Imidazopyrimidines as modulators of IL-17

Abstract

The present application provides compounds of formula I: [Formula 1] TIFF2023523770000222.tif26128[where, R 1 , R 2 , R 3 , R 4 , and R 5 or a pharmaceutically acceptable salt thereof, as defined herein, as well as methods of making and using the compounds disclosed herein to treat or ameliorate IL-17 mediated syndromes, disorders and / or diseases.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority under 35 U.S.C. §119(e) to and the benefit of U.S. Provisional Patent Application No. 63 / 017,679, filed April 30, 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0002] (Reference to electronically submitted sequence listing) This application contains a sequence listing, having a size of 5 KB, that has been submitted electronically via EFS-Web as an ASCII sequence listing with the filename "JBI6283WOPCT1SeqListing4-22-20.txt" created on April 22, 2020. The sequence listing submitted via EFS-Web is a part of the present specification and is incorporated herein by reference in its entirety.

[0003] FIELD OF THEINVENTION Disclosed herein are imidazopyrimidine compounds that modulate interleukin-17A, and pharmaceutical compositions thereof. Also disclosed herein are therapeutic uses of such compounds, for example, in the treatment and / or amelioration of IL-17A-mediated inflammatory syndromes, disorders, or diseases. [Background technology]

[0004] Interleukin-17 ("IL-17"), also known as IL-17A and CTLA-8, is produced primarily by CD4+ Th17 cells, but also by other immune cells such as CD8+ T cells, γδ T cells, NK cells, NKT cells, and innate lymphoid cells (ILCs). IL-17A exists as a homodimer (A / A) or a heterodimer with IL-17F (A / F) and signals via binding to the dimeric receptor complex IL-17RA and IL-17RC. IL-17RA is ubiquitously expressed at particularly high levels by hematopoietic cell types, while IL-17RC is preferentially expressed by 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 de novo gene transcription by triggering NF-kB, C / EBP, and MAPK pathways via ACT1-TRAF6-TRAF4. It can also stabilize target mRNA transcripts via the ACT1-TRAF2-TRAF5 complex (Amatya N et al., Trends in Immunology, 2017, 38, 310-322). IL-17A stimulates the release of inflammatory mediators such as IL-6, IL-8, G-CSF, TNF-α, and IL-1β, recruiting and activating lymphocytes to sites of injury or inflammation, and maintaining a proinflammatory state.

[0005] As discussed below, preclinical and clinical data demonstrate an important pathological role for IL-17A in multiple autoimmune and inflammatory diseases.

[0006] In psoriasis: IL-17A mRNA and / or protein levels are elevated in lesional skin and blood of psoriasis patients and correlate with disease severity. IL-17A acts directly on keratinocytes in synergy with other cytokines (TNFα, IFNγ, IL-22, etc.), triggering a self-amplifying inflammatory response in the skin and leading to the formation of psoriatic plaques. Blockade of IL-17A with antibodies against IL-17A or IL-23 completely reverses molecular and clinical disease features in the majority of psoriasis patients, revealing that IL-17A and IL-17-producing T cells play a key role in the immunopathogenesis of psoriasis. (Hawkes et al. Psoriasis Pathogenesis and the Development of Novel, Targeted Immune Therapies. J. Allergy Clin. Immunol. 2017, 140(3):645-653). The development and approval of IL-17 monoclonal antibodies such as secukinumab, ixekizumab, and brodalumab, and their transformative effects on psoriasis, have validated IL-17A as a valid target for the treatment of psoriasis. (Blauvelt A.and Chiricozzi A.The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis.Clin Rev Allergy Immunol.2018,55(3):379-390)

[0007] In psoriatic arthritis (PsA): IL-17A is mechanistically linked to PsA through NFκB activation, which triggers the transcription of several PsA-associated genes, including receptor activator of nuclear factor κB ligand (RANKL). RANKL induces differentiation of osteoclast precursor cells into activated osteoclasts, leading to bone resorption and, consequently, joint deformation in PsA (Adamopoulos IE and Mellins ED. Nature reviews Rheumatology 2015;11:189-94). PsA joints are enriched in IL-17+CD8+ T cells, and levels of this T cell subset correlate with disease activity (Menon B.et al.Arthritis & Rheumatology 2014;66:1272-81). Synovial fibroblasts isolated from PsA patients also contain elevated IL-17R expression ex vivo, as well as increased secretion of IL-6, CXCL8, and MMP3, compared with osteoarthritis patients. Secukinumab and ixekizumab are both FDA-approved drugs for PsA. In indirect comparison analyses after matching adjustment, secukinumab had higher ACR 20 / 50 / 70 response rates in patients with active PsA than anti-TNFα antibodies (Mease P.et al.Eur.J.Rheumatol.2019 Jul 1;6(3):113-121;Strand V.et al.J.Comp.Eff.Res.2019,8(7):497-510;Nash P.et al.,Rheumatol.Ther.2018,5(1):99-122). In a recent head-to-head study, ixekizumab was superior to adalimumab in simultaneously improving joint and skin disease (ACR50 and PASI100) in PsA patients with inadequate response to conventional synthetic disease-modifying antirheumatic drugs (Mease, PJ et al. Ann Rheum Diss 2020;79:123-131). By attacking the same target, IL-17A small molecule inhibitor compounds may be as effective or more effective than biologics, given that small molecules generally have better tissue penetration.

[0008] In rheumatoid arthritis (RA): IL-17A is recognized as important in the progression of rheumatoid arthritis. "The recognition of IL-17 as 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 macrophage effector functions in rheumatoid arthritis" Stamp,LK,MJJames,et al.Immunol.Cell Biol.2004,82(1):1-9. Furthermore, in rheumatoid arthritis, IL-17A acts locally on synovial cells and osteoblasts, contributing to synovitis and joint destruction. Robert and Miossec suggest using synovial biopsies and / or biomarkers to accurately identify patients who will respond to IL-17A inhibition. Their study concludes that IL-17 inhibitors should now be considered in the development of precision medicine in RA. (Robert M and Miossec P,Front.Med.,2019,5:364)

[0009] In ankylosing spondylitis (AS): Various studies have reported elevated IL-17A and Th17 in AS blood samples, as well as other cells producing IL-17 (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 spine revealed increased IL-17A producing cells in bones of facet joints (Appel H.et al.Arthritis Res Ther.2011;13(3):R95). Two highly IL-17A neutralizing antibodies, secukinumab (FDA approved for AS) and ixekizumab, have shown efficacy versus placebo, even in anti-TNF poor responders. In contrast, anti-IL-23p40 and p19 biologics have failed to show 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 distinct underlying mechanisms along the IL-23 / IL-17 pathway in AS and providing strong evidence to support the continued development of IL-17A inhibitors.

[0010] In hidradenitis suppurativa (HS): Increased IL-17 and IL-17-producing T helper cells have been reported in skin lesions of HS patients, and molecular proteomic and gene expression data have shown 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 (78%) patients with moderate-to-severe HS achieved HiSCR in an open-label pilot study with secukinumab (Prussick L. et al. British J. Dermatol. 2019 Sep;181(3):609-611.), and further clinical trials with anti-IL-17 mAbs in HS are ongoing.

[0011] In bullous pemphigoid (BP): IL-17 is elevated in blister fluid and perilesional skin of BP patients. (Le Jan S.et al.J.Invest.Dermatol.2014;134(12):2908-2917.;Chakievska LJ Autoimmun.2019,96:104-112). Exome sequencing of BP patients revealed mutations in 12 IL-17-related genes in one third of patients, providing a genetic link between the IL-17 pathway and BP (Chakievska LJ Autoimmun.2019,96:104-112). In experimental murine BP, IL-17A- / - mice were protected and anti-IL-17A treatment significantly reduced wild-type skin lesions (Chakievska LJ Autoimmun.2019,96:104-112). A phase 2 trial of ixekizumab in treatment-naïve and refractory BP patients is ongoing (NCT03099538).

[0012] In the case of atopic dermatitis (AD): IL-17 was elevated in peripheral blood and lesions of AD patients, and Th17 cells were found to infiltrate more significantly in acute lesions than in chronic lesions, suggesting a role in the acute phase of AD (Koga C.et al.Journal of Investigative Dermatology 2008,128,2625-2630). Molecular profiling analysis of ustekinumab phase II suggests a possible contribution of the IL-23 / Th17 / IL-17 pathway in AD (Khattri S.et al.Exp.Dermatol.2017 Jan;26(1):28-35).

[0013] In vitiligo: Many studies in vitiligo patients have demonstrated that the frequency of Th17 cells, both in circulation and in lesions, is increased, with high levels of IL-17, which positively correlate with the duration, extent and activity of the disease (Singh RK et al. Autoimm. Rev 2016, Apr; 15(4): 397-404). Studies in mice have demonstrated that depigmentation correlates with increased expression / secretion of IL-17, which regulates the development of vitiligo (Eby JM et al. Pigment Cell Melanoma Res. 2014, Nov; 27(6): 1075-85).

[0014] In multiple sclerosis (MS): IL-17 expression is increased in PBMCs, cerebrospinal fluid (CSF), and brain lesions and cells of 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 index, an indicator of blood-brain barrier (BBB) ​​dysfunction, coupled with in vitro data that IL-17A in combination with IL-6 reduces the expression of tight junction-related genes and compromises the monolayer integrity of BBB cell lines, highlighting the potential importance of targeting IL-17A in maintaining BBB integrity in RRMS (Setiadi AF et al. J Neuroimmunol. 2019,332:147-154). Secukinumab has provided promising initial results in a proof-of-concept trial in MS patients (Havrdova,EA et al. J.Neurol. 2016,263:1287-1295).

