyclopropyl-N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1,2,5- oxadiazole-3-carboxamide

[0893]

[0894] As described for the synthesis of intermediate 37, 4-cyclopropyl-1,2,5- The title compound was prepared by replacing trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid with oxadiazole-3-carboxylic acid (CAS 1083246-26-7) and stirring the solution at room temperature for 30 min instead of 2 h at 40° C. The crude material was purified by preparative HPLC (Boston Green ODS, 150 mm×30 mm, 5 μm, 10%-40% ACN / water (0.05% NH OH)) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δ9.50(d,J=8.8Hz,1H),8.90(d,J=7.0Hz,1H),8.63(d,J=7.5Hz,1H),7.82( s,1H),7.05(d,J=7.0Hz,1H),5.16(t,J=8.4Hz,1H),4.25-4.17(m,1H),2.70-2.56(m,2H),2.40(br s,2H),2.35(d,J=13.6Hz,2H),2.31-2.23(m,2H),2.19(d,J=8.5Hz,1H),2.02(d,J=10.3Hz,2H),1 .94-1.60(m,4H),1.47-1.34(m,1H),1.34-1.24(m,1H),1.23-1.16(m,1H),1.16-1.08(m,2H),0.99

[0895] -0.93(m,2H),0.57-0.43(m,3H),0.43-0.35(m,1H). MS(ESI)m / z:[M+H] + The measured value is 604.2.

[0896] Embodiment 63

[0897] N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-(2,2,2-trifluoroethyl)isothiazolyl Azole-3-carboxamide

[0898]

[0899] As described for the synthesis of intermediate 37, 4-(2,2,2-trifluoroethyl)isothiazolin was used. The title compound was prepared by replacing trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid with oxadiazole-3-carboxylic acid (Intermediate 68) and ACN with DCM, and stirring the solution at room temperature for 30 min instead of 2 h at 40° C. The crude material was purified by preparative HPLC (Boston Green ODS, 150 mm×30 mm, 5 μm, 10%-40% ACN / water (0.05% NH 4 OH)) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δ9.20-9.11(m,2H),8.90(d,J=7.0Hz,1H),8.63(d,J=7.8Hz,1H),7.80(s,1H),7.04(d, J=7.0Hz,1H),5.13(t,J=8.7Hz,1H),4.23(t,J=8.3Hz,1H),3.77(q,J=11.2Hz,2H),2.66-2.58(m,1H),2.40(br s,2H),2.34(d,J=11.8Hz,2H),2.31-2.23(m,1H),2.17(d,J=8.0Hz,1H),2.00(d,J=7.8Hz,2H), 1.91-1.58(m,4H),1.44-1.28(m,2H),1.28-1.16(m,2H),0.57-0.43(m,3H),0.42-0.34(m,1H). MS(ESI)m / z:[M+H] + The measured value is 645.4.

[0900] In vitro biological data

[0901] IL-17A (FLAG-tagged):IL-17RA (His-tagged) binding disruption Eu-HTRF assay

[0902] Antibodies against the FLAG tag of IL-17A (SEQ ID NO: 1) were labeled with the HTRF donor chromophore (Europium-cryptate). IL-17A exists as a dimer that is "locked" into the quaternary structure due to the formation of intramolecular disulfide bridges spanning the loops. The construct of IL-17RA used in the assay excludes the outer membrane portion of the receptor and is fused to a C-terminal 10xHis tag (SEQ ID NO: 2). Antibodies against the His tag of the IL-17RA chimera were labeled with the HTRF receptor chromophore ("D2"). Fluorescence resonance energy transfer (FRET) depends on the proximity of the donor chromophore to the receptor, and disruption of binding between IL-17A and IL-17RA causes a reduction / loss of FRET. Therefore, the assay allows the evaluation of the effect of compounds on binding to IL-17A and IL-17RA by monitoring the fluorescence intensity of the donor and the acceptor. The assay was performed as described below.