[0015] In asthma: IL-17 expression is increased in the lungs, sputum, bronchoalveolar lavage fluid, and serum of asthmatic patients, and the severity of airway hyperresponsiveness is positively correlated with the level of IL-17 expression. (Chakir J.et al.J.Allergy Clin.Immunol.2003,111(6):1293-8) It has been reported that IL-17 is increased 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 a chronic mouse asthma model (Camargo LDN et al. Front Immunol. 2018;8:1835; dos Santos TM et al. Front Physiol. 2018,9:1183).

[0016] In chronic obstructive pulmonary disease (COPD): Compared with non-COPD current smokers and healthy controls, an increase in Th17 cells was observed in COPD patients, and an inverse 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 profiles in bronchial epithelium showed that higher IL-17 signature expression was associated with non-responsiveness to inhaled corticosteroids, suggesting the existence of COPD subgroups that may benefit from IL-17 inhibitor therapy (Christenson SA et al., J. Clin. Invest. 2019;129(1):169-181).

[0017] In uveitis: IL-17 promotes the release of inflammatory mediators from retinal pigment epithelial cell lines and disrupts the barrier function of the retinal pigment epithelium (Chen Y.et al.,PLoS One.2011;6:e18139). IL-17 levels were elevated in 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 delayed the onset of ocular inflammation and significantly inhibited the development of experimental autoimmune uveitis in rats (Zhang R.et al.Curr.Eye Res.2009 Apr;34(4):297-303). Analysis of secondary efficacy data from a phase 3 study of subcutaneous (sc) secukinumab in uveitis suggested a beneficial effect of secukinumab in reducing the use of concomitant immunosuppressants (Dick AD et al.Ophthalmology.2013;120(4):777-87). Subsequent intravenous studies of secukinumab in uveitis demonstrated superior efficacy over 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 a patient with severe psoriasis and PsA, a non-infectious uveitis that did not respond to conventional immunosuppressants (Mugheddu C. et al. Dermatol. Ther. 2017 Sep;30(5);e12527.).

[0018] In multiple myeloma (MM): Serum levels of IL-17A were significantly higher in MM patients and in patients with advanced stage disease compared to healthy controls (Lemancewicz D.et al.,Med.Sci.Monit.2012;18(1):BR54-BR59). Administration of secukinumab once a week for 4 weeks after tumors were first detected in the mice in a SCIDhu model of human myeloma significantly inhibited tumor growth and reduced bone damage compared to isotype control mice (Prabhala R.et al.,Leukemia.2016 February;30(2):379-389).

[0019] In the case of systemic lupus erythematosus (SLE): Increased serum or plasma levels of IL-17, proliferation of IL-17-producing T cells in peripheral blood, and infiltration of Th17 cells in target organs such as the kidney were 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 has been observed in SLE patients, including 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 increases the severity of lupus nephritis, whereas blocking IL-17A using neutralizing antibodies results in a decrease in the severity of lupus nephritis (Wen, Z. et al. PLoS One. 2013, 8: e58161). In a phase 2 study, ustekinumab, an anti-IL-12 / 23p40 monoclonal antibody that blocks the IL-23 / IL-17 pathway, demonstrated efficacy in SLE patients (van Vollenhoven RF et al. Lancet 2018;392:1330-39). Human expression studies, animal models, and clinical trials indicate 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). Summary of the Invention [Problem to be solved by the invention]

[0020] In summary, animal and human studies indicate that IL-17A plays a key role in the pathogenesis of multiple diseases and / or conditions mentioned above. The importance of targeting IL-17A is demonstrated by the transforming effects of IL-17A neutralizing antibodies in patients. Although oral small molecule IL-17A inhibitors have not yet progressed to late-stage clinical trials, they are an attractive area for discovery, as their development could expand treatment options for many patients who do not have access to biologics. Furthermore, safe and effective small molecule IL-17A inhibitors could potentially provide significant benefits to patients, such as convenient dosing regimens and reduced costs, which could result in effective long-term disease management. Thus, new small molecule IL-17A modulators (e.g., inhibitors) are needed. [Means for solving the problem]

[0021] The present application relates to a compound of formula I:

[0022] [ka] [In the formula, R 1 -C (1~6) Alkyl or -C (0~3) Alkyl C (3~6) is cycloalkyl, -C (1~6) Alkyl and -C (0~3) Alkyl C (3~6) Cycloalkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R 2 -C (3~5) is cycloalkyl, R 3 -C (0~1) Alkyl C (3~6) Cycloalkyl, -C (0~1) Alkyl C (3~6) Cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 4 -C (3~4)cycloalkyl or 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S; C (3~4) Cycloalkyl is unsubstituted or has 1 to 3 R 4a is substituted with a group, The 5- to 6-membered heteroaryl is unsubstituted or has one or two R 4b is substituted with a group, Each R 4a The group is an unsubstituted -C (1~4) -C substituted with alkyl or 1 to 6 fluorine atoms (1~4) independently selected from alkyl, Each R 4b The group is -C (0~2) Alkyl C (3~4) Cycloalkyl or -C (1~5) independently selected from alkyl, -C (0~2) Alkyl C (3~4) Cycloalkyl and -C (1~5) Alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R 5 is H or F, During the ceremony, R 4 Ga-C (3~4) When cycloalkyl, the compound of formula I has formula Ia:

[0023] [ka] or a pharma- ceutically acceptable salt thereof.

[0024] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0025] Also described herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharma- ceutically acceptable salt thereof.

[0026] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0027] In some embodiments, disclosed herein is the use of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0028] In some embodiments, provided herein are processes and intermediates disclosed herein that are useful for preparing a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0029] The disclosure also provides any of the compounds or methods described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] definition Various publications, articles and patents are cited or described in the Background and throughout this specification, and each of these references is incorporated herein by reference in its entirety. Any discussion of documents, operations, materials, devices, articles and the like which is included in the specification is for the purpose of providing a context for the invention. Such discussion is not an admission that any or all of these items constitute part of the prior art to any invention disclosed or claimed.

[0031] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise specified, specific terms used herein have the meanings described herein. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth herein in their entirety.

[0032] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

[0033] To aid the reader of this application, the description of the specification is divided into various paragraphs or sections or directed to various embodiments of this application. These separations should not be considered as separating the substance of a paragraph or section or embodiment from the substance of another paragraph or section or embodiment. On the contrary, those skilled in the art will understand that the description of this specification has broad application and encompasses all combinations of various paragraphs, paragraphs, and sentences that may be conceived. Discussion of any embodiment is meant to be merely exemplary and is not intended to suggest that the scope of the present disclosure, including the claims, is limited to these examples.

[0034] The term "administration" with respect to the methods of the present invention means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of formula I, or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof. Such methods include administering a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof, either simultaneously or sequentially at different times during the course of treatment or as a combination therapy.

[0035] The term "subject" refers to a patient, which may be an animal, preferably a mammal, most preferably a human, to be treated or have 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.

[0036] The term "therapeutically effective amount" or "effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue system, animal or human that is being sought by a researcher, veterinarian, physician, or other clinician, including preventing, treating, or ameliorating the symptoms of the syndrome, disorder, or disease being treated.

[0037] As used herein, "IL-17" or "IL-17A" refers to interleukin 17A. "IL-17" or "IL-17A" is also referred to as IL17, CTLA8, CTLA-8. Interleukin 17A is a proinflammatory cytokine. This cytokine is produced by a group of immune cells in response to their stimulation. An exemplary amino acid sequence of human IL-17 is shown in GenBank Accession No. NP_002181.1, which can be encoded by a nucleic acid sequence such as GenBank Accession No. NM_002190.3.

[0038] As used herein, the term "modulator" refers to any agent or molecule capable of binding to IL-17, including small molecule compounds.

[0039] As used herein, the term "composition" is intended to encompass a product containing specified ingredients in specified amounts, as well as any product that results directly or indirectly from combining specified amounts of the specified ingredients.

[0040] As used herein, the terms "treat", "treating", or "treatment" of any disease, condition, syndrome, or disorder, in one embodiment, refer to ameliorating the disease, condition, syndrome, or disorder (i.e., slowing or preventing or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating", or "treatment" refers to alleviating or improving at least one physiological or biochemical parameter associated with or causing the disease, condition, syndrome, or disorder, including those that may not be discernible by the patient. In a further embodiment, "treat", "treating", or "treatment" refers to modulating the disease, condition, syndrome, or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat", "treating", or "treatment" refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome, or disorder.

[0041] As used herein, the term "QD" means once daily.

[0042] As used herein, the term "BID" means twice a day.

[0043] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon. For example, an alkyl group can be one to twelve carbon atoms (i.e., C1-C 12)alkyl) or 1 to 6 carbon atoms (i.e., (C1-C6)alkyl). Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), tert-butyl (t-Bu, t-butyl, -CH(CH3)3), 1-pentyl (n-pentyl, -CH 2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 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 Any alkyl group may be unsubstituted or substituted.

[0044] The term “C (a~b) " (where a and b are integers indicating the specified number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl radical, or to the alkyl portion of a radical where alkyl is shown as a prefix root having a through b carbon atoms, inclusive. For example, C (1~4) represents a radical having 1, 2, 3 or 4 carbon atoms.

[0045] The term "heterocycle" or "heterocyclyl" refers to a single saturated or partially unsaturated ring having at least one atom other than carbon in the ring, the atom being 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.

[0046] The term "cycloalkyl" refers to a group consisting of 3 to 8 carbon atoms (i.e., C (3~8) cycloalkyl), preferably having 3 to 6 carbon atoms (i.e., C (3~6) "cycloalkyl" refers to a saturated or partially unsaturated all-carbocyclic ring system having a single ring or multiple rings, either spirocyclic or bicyclic. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise stated in the specification, cycloalkyl groups can be unsubstituted or substituted. Some cycloalkyl groups may exist as spirocycloalkyls, where two cycloalkyl rings are fused through one carbon atom, for example, but not limited to, an example of a spiropentyl group is:

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

[0048] [ka] For example, but not limited to, examples of cycloheptyl groups include:

[0049] [ka] For example, but not limited to, examples of cyclooctyl groups include:

[0050] [ka] Unless otherwise stated in the specification, cycloalkyl groups may be unsubstituted or substituted. Bicyclic cycloalkyl ring systems include:

[0051] [ka] Also included.

[0052] The term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur. The term "heteroaryl" includes a single aromatic ring of 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, or furyl.

[0053] The term "halogen" refers to bromo (-Br), chloro (-Cl), fluoro (-F) or iodo (-I).

[0054] When the compounds of Formula I disclosed herein contain at least one stereocenter, they may consequently exist as enantiomers or diastereomers, and it is understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0055] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0056] "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 "scalemic" mixture of enantiomers is a mixture of enantiomers in a ratio other than 1:1.

[0057] When the process for preparing the compounds according to the invention gives rise to a mixture of stereoisomers, these isomers can be separated by conventional methods such as preparative chromatography. The compounds can be prepared in racemic, scalemic mixtures, or the individual enantiomers can be prepared either by enantioselective synthesis or resolution. The compounds can be resolved into their component enantiomers by standard methods such as the formation of diastereomeric pairs by salt formation with optically active acids such as (-)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds can also be resolved by forming diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral column vial HPLC or SFC. In some cases, 1 Leading to complex multiplets and peak confluence in H NMR spectra, 1 Rotamers of the compounds may exist, observable by 1 H NMR.

[0058] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. Chiral centers of known absolute configuration are labeled with the prefixes R and S, assigned by standard sequence rule manipulations, and preceded by the appropriate locant, if necessary (Pure & Appl. Chem. 45, 1976, 11-30). Specific examples are (R * ) or (S * (R * ) or (S *When (R ) is used in the name of a compound or in the chemical description of a compound, it is intended to convey that the compound is a pure single isomer at that stereocenter. However, the absolute configuration of that stereocenter has not been established. Thus, (R * A compound designated as (R) or (S) refers to a compound that is a single isomer pure at its stereocenter, having either the (R) or (S) absolute configuration; * A compound designated as 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

[0059] [ka] teeth,

[0060] [ka] It refers to a compound which is

[0061] Pseudo-asymmetric stereogenic centers are treated in the same manner as chiral centers but are given the lower case symbol r or s (Angew. Chem. Int. Ed. Engl. 1982, 21, 567-583).

[0062] In any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by using conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW MacOmie, Plenum Press, 1973, and TW Greene & PG M Huts, Protective Groups in Organic Synthesis, John Wiley Sons, 1991. The protecting groups can be removed at a subsequent convenient stage using methods well known in the art.

[0063] Furthermore, within the scope of the present invention, any element, particularly when referring to a compound of formula I or a pharma- ceutically acceptable salt thereof, is intended to include all isotopes and isotopic mixtures of such element, whether naturally occurring or synthetically produced, in natural abundance or in 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 (i.e., tritium or T). In some embodiments, the compounds described herein include 2 H (i.e., deuterium) isotopes. For example, -C (1~6) Groups represented by alkyl include -CH3 as well as CD3, CH2CH3 as well as CD2CD3, etc. Similarly, references to carbon and oxygen include, respectively, 12 C. 13 C and 14 C and 15 O and 16 O and 17 O and 18 They include within their scope O. Such isotopes may be radioactive or non-radioactive isotopes. Radiolabeled compounds of formula I include 3 H, 11 C. 18 F, 35 S, 122 I,123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 The radioisotope may be selected from the group including Br. Preferably, the radioisotope is 3 H, 11 C and 18 It is selected from the group F.

[0064] Compounds of Formula I The present application relates to a compound of formula I:

[0065] [ka] [In the formula, R 1 -C (1~6) Alkyl or -C (0~3) Alkyl C (3~6) is cycloalkyl, -C (1~6) Alkyl and -C (0~3) Alkyl C (3~6) Cycloalkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R 2 -C (3~5) is cycloalkyl, R 3 -C (0~1) Alkyl C (3~6) Cycloalkyl, -C (0~1) Alkyl C (3~6) Cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 4 -C (3~4) cycloalkyl or 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S; C (3~4) Cycloalkyl is unsubstituted or has 1 to 3 R 4a is substituted with a group, The 5- to 6-membered heteroaryl is unsubstituted or has one or two R 4b is substituted with a group, Each R 4a The group is an unsubstituted -C (1~4) -C substituted with alkyl or 1 to 6 fluorine atoms (1~4) independently selected from alkyl, Each R 4b The group is -C (0~2) Alkyl C (3~4) Cycloalkyl or -C (1~5) independently selected from alkyl, -C (0~2) Alkyl C (3~4) Cycloalkyl and -C (1~5) Alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R 5 is H or F, During the ceremony, R 4 Ga-C (3~4) When cycloalkyl, the compound of formula I has formula Ia:

[0066] [ka] or a pharma- ceutically acceptable salt thereof.

[0067] In some embodiments, disclosed herein is a compound of formula I, wherein: R 1 -C (1~6) Alkyl or -C (0~3) Alkyl C (3~6) is cycloalkyl, -C (1~6) Alkyl and -C (0~3) Alkyl C (3~6) Cycloalkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R 2 -C (3~5) is cycloalkyl, R 3 -C (0~1) Alkyl C (3~6) Cycloalkyl, -C (0~1) Alkyl C (3~6)Cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 4 is a 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S; The 5- to 6-membered heteroaryl is unsubstituted or has one or two R 4b is substituted with a group, Each R 4b The group is -C (0~2) Alkyl C (3~4) Cycloalkyl or -C (1~5) independently selected from alkyl, -C (0~2) Alkyl C (3~4) Cycloalkyl and -C (1~5) Alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R 5 is H or F, or a pharma- ceutically acceptable salt thereof.

[0068] In some embodiments, disclosed herein is a compound of formula I, wherein: R 5 is H; or a pharma- ceutically acceptable salt thereof.

[0069] In some embodiments, disclosed herein is a compound of formula I, wherein: R 1 -C (1~4) Alkyl or -C (0~3) Alkyl C (3~5) is cycloalkyl, -C (1~4) Alkyl and -C (0~3) Alkyl C (3~5) and cycloalkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0070] In some embodiments, disclosed herein is a compound of formula I, wherein: R 1 -C (1~3) Alkyl or -C (0~3) Alkyl C (3~5)is cycloalkyl, -C (1~3) Alkyl and -C (0~3) Alkyl C (3~5) and cycloalkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0071] In some embodiments, disclosed herein is a compound of formula I, wherein: R 1 -C (1~3) Alkyl, -C (1~3) and alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0072] In some embodiments, disclosed herein is a compound of formula I, wherein: R 1 is C (0~3) Alkyl C (3~5) Cycloalkyl, -C (0~3) Alkyl C (3~5) and cycloalkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0073] In some embodiments, disclosed herein is a compound of formula I, wherein: R 1 is C (1~2) Alkyl C (3~5) Cycloalkyl, -C (1~2) Alkyl C (3~5) and cycloalkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0074] In some embodiments, disclosed herein are compounds of formula I, 1 teeth,

[0075] [ka] or a pharma- ceutically acceptable salt thereof.

[0076] In some embodiments, disclosed herein are compounds of formula I, 1 or a pharma- ceutically acceptable salt thereof.

[0077] [ka]

[0078] In some embodiments, disclosed herein are compounds of formula I, 1 or a pharma- ceutically acceptable salt thereof.

[0079] [ka]

[0080] In some embodiments, disclosed herein is a compound of formula I, wherein: R 2 -C (3~4) or a pharma- ceutically acceptable salt thereof.

[0081] In some embodiments, disclosed herein is a compound of formula I, wherein: R 2 is cyclopropyl; or a pharma- ceutically acceptable salt thereof.

[0082] In some embodiments, disclosed herein is a compound of formula I, wherein: R 3 -C (0) Alkyl C (5~6) Cycloalkyl, -C (0) Alkyl C (5~6) and cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0083] In some embodiments, disclosed herein is a compound of formula I, wherein: R 3 -C (0) Alkyl C (5~6) Cycloalkyl, -C (0) Alkyl C (5~6) and cycloalkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0084] In some embodiments, disclosed herein is a compound of formula I, wherein: R 3 -C (0) Alkyl C (6) Cycloalkyl, -C (0) Alkyl C (6) and cycloalkyl is unsubstituted or substituted with 1 to 2 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0085] In some embodiments, disclosed herein is a compound of formula I, wherein: R 3 teeth,

[0086] [ka] or a pharma- ceutically acceptable salt thereof.

[0087] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 is a 5-6 membered heteroaryl having 1-4 heteroatoms selected from N and O; The 5- to 6-membered heteroaryl is unsubstituted or has one or two R 4b is substituted with a group, Each R 4b The group is -C (0~1) Alkyl C (3) Cycloalkyl or -C (1~3) independently selected from alkyl, -C (0~1) Alkyl C (3) Cycloalkyl and -C (1~3)and alkyl is unsubstituted or substituted with 1 to 4 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0088] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 is pyridinyl, which is unsubstituted or C (1~2) Alkyl-substituted, C (1~2) and alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0089] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 teeth,

[0090] [ka] or a pharma- ceutically acceptable salt thereof.