[0903] 40nL of 2-fold serially diluted compound solutions for a total of 22 dilution points were added to each well of a 1536-well white small volume non-binding plate (Greiner #782904), and then 2μL of FLAG-tagged IL-17A was added to each well at 2× final concentration (2.5nM) in PBS+0.01% Triton-X100 solution. The assay plate was briefly centrifuged and then incubated at room temperature for 1 hour. A mixed solution containing 2×5nM10HISxIL-17RA, 2×2.5nM Eu-anti-FLAG (CISBIO), 2×5nM D2-anti-HIS (CISBIO) in PBS+0.01% Triton-X100+200mM potassium fluoride (Sigma 60238) was prepared and 2μL of the mixture was added to each well of the assay plate. The plate was briefly centrifuged and then incubated at room temperature for 2h. HTRF intensities at donor (620 nm) and acceptor (665 nm) wavelengths were measured using BMG Pherastar. The ratio between the intensities at the two wavelengths was calculated and plotted against compound concentration, and the data were fitted to a one-site competition model to generate the IC of the compound. 50 .

[0904] IL-17A acts directly on keratinocytes by binding to the dimeric receptor IL-17RA / RC and drives the production of many inflammatory mediators known to be elevated in psoriatic lesions. Small molecule inhibitors of IL-17A that block the interaction of IL-17A with IL-17R will inhibit IL-17A signaling in its target cells such as keratinocytes. The functional activity of the compounds was evaluated for their effects on IL-17A-induced G-CSF production in human normal keratinocytes (NHK).

[0905] NHK determination

[0906] Adult normal human keratinocytes were cultured in keratinocyte growth medium (Lonza) in flasks until approximately 90% confluence was reached, and then the cells were transferred to 384-well plates at a density of 3000-4000 cells / well. Recombinant human IL-17A (Gibco PHC9174) was preincubated with titrated compounds or DMSO for 1 h at room temperature and then added to the cell culture plates. The final concentration of IL-17A was 5 ng / mL in cultures containing 5% FBS, and the final concentration of DMSO was 0.2%. The cells were cultured / treated at 37°C for 24 h. The supernatant was collected and G-CSF production was measured by HTRF technology using a human G-CSF kit (CisBio). G-CSF concentrations were extrapolated from the standard curve, and the IC 50Determined using GraphPad Prism. Cell viability was also assessed using the CellTiter-Glo kit (Promega) and the effects of compounds on cell viability were compared to DMSO controls.

[0907] In cases where compounds were tested more than once, the IC 50 The value is the simple average of the measurements.

[0908]

[0909]

[0910]

[0911] While the above description illustrates the principles of the invention by providing embodiments thereof, it should be understood that the practice of the invention encompasses all general variations, changes and / or modifications within the scope of the following claims and their equivalents.

[0912] All documents cited herein are incorporated by reference.

[0913] SEQ ID NO:1

[0914] Name: IL-17A-Flag

[0915] MATGSRTSLLLAFGLLCLPWLQEGSAGSDYKDDDDKGSGSGSLEVLFQGPGITIPRNPGCPNSEDKNFPRTVMVNLNIHNRNTNTNPKRSSDYYNRSTSPWNLHRNEDPERYPSVIWEAQCRHLGCINADGNVDYHMNSVPIQQEILVLRREPPHCPNSFRLEKILVSVGCTCVTPIVHHVQ