[0091] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 is unsubstituted or contains one or two R 4b a pyrazolyl, triazolyl, isoxazolyl, or oxadiazolyl substituted with a group; Each R 4b The group is -C (0~1) Alkyl C (3) Cycloalkyl or -C (1~3) independently selected from alkyl, -C (0~1) Alkyl C (3) Cycloalkyl and -C (1~3) and alkyl is unsubstituted or substituted with 1 to 4 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0092] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 is unsubstituted or contains one or two R4b a pyrazolyl, triazolyl, isoxazolyl, or oxadiazolyl substituted with a group; Each R 4b The group is -C (1) Alkyl C (3) Cycloalkyl or -C (1~3) independently selected from alkyl, -C (1) Alkyl C (3) Cycloalkyl and -C (1~3) and alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0093] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 is unsubstituted or contains one or two R 4b a pyrazolyl, triazolyl, isoxazolyl, or oxadiazolyl substituted with a group; Each R 4b independently -C (1~3) Alkyl, -C (1~3) and alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, or a pharma- ceutically acceptable salt thereof.

[0094] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 is unsubstituted or contains one or two R 4b or a pharma- ceutically acceptable salt thereof, wherein R is 1H-pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, isoxazol-4-yl, or 1,2,5-oxadiazolyl substituted with a group;

[0095] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 is unsubstituted or contains one or two R 4bor a pharma- ceutically acceptable salt thereof, wherein R is 1H-pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, isoxazol-4-yl, isoxazol-3-yl, or 1,2,5-oxadiazolyl substituted with a group;

[0096] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 is unsubstituted or contains one or two R 4b or a pharma- ceutically acceptable salt thereof, wherein the compound is 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, isoxazol-4-yl, or 1,2,5-oxadiazol-3-yl, substituted with a group.

[0097] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 is unsubstituted or contains one or two R 4b or a pharma- ceutically acceptable salt thereof, wherein the compound is 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, isoxazol-4-yl, isoxazol-3-yl or 1,2,5-oxadiazol-3-yl substituted with

[0098] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 teeth,

[0099] [ka] or a pharma- ceutically acceptable salt thereof.

[0100] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 teeth,

[0101] [ka] or a pharma- ceutically acceptable salt thereof.

[0102] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 teeth,

[0103] [ka] or a pharma- ceutically acceptable salt thereof.

[0104] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 teeth,

[0105] [ka] or a pharma- ceutically acceptable salt thereof.

[0106] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 teeth,

[0107] [ka] or a pharma- ceutically acceptable salt thereof.

[0108] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 teeth,

[0109] [ka] or a pharma- ceutically acceptable salt thereof.

[0110] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 -C (3) is cycloalkyl, C (3) Cycloalkyl is unsubstituted or has 1 to 3 R 4a is substituted with a group, Each R 4a The group is an unsubstituted -C (1~2) Alkyl or -C substituted with 1 to 3 fluorine atoms (1~2) independently selected from alkyl, Compounds of formula I have the formula Ia:

[0111] [ka] or a pharma- ceutically acceptable salt thereof.

[0112] In some embodiments, disclosed herein are compounds of formula I, wherein: R 4 is unsubstituted or -CF3 substituted with one -C (3) is cycloalkyl, Compounds of formula I have the formula Ia:

[0113] [ka] or a pharma- ceutically acceptable salt thereof.

[0114] In some embodiments, disclosed herein is a compound of formula I, wherein: R 4 teeth,

[0115] [ka] and Compounds of formula I have the formula Ia:

[0116] [ka] or a pharma- ceutically acceptable salt thereof.

[0117] In some embodiments, disclosed herein is a compound of formula Ia:

[0118] [ka] or a pharma- ceutically acceptable salt thereof.

[0119] In some embodiments, disclosed herein is a compound of Formula I, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table 1A below.

[0120] [Table 1-1]

[0121] [Table 1-2]

[0122] [Table 1-3]

[0123] [Table 1-4]

[0124] [Table 1-5]

[0125] In some embodiments, disclosed herein is a compound of Formula I, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the compounds of Table 1AA below.

[0126] [Table 2-1]

[0127] [Table 2-2]

[0128] [Table 2-3]

[0129] [Table 2-4]

[0130] [Table 2-5]

[0131] [Table 2-6]

[0132] In some embodiments, disclosed herein is a compound of Formula I, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table 1B below.

[0133] [Table 3]

[0134] In some embodiments, disclosed herein is a compound having formula I,

[0135] [ka] or a pharma- ceutically acceptable salt thereof.

[0136] In some embodiments, disclosed herein is a compound having formula I,

[0137] [ka] or a pharma- ceutically acceptable salt thereof.

[0138] In some embodiments, disclosed herein is a compound having formula I,

[0139] [ka] or a pharma- ceutically acceptable salt thereof.

[0140] In some embodiments, disclosed herein is a compound having formula I,

[0141] [ka] or a pharma- ceutically acceptable salt thereof.

[0142] In some embodiments, disclosed herein is a compound having formula I,

[0143] [ka] or a pharma- ceutically acceptable salt thereof.

[0144] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration (e.g., a tablet or capsule).

[0145] In some embodiments, disclosed herein is a pharmaceutical composition made by mixing a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0146] In some embodiments, disclosed herein is a process for making a pharmaceutical composition, comprising mixing a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0147] III. Therapeutic Uses The present application also relates to a method for treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder or disease, comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0148] In some embodiments, disclosed herein are methods for treating or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt thereof.

[0149] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease comprising administering a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0150] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriasis.

[0151] In some embodiments, disclosed herein is a method of treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt thereof, to a subject in need thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

[0152] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt thereof, to a subject in need thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

[0153] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of Formula I or a pharma- ceutical acceptable salt thereof to a subject in need thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0154] In some embodiments, disclosed herein is a method of treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.

[0155] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt thereof, to a subject in need thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.

[0156] 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 pharma- ceutical acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

[0157] In some embodiments, disclosed herein is a method of 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 pharma- ceutical acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is vitiligo.

[0158] 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 pharma- ceutical acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.

[0159] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I or a pharma- ceutical acceptable salt thereof to a subject in need thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

[0160] In some embodiments, disclosed herein is a method of 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 pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is asthma.

[0161] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt thereof, to a subject in need thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is uveitis.

[0162] 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 pharma- ceutical acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disorder.

[0163] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt thereof, to a subject in need thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is multiple myeloma.

[0164] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I or a pharma- ceutical acceptable salt thereof to a subject in need thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

[0165] In some embodiments, disclosed herein is a method of treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the compound of formula I or a pharma- ceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).

[0166] In some embodiments, disclosed herein is a method of treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the therapeutically effective amount is a dosage of about 10 mg to 300 mg QD. In some embodiments, the therapeutically effective amount is a dosage of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a dosage of about 50 mg to 100 mg QD.

[0167] In some embodiments, disclosed herein is a method of treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof to a subject in need thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the therapeutically effective amount is a dose of about 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.

[0168] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0169] In some embodiments, disclosed herein is the use of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0170] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I or a pharma- ceutical acceptable salt thereof, a composition thereof, or a medicament thereof to a subject in need thereof.

[0171] In some embodiments, disclosed herein are methods of 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, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus, comprising administering a therapeutically effective amount of a compound of Formula I, or a pharma- ceutical acceptable salt thereof, a composition thereof, or a medicament thereof, to a subject in need thereof.

[0172] In some embodiments, disclosed herein is a method of 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, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmacologic acceptable salt thereof, composition thereof, or medicament thereof, to a subject in need thereof.

[0173] 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 pharma- ceutical acceptable salt thereof.

[0174] 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 pharma- ceutically acceptable salt thereof.

[0175] IV. Combination Therapy A compound of formula I, or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof, may also be used in combination with one or more additional therapeutic agents.

[0176] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, and immunosuppressants.

[0177] In some embodiments, the one or more additional therapeutic agents are (a) anti-TNFα agents, such as infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), etanercept (Enbrel®), thalidomide (Immunoprin®), lenalidomide (Revlimid®, and pomalidomide (Pomalyst® / Imnovid®); (b) anti-p40 antibody agents, such as ustekinumab (Stelara®), and (c) an anti-p19 antibody agent, such as guselkumab (Tremfya®), tildrakizumab (Ilumya™ / Ilumetri), risankizumab (Skyrizi™), and mirikizumab.

[0178] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharma- ceutical acceptable salt thereof, composition thereof, or pharmaceutical preparation thereof, in combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, immunomodulatory agents, or immunosuppressants, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus.

[0179] 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, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof, in combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents or immunosuppressants, wherein the syndrome, disorder, or disease is psoriasis, psoriatic arthritis, ankylosing spondylitis. In some embodiments, the IL-17 mediated inflammatory syndrome, disorder, or disease is psoriasis. In some embodiments, the IL-17 mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis. In some embodiments, the IL-17 mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0180] V. Dosing Regimen When used as IL-17A modulators, the compounds disclosed herein may be administered in an effective amount within the dosage range of about 0.5 mg to about 1 g, preferably about 0.5 mg to about 500 mg, once daily or in divided doses. In some embodiments, the dosage is about 5 mg to 400 mg. In some embodiments, the dosage is about 10 mg to 300 mg. In some embodiments, the dosage is about 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of formula I, or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of a compound of formula I, or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of a compound of formula I, or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 300, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of a compound of formula I, or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0181] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 10 mg to 300 mg QD. In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.

[0182] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.

[0183] The dosage administered will be affected by factors such as the route of administration, the health, weight, and age of the recipient, frequency of treatment, and the presence of concurrent, unrelated treatments.

[0184] It is also obvious to those skilled in the art that the therapeutically effective amount of the compound of the present invention or its pharmaceutical composition varies according to the desired effect.Therefore, the optimal dosage can be easily determined by those skilled in the art and varies according to the specific compound used, the method of administration, the strength of the preparation, and the progression of the disease.In addition, factors related to the specific subject being treated, including the subject's age, weight, diet, and administration time, will cause the need to adjust the dosage to an appropriate therapeutic concentration.Therefore, the dosages above are examples of average cases.Of course, there may be individual cases in which higher or lower dosage ranges are effective, and such cases are also within the scope of the present invention.

[0185] VI. Pharmaceutically Acceptable Salts Pharmaceutically acceptable acid / anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estrus, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, The acid salts include, but are not limited to, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucoate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, and triethiodide.The organic or inorganic acid includes, but is not limited to, hydroiodic acid, perchloric acid, sulfuric acid, phosphoric acid, propionic acid, glycolic acid, methanesulfonic acid, hydroxyethanesulfonic acid, oxalic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, saccharic acid, or trifluoroacetic acid.

[0186] Pharmaceutically acceptable basic / cationic salts include, but are not limited to, aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethane or "TRIS"), ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH3, NH4OH, N-methyl-D-glucamine, piperidine, potassium, potassium-t-butoxide, potassium hydroxide (aqueous), procaine, quinine, sodium, sodium carbonate, sodium 2-ethylhexanoate, sodium hydroxide, triethanolamine or zinc.

[0187] VII. Pharmaceutical Compositions The compound of formula I or its pharmaceutically acceptable salt can be formulated into pharmaceutical compositions containing any known pharmaceutically acceptable carrier.Representative carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antibacterial and antifungal agent, and isotonicity agent.Representative excipients that can also be components of the formulation include fillers, binders, disintegrants and lubricants.

[0188] The pharma- ceutically acceptable salts of the compounds of formula I or its pharma-ceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts formed from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate. Basic salts include ammonium salts, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with organic bases such as dicyclohexylamino salts, and salts with amino acids such as arginine. In addition, basic nitrogen-containing groups may be quaternized, for example, by alkyl halides.

[0189] The pharmaceutical composition of the present invention can be administered by any means that achieves its intended purpose. Examples include parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal or ocular administration. Alternatively, or in conjunction, it may be administered by oral route. Suitable formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form, such as water-soluble salts, acidic solutions, alkaline solutions, aqueous dextrose solutions, isotonic carbohydrate solutions, and cyclodextrin inclusion complexes.

[0190] Also disclosed herein is a method for making a pharmaceutical composition comprising mixing a pharma- ceutically acceptable carrier with any of the compounds of formula I, or a pharma- ceutically acceptable salt thereof. Additionally, the application encompasses a pharmaceutical composition made by mixing a pharma- ceutically acceptable carrier with any of the compounds of the present invention. EXAMPLES

[0191] Abbreviation The following abbreviations may be used herein and throughout this application:

[0192] [Table 4-1]

[0193] [Table 4-2]

[0194] In some embodiments, provided herein are processes and intermediates disclosed herein that are useful for preparing a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0195] General scheme: Compounds of formula I are synthesized according to the synthetic methods described herein, which are merely meant to represent synthetic examples and are not meant to be limiting in any way. Unless otherwise specified, the substituents in schemes 1-11 are as defined above for formula I. If no temperature or temperature range is stated, it is understood that the reaction is carried out at room temperature.

[0196] [ka]

[0197] Compounds of formula I can be prepared according to Scheme 1. Removal of the Boc group of A-Ia under acidic conditions such as aqueous hydrochloric acid or TFA (neat) or TFA in DCM gives the corresponding amine A-Ib. The above conditions for removing the Boc group are referred to as "Boc deprotection conditions". The amine A-Ib can then be converted to a carboxylic acid (R 4 -CO2H(A-Ic)) to give a compound of formula I. Examples of amide bond formation techniques include (i) and (ii): (i) reaction of amine A-Ib with carboxylic acid A-Ic, in which the carboxylic acid is activated with a suitable activating agent, for example a carbodiimide such as DCC or EDCI, optionally in the presence of a catalyst such as HOBt and / or DMAP; a halotrisaminophosphonium salt such as BOP, PyBOP, or PyBroP; a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or another suitable coupling agent such as HBTU, HATU, or 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®). These coupling reactions are carried out in a suitable solvent such as DCM, THF, DMF and mixtures thereof, optionally in the presence of a tertiary amine such as N-methylmorpholine, diisopropylethylamine, or triethylamine, to give compounds of formula I. (ii) Alternatively, the coupling of amine A-Ib with a carboxylic acid chloride (R 4 -COCl(A-Id)) or acid anhydride ((R 4 -C(O))2O(A-Ie)) in a solvent such as THF or DCM in the presence of a base such as TEA, DIPEA, pyridine or NMO provides compounds of formula I.

[0198] [ka]

[0199] Alternatively, compounds of formula I can be prepared according to Scheme 2. The amine A-If is then coupled to a carboxylic acid (R 1-CO2H(A-Ig)) to give a compound of formula I. Examples of amide bond formation techniques include (i) and (ii): (i) reaction of an amine A-If with a carboxylic acid A-Ig, in which the carboxylic acid is activated with a suitable activating agent, for example a carbodiimide such as DCC or EDCI, optionally in the presence of a catalyst such as HOBt and / or DMAP; a halotrisaminophosphonium salt such as BOP, PyBOP, or PyBroP; a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or another suitable coupling agent such as HBTU, HATU, or 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®). These coupling reactions are carried out in a suitable solvent such as DCM, THF, DMF and mixtures thereof, optionally in the presence of a tertiary amine such as N-methylmorpholine, diisopropylethylamine, or triethylamine, to give compounds of formula I. (ii) Alternatively, the coupling of amine A-If with a carboxylic acid chloride (R 1 -COCl(A-Ih)) or acid anhydride ((R 1 -C(O))2O(A-Ii)) in a solvent such as THF or DCM in the presence of a base such as TEA, DIPEA, pyridine or NMO provides compounds of formula I.

[0200] [ka]

[0201] Compounds of formula A-Ia can be prepared according to the sequence shown in Scheme 3. Condensation of 2-(methylthio)pyrimidine-4-carbaldehyde with (S)-(-)-2-methyl-2-propanesulfinamide gives the corresponding sulfinimide compound A-III. 2Addition of a nucleophilic carbon-containing reagent such as methyl 3-methyl-4-methyl-1,4-dihydro-2,4-triazol-1 ... 5 is H] in the presence of a catalyst such as di-μ-chlorobis[(1,2,5,6-η)-1,5-cyclooctadiene]diiridium to give compounds A-VIIa. Deprotection of the Cbz group using a reagent such as ammonium formate in the presence of a palladium catalyst in a solvent such as aqueous methanol gives the corresponding amines, which are separated into diastereomers using SFC to give compounds A-VIIIa. The above conditions for removing the Cbz group are referred to as "Cbz deprotection conditions". Subsequent amide bond formation using the conditions described in Scheme 2 gives compounds of general structure A-Ia.

[0202] [ka]

[0203] Alternatively, compound A-1a can be prepared as shown in Scheme 4. Using the amide bond coupling conditions described in Scheme 2, amine compound A-IVa can be coupled to a carboxylic acid R 1COH (compound A-Ig) to give compound A-IXa. Oxidation of the methyl sulfide compound A-IXa with an oxidation reagent such as mCPBA gives the corresponding sulfone (structure not shown), which upon treatment with ammonia in a solvent such as isopropanol gives compound A-Xa. Coupling of compound A-Xa with ylide compound B-1a [wherein R 5 is H] in the presence of a catalyst such as di-μ-chlorobis[(1,2,5,6-η)-1,5-cyclooctadiene]diiridium to give compound A-Ia.

[0204] [ka]

[0205] Compound B-1a can be prepared as shown in Scheme 5. Treatment of aldehyde B-IIa with (S)-(-)-2-methyl-2-propanesulfinamide in the presence of a dehydrating reagent such as copper II sulfate in a solvent such as DCM gives sulfinimine B-IIb. Cyanation of compound B-IIb using TMSCN in the presence of a catalyst such as Sc(OTf)3 in a solvent such as DCM gives nitrile compound B-IIIc. Co-hydrolysis of the nitrile and sulfinamide groups of compound B-IIIc under acidic conditions such as aqueous hydrochloric acid gives the corresponding amino acid (structure not shown). The free NH2 of the corresponding amino acid is protected as a t-butyl carbamate (Boc group) by reaction with di-tert-butyl dicarbonate ((Boc)2O) in a solvent such as DCM, THF, or a mixture thereof to give compound B-IVd. Treatment of compound B-IVd with isobutyl chloroformate in the presence of a base such as Et3N in a solvent such as THF gives the corresponding mixed anhydride (structure not shown). This mixed anhydride is generated in situ by mixing trimethylsulfoxonium iodide with a base such as sodium tert-butoxide (dimethyl(oxo)-λ 6 -sulfanylidene)methane to give the ylide compound B-Ia.