[0916] SEQ ID NO:2

[0917] Name: IL-17RA

[0918] MKFLVNVALVFMVVYISYIYALRLLDHRALVCSQPGLNCTVKNSTCLDDSWIHPRNLTPSSPKDLQIQLHFAHTQQGDLFPVAHIEWTLQTDASILYLEGAELSVLQLNTNERLCVRFEFLSKLRHHHRRWRFTFSHFVVDPDQEYEVTVHHLPKPIPDGDP NHQSKNFLVPDCEHARMKVTTPCMSSGSLWDPNITVETLEAHQLRVSFTLWNESTHYQILLTSFPHMENHSCFEHMHHIPAPRPEEFHQRSNVTLTLRNLKGCCRHQVQIQPFFSSCLNDCLRHSATVSCPEMPDTPEPIPDYMPLWGSGGHHHHHHHHHH* Sequence Listing <110> Janssen Biotech, Inc. Goldberg, Steven Martin, Connor Rhorer, Timothy Tanis, Virginia Xue, Xiaohua <120> Imidazopyrimidines as IL-17 modulators <130> JBI6283WOPCT1 <140> To be transferred <141> Same <150> 63 / 017679 <151> April 30, 2020 <160> 2 <170> PatentIn Version 3.5 <210> 1 <211> 182 <212> PRT <213> Synthesis <220> <223> FLAg-tagged human IL17A <400> 1 Met Ala Thr Gly Ser Arg Thr Ser Leu Leu Leu Ala Phe Gly Leu Leu 1 5 10 15 Cys Leu Pro Trp Leu Gln Glu Gly Ser Ala Gly Ser Asp Tyr Lys Asp 20 25 30 Asp Asp Asp Lys Gly Ser Gly Ser Gly Ser Leu Glu Val Leu Phe Gln 35 40 45 Gly Pro Gly Ile Thr Ile Pro Arg Asn Pro Gly Cys Pro Asn Ser Glu 50 55 60 Asp Lys Asn Phe Pro Arg Thr Val Met Val Asn Leu Asn Ile His Asn 65 70 75 80 Arg Asn Thr Asn Thr Asn Pro Lys Arg Ser Ser Asp Tyr Tyr Asn Arg 85 90 95 Ser Thr Ser Pro Trp Asn Leu His Arg Asn Glu Asp Pro Glu Arg Tyr 100 105 110 Pro Ser Val Ile Trp Glu Ala Gln Cys Arg His Leu Gly Cys Ile Asn 115 120 125 Ala Asp Gly Asn Val Asp Tyr His Met Asn Ser Val Pro Ile Gln Gln 130 135 140 Glu Ile Leu Val Leu Arg Arg Glu Pro Pro His Cys Pro Asn Ser Phe 145 150 155 160 Arg Leu Glu Lys Ile Leu Val Ser Val Gly Cys Thr Cys Val Thr Pro 165 170 175 Island Val His His Val Gln 180 <210> 2 <211> 323 <212> PRT <213> artificially synthesized <220> <223> IL17A has its label <400> 2 Met Lys Phe Leu Val Asn Val Ala Leu Val Phe Met Val Val Tyr Ile 1 5 10 15 Ser Tyr Ile Tyr Ala Leu Arg Leu Leu Asp His Arg Ala Leu Val Cys 20 25 30 Ser Gln Pro Gly Leu Asn Cys Thr Val Lys Asn Ser Thr Cys Leu Asp 35 40 45 Asp Ser Trp Ile His Pro Arg Asn Leu Thr Pro Ser Ser Pro Lys Asp 50 55 60 Leu Gln Ile Gln Leu His Phe Ala His Thr Gln Gln Gly Asp Leu Phe 65 70 75 80 Pro Val Ala His Ile Glu Trp Thr Leu Gln Thr Asp Ala Ser Ile Leu 85 90 95 Tyr Leu Glu Gly Ala Glu Leu Ser Val Leu Gln Leu Asn Thr Asn Glu 100 105 110 Arg Leu Cys Val Arg Phe Glu Phe Leu Ser Lys Leu Arg His His His 115 120 125 Arg Arg Trp Arg Phe Thr Phe Ser His Phe Val Val Asp Pro Asp Gln 130 135 140 Glu Tyr Glu Val Thr Val His His Leu Pro Lys Pro Ile Pro Asp Gly 145 150 155 160 Asp Pro Asn His Gln Ser Lys Asn Phe Leu Val Pro Asp Cys Glu His 165 170 175 Ala Arg Met Lys Val Thr Thr Pro Cys Met Ser Ser Gly Ser Leu Trp 180 185 190 Asp Pro Asn Ile Thr Val Glu Thr Leu Glu Ala His Gln Leu Arg Val 195 200 205 Ser Phe Thr Leu Trp Asn Glu Ser Thr His Tyr Gln Ile Leu Leu Thr 210 215 220 Ser Phe Pro His Met Glu Asn His Ser Cys Phe Glu His Met His His 225 230 235 240 Ile Pro Ala Pro Arg Pro Glu Glu Phe His Gln Arg Ser Asn Val Thr 245 250 255 Leu Thr Leu Arg Asn Leu Lys Gly Cys Cys Arg His Gln Val Gln Ile 260 265 270 Gln Pro Phe Phe Ser Ser Cys Leu Asn Asp Cys Leu Arg His Ser Ala 275 280 285 Thr Val Ser Cys Pro Glu Met Pro Asp Thr Pro Glu Pro Ile Pro Asp 290 295 300 Tyr Met Pro Leu Trp Gly Ser Gly Gly His His His His His His His 305 310 315 320 His His His