[0206] [ka]

[0207] Ylide compound BI can be prepared as shown in Scheme 6. Treatment of 4,4-difluorocyclohexanecarbaldehyde with (S)-(-)-2-methyl-2-propanesulfinamide in the presence of a dehydrating reagent such as copper II sulfate in a solvent such as DCM gives sulfinimine B-II. Cyanation of compound B-II using TMSCN in the presence of a catalyst such as Sc(OTf)3 in a solvent such as DCM gives nitrile compound B-III. Simultaneous hydrolysis of the nitrile and sulfinamide groups in compound B-III under acidic conditions such as aqueous hydrochloric acid gives the corresponding amino acid (structure not shown). The free NH2 of the corresponding amino acid is protected as a t-butyl carbamate (Boc group) by reaction with di-tert-butyl dicarbonate ((Boc)2O) in a solvent such as DCM, THF or a mixture thereof to give compound B-IV. Treatment of compound B-IV with isobutyl chloroformate in the presence of a base such as Et3N in a solvent such as THF gives the corresponding mixed anhydride (structure not shown). This mixed anhydride is generated in situ by mixing trimethylsulfoxonium iodide with a base such as sodium tert-butoxide (dimethyl(oxo)-λ 6 -sulfanylidene)methane to give the ylide compound BI.

[0208] [ka]

[0209] Formula A-Ib [wherein, R 5 is F] is a compound of formula A-Ia, 5is H. Removal of the Boc protecting group in compound A-Ia using Boc deprotection conditions, followed by treatment with a fluorinating agent such as Selectfluor® in a solvent such as acetonitrile, provides compound A-Ib.

[0210] [ka]

[0211] Substituted 1,2,3-triazole-5-carboxylic acid compounds C-II can be prepared as shown in Scheme 8. 1H-1,2,3-triazole-5-carboxylic acid esters are reacted with a base such as potassium carbonate and an alkyl bromide (R 4b Alkylation by treatment with an alkylating agent such as Br affords a mixture of N1, N2 or N3-1,2,3-triazole-5-carboxylate compounds CI, which are separated by FCC. Hydrolysis of the ester with an aqueous base such as sodium hydroxide in a solvent such as THF affords the carboxylic acid C-II.

[0212] [ka]

[0213] Heteroaromatic carboxylic acid chlorides, D-Ib and D-IIb, can be prepared as shown in Scheme 9. Isoxazole-4-carboxylic acid D-Ia is treated with excess thionyl chloride to give acid chloride D-Ib. 4-Methyl-1,2,5-oxadiazole-3-carboxylic acid D-IIa is treated with excess thionyl chloride to give acid chloride D-IIb.

[0214] [ka]

[0215] 3-Substituted isoxazole 4-carboxylic acids E-III can be prepared as shown in Scheme 10. Condensation of 4,4,4-trifluorobutanal with hydroxylamine hydrochloride in a solvent such as ethanol gives the corresponding oxime EI. Subsequent treatment with NCS and cycloaddition with ethyl-3-(diethylamino)acrylate in a solvent such as chloroform gives the ester E-II. Saponification of the ester with sodium hydroxide in aqueous ethanol gives the isoxazole 4-carboxylic acid E-III.

[0216] [ka]

[0217] Compound A-If can be prepared as shown in scheme 11. Compound A-VIIIa is protected as a carbamate, such as benzyloxycarbonyl (Cbz), or as fluorenylmethyloxycarbonyl (Fmoc) to obtain compound A-1j. Compound A-Ij, where PG is Cbz, is prepared by subjecting A-VIIIa to Cbz protection conditions. Compound A-Ij, where 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 obtain compound A-Ik. Compound A-Ik is subjected to amide bond forming conditions, such as those described in scheme 1 for the preparation of the compound of formula I from compound A-Ib, to obtain compound A-Im. If the carbamate compound A-Im is a Cbz group, it can be removed using Cbz protecting group removal conditions to give A-If. If the carbamate compound A-Im is an Fmoc group, it can be removed by treatment with a base such as piperidine in a solvent such as DMF to give A-If.

[0218] In obtaining the compounds described in the Examples below and the corresponding analytical data, the following experimental and analytical protocols were followed, unless otherwise indicated.

[0219] Unless otherwise stated herein, reaction solutions were 2(g) Or Ar (g) The mixture was stirred at room temperature under atmospheric pressure. When solutions were "concentrated to dryness", they were concentrated using a rotary evaporator under reduced pressure, and the solution was then dried, typically over a drying agent such as MgSO4 or Na2SO4.

[0220] Normal phase flash column chromatography (FCC) was performed on silica gel using prepackaged silica gel columns such as RediSep®, using ethyl acetate (EtOAc) / hexane, CH2Cl2 / MeOH, or CH2Cl2 / 10% 2N NH3 in MeOH as eluents unless otherwise noted.

[0221] Thin-layer chromatography was performed using Merck silica gel 60F. 254 Preparative thin-layer chromatography was performed using EM Science silica gel 60 F with a 20 cm x 4 cm concentration zone (2.5 cm x 7.5 cm, 250 μm or 5.0 cm x 10.0 cm, 250 μm precoated silica gel plates). 254 Mass spectra were performed using 20 cm x 20 cm 0.5 mm precoated plates. Mass spectra were obtained on an Agilent series 1100 MSD in positive mode using electrospray ionization (ESI) unless otherwise noted. Calculated masses correspond to exact masses. NMR spectra were obtained on either a Bruker model DPX400 (400 MHz), DPX500 (500 MHz), or DRX600 (600 MHz) spectrometer. The following NMR spectra were obtained using the NMR spectroscopy: 1 The format of the 1 H NMR data is as follows: chemical shift (ppm) downfield relative to tetramethylsilane (multiplicity, coupling constant J (Hz), integration).

[0222] Whenever a yield is given as a percentage, such yield refers to the mass of the entity for which the yield is given relative to the maximum amount of the same entity obtainable under the specified stoichiometric conditions. Reagent concentrations given as percentages refer to mass ratios unless otherwise specified.

[0223] In general, compound names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, Mass.) or OE MetaChem V1.4.0.4 (Open Eye).

[0224] Intermediates Intermediate 1 (S,E)-2-Methyl-N-((2-(methylthio)pyrimidin-4-yl)methylene)propane-2-sulfinamide

[0225] [ka]

[0226] A 500 mL 3-neck flask equipped with an overhead stirrer was charged with 2-(methylthio)pyrimidine-4-carbaldehyde (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) under nitrogen at 20-30 °C. The mixture was concentrated under vacuum. The residue was charged with saturated aqueous NaHCO3 (60 mL), H2O (400 mL) and EtOAc (300 mL) and stirred for 15 min. The resulting mixture was filtered and the 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 under vacuum. The residue was purified by FCC (10:1 petroleum ether / ethyl acetate) to give the title compound as a yellow solid.

[0227] Intermediate 2 (S)-N-(cyclopropyl(2-(methylthio)pyrimidin-4-yl)methyl)-2-methylpropane-2-sulfinamide

[0228] [ka]

[0229] A 2 L 3-neck flask equipped with an overhead stirrer was charged with (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) under nitrogen. The resulting solution was cooled to -78 °C and cyclopropylmagnesium bromide (341 mL, 183.8 mmol, 0.6 M in THF) was added dropwise at -78 °C over 30 min. The resulting reaction mixture was stirred at -78 °C for 1 h. After completion of the reaction, the mixture was quenched with 20 wt% aqueous citric acid (100 mL). Then, HO (2 L) was added and the mixture was extracted with EtOAc (2 x 1 L). The combined organic phase was concentrated under vacuum to give the title compound as a brown oil.

[0230] Intermediate 3 Cyclopropyl(2-(methylthio)pyrimidin-4-yl)methanamine

[0231] [ka]

[0232] A 2 L 3-neck 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 at 15-20 °C, HCl solution (380 mL, 1520 mmol, 4 M in 1,4-dioxane) was added dropwise over 30 min. The resulting mixture was stirred at 15-20 °C for 1 h. After completion of the reaction, the reaction mixture was concentrated under vacuum. The residue was dissolved in H2O (1150 mL) and then extracted with MTBE (3 x 600 mL). After phase separation, the pH of the aqueous phase was adjusted to pH 8-9 by adding 0.1 N aqueous K2CO3 solution. The resulting solution was extracted with EtOAc (6 x 600 mL). The combined EtOAc layers were concentrated in vacuo to give the title compound as a yellow solid.

[0233] Intermediate 4 N-(cyclopropyl(2-(methylthio)pyrimidin-4-yl)methyl)-4,4,4-trifluorobutanamide

[0234] [ka]

[0235] To a mixture of cyclopropyl(2-(methylthio)pyrimidin-4-yl)methanamine (7.1 g, 36.4 mmol, intermediate 3), 4,4,4-trifluorobutyric acid (5.86 g, 40 mmol), HOBt (5.16 g, 38.2 mmol) and ACN (150 mL) was added DIPEA (7.52 mL, 43.6 mmol) and the mixture was stirred for 10 min. EDCI (7.32 g, 38.2 mmol) was then added and the resulting mixture was stirred at room temperature for 1 h followed by 60° C. for 1 min and then allowed to cool to room temperature. The reaction was quenched by the addition of water (800 mL). A precipitate formed and the suspension was stirred at room temperature for 30 min. The solid was collected by filtration, washed with water and lyophilized to give the title compound as a white solid.

[0236] Intermediate 5 N-(cyclopropyl(2-(methylsulfonyl)pyrimidin-4-yl)methyl)-4,4,4-trifluorobutanamide

[0237] [ka]

[0238] 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 being allowed to warm to room temperature for an additional 1 h. The mixture was partitioned between saturated aqueous bicarbonate solution and DCM. The layers were separated and the organic layer was washed with water followed by 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.

[0239] Intermediate 6 N-((2-aminopyrimidin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide

[0240] [ka]

[0241] To a sealed tube was added N-(cyclopropyl(2-(methylsulfonyl)pyrimidin-4-yl)methyl)-4,4,4-trifluorobutanamide (600 mg, 1.71 mmol, Intermediate 5) and ammonia solution (10 mL, 20 mmol, 2M in 2-propanol). The tube was sealed and the mixture was stirred at 75° C. for 18 h. The mixture was allowed to cool to room temperature and then concentrated to dryness. The residue was purified by FCC (0-100% (10% MeOH in EtOAc) / Hexanes) to give the title compound as a white solid.

[0242] Intermediate 7 (S,E)-N-((4,4-difluorocyclohexyl)methylene)-2-methylpropane-2-sulfinamide

[0243] [ka]

[0244] To a mixture of 4,4-difluorocyclohexanecarbaldehyde (3 mL, 21.6 mmol), (S)-(-)-2-methyl-2-propanesulfinamide (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. Then Celite® was added and the mixture was filtered. The filter cake was rinsed with EtOAc and the combined filtrate was concentrated. The residue was purified by FCC (0-40% EtOAc / Hexane) to give the title compound as a clear, colorless oil.

[0245] Intermediate 8 (S)-N-((S)-Cyano(4,4-difluorocyclohexyl)methyl)-2-methylpropane-2-sulfinamide

[0246] [ka]

[0247] To a solution of (S,E)-N-((4,4-difluorocyclohexyl)methylene)-2-methylpropane-2-sulfinamide (3.22 g, 12.8 mmol, intermediate 7) and TMSCN (3.21 mL, 25.6 mmol) in DCM (85 mL) was added scandium trifluoromethanesulfonate (727 mg, 1.48 mmol) and the resulting suspension was stirred at room temperature for 72 h. The mixture was then filtered through a pad of silica gel, 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 give the title compound as a colorless crystalline solid.

[0248] Intermediate 9 (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid

[0249] [ka]

[0250] 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% in water) was stirred at 80° C. for 24 h and then cooled to room temperature. Water was then added to dissolve the solid that formed on cooling and the mixture was washed twice with EtOAc and concentrated to dryness. The residue was diluted with 1N aqueous NaOH (10 mL) and washed twice with EtOAc. THF (10 mL) was then added followed by di-tert-butyl dicarbonate (0.8 mL, 3.7 mmol) and the mixture was stirred at room temperature for 45 h. The mixture was then washed with Et2O and the aqueous layer was made acidic by the addition of 1N aqueous HCl. The aqueous 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.

[0251] Intermediate 10 tert-Butyl (S)-(1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-lambda 6 -Sulfanylidene)-2-oxopropyl)carbamate

[0252] [ka]

[0253] Trimethylsulfoxonium 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 under reflux for 2 h. The solution was then cooled to 0° C. In a separate flask, (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 and the solution was then added dropwise to a 0° C. solution of isobutyl chloroformate (0.9 mL, 6.96 mmol) in THF (21 mL). The resulting mixture was stirred at 0° C. for 30 min. The suspension was then filtered and the solid was washed with 0° C. THF (2 mL). The combined washings and filtrate were cooled at 0°C and then added dropwise to the ylide solution. The resulting mixture was stirred at 0°C for 2 h. The mixture was then partitioned between water and EtOAc. The aqueous solution was further extracted with EtOAc (2x) and then the organic layers were 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.

[0254] Intermediate 11 tert-Butyl ((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0255] [ka]

[0256] In a 50 mL three-neck flask equipped with a magnetic stirrer, add N-((2-aminopyrimidin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (1.0 g, 3.47 mmol, Intermediate 6), tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-lambda)-2-yl-2,4-difluoropropanediol (1.0 g, 3.47 mmol, Intermediate 6), and 1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-lambda). 6 A mixture of 1,10-phenanthroline (40 mg, 0.14 mmol), NaOTf (40 mg, 0.14 mmol), 4Å MS (3.0 g, 300% w / w) and DCE (15 mL) was added to the reaction mixture. The mixture was warmed to 80-85°C and kept at this temperature for 20 h. After this time, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by FCC (50% petroleum ether / EtOAc) to give the title compound as a yellow solid.

[0257] Intermediate 12 tert-Butyl ((S)-(7-((S)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0258] [ka]

[0259] Intermediate 13 tert-Butyl ((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0260] [ka]

[0261] tert-Butyl ((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)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, 50×250 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.

[0262] Intermediate 14 N-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide

[0263] [ka]

[0264] To a solution of tert-butyl ((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)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 washed with further EtOAc before 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.

[0265] Intermediate 15 Methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate

[0266] [ka]

[0267] To a mixture of methyl 1H-1,2,3-triazole-4-carboxylate (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 mixture was then filtered through a pad of Celite®, rinsed with EtOAc and the filtrate was concentrated under vacuum. 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 x 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 (0-75% EtOAc / hexanes; second eluting isomer) to give the title compound as a white solid.

[0268] Intermediate 16 Methyl 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylate

[0269] [ka]

[0270] The title compound was prepared as described for the synthesis of Intermediate 15. The title compound was the first eluting isomer isolated as a colorless oil.

[0271] Intermediate 17 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid

[0272] [ka]

[0273] 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 aqueous NaOH (58 mL, 115 mmol) and the mixture was stirred at room temperature for 15 h. After that, 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 addition of 1N aqueous HCl 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.

[0274] Intermediate 18 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid

[0275] [ka]

[0276] 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 afford the title compound as a white solid.

[0277] Intermediate 19 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxamide

[0278] [ka]

[0279] A mixture of N-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (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. After this time 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, a diastereomeric mixture, as a pale yellow film.

[0280] Intermediate 20 Benzyl(cyclopropyl(2-(methylthio)pyrimidin-4-yl)methyl)carbamate

[0281] [ka]

[0282] A 1 L 3-neck 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 to 5 °C and CbzCl (48 g, 282 mmol) was added dropwise over 30 min. The resulting mixture was stirred at -5 to 5 °C for 1 h. The reaction was then quenched with HO (100 mL) and the phases separated. The organic phase was concentrated in vacuo to give the title compound as a yellow solid.

[0283] Intermediate 21 Benzyl (cyclopropyl(2-(methylsulfonyl)pyrimidin-4-yl)methyl)carbamate

[0284] [ka]

[0285] A 3 L 3-neck 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) under nitrogen. After cooling at 0-10 °C, Oxone® (638 g, 1038 mmol) was added in one portion at 0-10 °C, and the resulting mixture was stirred at the same temperature for 3 h. Then 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 5-6 by addition of 0.1 N aqueous Na2CO3. The phases were separated and the organic layer was concentrated to dryness. The residue was purified by FCC (15-50% EtOAc / petroleum ether) to give the title compound as a brown oil.

[0286] Intermediate 22 Benzyl ((2-aminopyrimidin-4-yl)(cyclopropyl)methyl)carbamate

[0287] [ka]

[0288] The title compound was prepared as described for the synthesis of Intermediate 6, 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. The crude material was purified by FCC (35% EtOAc / petroleum ether) to afford the title compound as an off-white solid.

[0289] Intermediate 23 tert-Butyl ((1S)-(7-((((benzyloxy)carbonyl)amino)(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0290] [ka]

[0291] Into a 500 mL three-neck flask equipped with an overhead stirrer was added benzyl((2-aminopyrimidin-4-yl)(cyclopropyl)methyl)carbamate (11.0 g, 36.9 mmol, Intermediate 22), tert-butyl(S)-(1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-lambda)-lambda 6 [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), 4 Å MS (22.0 g, 200% w / w) and toluene (165 mL) were respectively charged under nitrogen. The resulting mixture was stirred at 80-85 °C for 40 h. After that, 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.

[0292] Intermediate 24 tert-Butyl ((1S)-(7-(amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0293] [ka]

[0294] A 500 mL 3-neck 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 HO (26.5 mL) under nitrogen. After stirring at 25-35 °C for 3 h, the mixture was filtered and the filtrate was concentrated under vacuum to remove MeOH. The resulting aqueous solution was extracted with 2-MeTHF (2 x 300 mL). The combined organic phase was concentrated to dryness to give the title compound as an off-white solid.

[0295] Intermediate 25 tert-Butyl ((S)-(7-((S)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0296] [ka]

[0297] Intermediate 26 tert-Butyl ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0298] [ka]

[0299] 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, 50×250 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.

[0300] Intermediate 27 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

[0301] [ka]

[0302] 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-trifluoromethylbutyric 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. The mixture was then 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 a pale foam.

[0303] Intermediate 28 N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluoro-3-methylbutanamide

[0304] [ka]

[0305] 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 addition of 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 light brown foam.

[0306] Intermediate 29 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

[0307] [ka]

[0308] 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, then EDCI (43 mg, 0.22 mmol) was added. The resulting mixture was stirred at 40° C. for 30 min. The mixture was then 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.

[0309] Intermediate 30 Methyl 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylate

[0310] [ka]

[0311] 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.

[0312] Intermediate 31 2-(Cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid

[0313] [ka]

[0314] 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) instead of methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate to afford the title compound as a white solid.

[0315] Intermediate 32 (EZ)-4,4,4-Trifluorobutanal oxime

[0316] [ka]

[0317] Potassium carbonate (3.29 g, 23.8 mmol) was added to a mixture of 4,4,4-trifluorobutanal (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. The mixture was then 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.