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R 1 For -C (1-6) Alkyl or -C (0-3) Alkyl C (3-6) Cycloalkyl; Wherein the-C (1-6) The alkyl group and the -C (0-3) Alkyl C (3-6) Cycloalkyl is unsubstituted or substituted with one to six fluorine atoms; R 2 For -C (3-5) Cycloalkyl; R 3 For -C (0-1) Alkyl C (3-6) Cycloalkyl, wherein the -C (0-1) Alkyl C (3-6) Cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; R 4 For -C (3-4) cycloalkyl or 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O and S; Wherein C (3-4) The cycloalkyl group is unsubstituted or substituted with one to three R 4a group substitution; and wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted by one or two R 4b Group substitution; Each R 4a The groups are independently selected from -C (1-4) Alkyl; and Each R 4b The groups are independently selected from -C (0-2) Alkyl C (3-4) Cycloalkyl or -C (1-5) Alkyl, wherein the -C (0-2) Alkyl C (3-4) Cycloalkyl and -C (1-5) The alkyl group is unsubstituted or substituted with one to six fluorine atoms; R 5 is H or F; in When R 4 For -C (3-4) When is cycloalkyl, the compound of formula I is a compound of formula Ia:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 For -C (1-6) Alkyl or -C (0-3) Alkyl C (3-6) Cycloalkyl; Wherein the-C (1-6) The alkyl group and the -C (0-3) Alkyl C (3-6) Cycloalkyl is unsubstituted or substituted with one to six fluorine atoms; R 2 For -C (3-5) Cycloalkyl; R 3 For -C (0-1) Alkyl C (3-6) Cycloalkyl, wherein the -C (0-1) Alkyl C (3-6) Cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; R 4 is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O and S; wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted by one or two R 4b Group substitution; Each R 4b The groups are independently selected from -C (0-2) Alkyl C (3-4) Cycloalkyl or -C (1-5) Alkyl, wherein the -C (0-2) Alkyl C (3-4) Cycloalkyl and -C (1-5) The alkyl group is unsubstituted or substituted with one to six fluorine atoms; and R 5 It is H or F.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R 5 For H.

4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R 1 For -C (1-4) Alkyl or -C (0-3) Alkyl C (3-5) Cycloalkyl; Wherein the-C (1-4) The alkyl group and the -C (0-3) Alkyl C (3-5) The cycloalkyl group is unsubstituted or substituted with one to six fluorine atoms.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R 1 C (1-2) Alkyl C (3-5) Cycloalkyl, wherein the -C (1-2) Alkyl C (3-5) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms.

6. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 for:

7. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 It is cyclopropyl.

8. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 3 for 9. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 4 Not replaced or replaced by C (1-2) Alkyl-substituted pyridyl, the C (1-2) The alkyl group is unsubstituted or substituted with one to three fluorine atoms.

10. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 4 is unsubstituted or replaced by one or two R 4b substituted pyrazolyl, triazolyl, isocyanate Azolyl or Oxazolyl, Each R 4b The groups are independently selected from -C (0-1) Alkyl C (3) Cycloalkyl or -C (1-3) Alkyl, wherein the -C (0-1) Alkyl C (3) Cycloalkyl and -C (1-3) The alkyl group is unsubstituted or substituted with one to four fluorine atoms.

11. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 4 is unsubstituted or replaced by one or two R 4b 1H-pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, isocyanate Azol-4-yl or 1,2,5- Oxazolyl.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 for:

13. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 4 for:

14. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 4 for:

15. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 4 for:

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 4 For -C (3) Cycloalkyl; Wherein C (3) The cycloalkyl group is unsubstituted or substituted with one to three R 4a group substitution; and Each R 4a The groups are independently selected from -C (1-2) Alkyl; and Wherein the compound of formula I is a compound of formula Ia:

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

20. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating and / or ameliorating IL-17A-mediated inflammatory syndrome, disorder or disease.

21. The use according to claim 20, 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 disease, multiple myeloma and systemic lupus erythematosus.

22. The use according to claim 21, wherein the IL-17A mediated inflammatory syndrome, disorder or disease is psoriasis, psoriatic arthritis, rheumatoid arthritis, atopic dermatitis or systemic lupus erythematosus.

23. The use according to claim 20 or 21, wherein the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof is administered orally.

24. The use according to claim 20 or 21, wherein the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof is administered as a tablet or capsule.

Images