[0318] Intermediate 33 Ethyl 3-(3,3,3-trifluoropropyl)isoxazole-4-carboxylate

[0319] [ka]

[0320] NCS (392 mg, 2.93 mmol) was added to a solution of (EZ)-4,4,4-trifluorobutanal oxime (394 mg, 2.79 mmol, intermediate 32) and chloroform (2 mL). The reaction mixture was stirred at room temperature for 3 h. Ethyl-3-(diethylamino)acrylate (400 mg, 2.79 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. At this point, the mixture was concentrated under reduced pressure. The residue was then dissolved in EtOAc (10 mL) and washed with water (10 mL) followed by brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The product was purified by preparative HPLC (Boston Green column, ODS150×30 mm×5 μm (eluent: 50%-80% (v / v) water / (0.2% formic acid)-ACN)), suspended in water (10 mL), frozen using dry ice / acetone, and then lyophilized to obtain the title compound.

[0321] Intermediate 34 3-(3,3,3-trifluoropropyl)isoxazole-4-carboxylic acid

[0322] [ka]

[0323] Sodium hydroxide (84 mg, 2.1 mmol) was added to a mixture of ethyl 3-(3,3,3-trifluoropropyl)isoxazole-4-carboxylate (100 mg, 0.42 mmol, Intermediate 33), HO (0.5 mL), and EtOH (2.5 mL). The mixture was stirred at room temperature for 3 h, then concentrated under reduced pressure, and the residue was diluted with water (10 mL). The mixture was acidified to pH 3 with 1N aqueous HCl, frozen using dry ice / acetone, and then lyophilized to give the title compound as a white solid.

[0324] Intermediate 35 tert-Butyl ((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0325] [ka]

[0326] 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). Hunig'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. After this time 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 Na.sub.2SO.sub.4, filtered and concentrated to give the title compound as a yellow foam.

[0327] Intermediate 36 N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide

[0328] [ka]

[0329] 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.

[0330] Intermediate 37 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

[0331] [ka]

[0332] 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). Hunig'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. After this time, the solution was cooled to room temperature and water and EtOAc were added. The layers were separated and the aqueous layer was extracted again with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC (XBridge C18, 40%-100% MeCN / NH4OH in water (20 mM)) to give the title compound as a white solid.

[0333] Intermediate 38 tert-Butyl ((S)-(7-((S)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0334] [ka]

[0335] 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 afford the title compound as a light orange-brown foam.

[0336] Intermediate 39 N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(3,3-difluorocyclobutyl)acetamide

[0337] [ka]

[0338] 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.

[0339] Intermediate 40 4-Methyl-1,2,5-oxadiazole-3-carbonyl chloride

[0340] [ka]

[0341] A mixture of 4-methyl-1,2,5-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.

[0342] Intermediate 41 N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide

[0343] [ka]

[0344] The title compound was prepared as described in the synthesis of Intermediate 28, 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. The crude residue was lyophilized to afford the title compound as an off-white solid.

[0345] Intermediate 42 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

[0346] [ka]

[0347] 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.

[0348] Intermediate 43 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0349] [ka]

[0350] The title compound was prepared as described in 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.

[0351] Intermediate 44 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0352] [ka]

[0353] The title compound was prepared as described in the synthesis of intermediate 19, using 1-isopropyl-1H-pyrazole-5-carboxylic acid instead of 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid.

[0354] Intermediate 45 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[0355] [ka]

[0356] The title compound was prepared as described in 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.

[0357] Intermediate 46 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide

[0358] [ka]

[0359] The title compound was prepared as described in 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.

[0360] Intermediate 47 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[0361] [ka]

[0362] The title compound was prepared as described in 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.

[0363] Intermediate 48 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0364] [ka]

[0365] The title compound was prepared as described in 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.

[0366] Intermediate 49 N-((S)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide

[0367] [ka]

[0368] The title compound was prepared as described in the synthesis of Intermediate 28, 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. The crude residue was lyophilized to afford the title compound as an off-white solid.

[0369] Intermediate 50 3-Cyclopropyl-N-((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)isoxazole-4-carboxamide

[0370] [ka]

[0371] The title compound was prepared as described for the synthesis of intermediate 29, using 3-cyclopropylisoxazole-4-carboxylic acid instead of 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid.

[0372] Intermediate 51 N-((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isoxazole-4-carboxamide

[0373] [ka]

[0374] The title compound was prepared as described for the synthesis of Intermediate 29, using 3-(3,3,3-trifluoropropyl)isoxazole-4-carboxylic acid (Intermediate 34) instead of 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid.

[0375] Intermediate 52 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

[0376] [ka]

[0377] 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.

[0378] Intermediate 53 N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluoro-3-methylbutanamide

[0379] [ka]

[0380] 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.

[0381] Intermediate 54 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

[0382] [ka]

[0383] 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 using 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid instead of 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid.

[0384] Intermediate 55 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

[0385] [ka]

[0386] 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 using 1-isopropyl-1H-1,2,4-triazole-5-carboxylic acid instead of 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid.

[0387] Intermediate 56 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

[0388] [ka]

[0389] 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 using 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 in examples 5 and 6.

[0390] Intermediate 57 N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)-3-fluoroimidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide

[0391] [ka]

[0392] To a vial with a stir bar was placed N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (200 mg, 0.44 mmol, Intermediate 41), Selectfluor™ (386 mg, 1.09 mmol), and MeCN (8 mL). The reaction was stirred for 1 h and proceeded to 60% conversion. The reaction was quenched by addition of water and extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude material was purified by preparative HPLC (XBridge® Prep, 5 μM, C18 OBD™, 50×100 mm, 0-100% acetonitrile / water (containing 20 mM NH4OH)). The product containing fractions were lyophilized to give the title compound as a white solid.

[0393] Intermediate 58 tert-Butyl ((1S)-(7-((1R)-cyclopropyl(2-(2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0394] [ka]

[0395] 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.

[0396] Intermediate 59 N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)-2-(2,2-difluorocyclopropyl)acetamide

[0397] [ka]

[0398] 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 afford the title compound as a yellow amorphous solid.

[0399] Intermediate 60 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

[0400] [ka]

[0401] 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 reaction was 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.

[0402] Intermediate 61 (9H-Fluoren-9-yl)methyl ((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-a]pyrimidin-7-yl)(cyclopropyl)methyl)carbamate hydrochloride

[0403] [ka]

[0404] 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, 1M 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.

[0405] Intermediate 62 (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

[0406] [ka]

[0407] 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-oxadiazole-3-carboxylic acid (550 mg, 4.3 mmol) followed by HATU (1.6 g, 4.3 mmol) and the resulting mixture was stirred at room temperature for 16 h. The reaction was then quenched by the addition of saturated aqueous NaHCO3 and extracted with EtOAc (3 x 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.

[0408] Intermediate 63 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

[0409] [ka]

[0410] Piperidine (0.58 g, 6.8 mmol) was added to a mixture of (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 (1.6 g, 2.3 mmol, intermediate 62) in DCM (15 mL) and 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, followed by 0-15% MeOH / EtOAc) followed by SFC (DAICEL CHIRALPAK AD, 30×250 mm, 10 mm, 60% EtOH(0.1% NH4OH) / CO2) to give the title compound as a white solid.

[0411] Intermediate 64 3-Fluorobicyclo[1.1.1]pentane-1-carbonyl chloride

[0412] [ka]

[0413] 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 oxalyl chloride (438 mg, 3.45 mmol) in DCM (1 mL). The resulting solution was stirred at room temperature for 2 h. The solvent was then removed under reduced pressure to give the title compound as a yellow oil.

[0414] Intermediate 65 2-Diazo-1-(3-fluorobicyclo[1.1.1]pentan-1-yl)ethan-1-one

[0415] [ka]

[0416] To a solution of 3-fluorobicyclo[1.1.1]pentane-1-carbonyl chloride (330 mg, 2.22 mmol, Intermediate 64) in ACN (2 mL) and THF (2 mL) was added (diazomethyl)trimethylsilane (2.22 mL, 4.44 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 h. The reaction was concentrated to dryness and then dissolved in Et2O and washed with 0.5 M aqueous citric acid, followed by saturated aqueous NaHCO3 (5 mL). The organic layer was concentrated to dryness to give the title compound as a yellow oil.

[0417] Intermediate 66 Ethyl 5-(pyrrolidin-1-yl)-4-(2,2,2-trifluoroethyl)-4,5-dihydroisoxazole-3-carboxylate

[0418] [ka]

[0419] 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 five portions at 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 carried on crude without further purification.

[0420] Intermediate 67 Ethyl 4-(2,2,2-trifluoroethyl)isoxazole-3-carboxylate

[0421] [ka]

[0422] mCPBA (180 mg, 1.1 mmol) was added to a solution of ethyl 5-(pyrrolidin-1-yl)-4-(2,2,2-trifluoroethyl)-4,5-dihydroisoxazole-3-carboxylate (190 mg, 0.66 mmol, Intermediate 66) in DCM (2.5 mL) at room temperature. The reaction was stirred at room temperature for 2 h and then quenched with a saturated aqueous solution of NaHCO3. The biphasic mixture was transferred to a separatory funnel and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. Purification by FCC (0-45% EtOAc / hexanes) afforded the title compound.

[0423] Intermediate 68 4-(2,2,2-trifluoroethyl)isoxazole-3-carboxylic acid

[0424] [ka]

[0425] Ethyl 4-(2,2,2-trifluoroethyl)isoxazole-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 starting material was completely consumed (ca. 1 h), at which point the reaction was acidified with 1N aqueous HCl and diluted with water (10 mL). The mixture was extracted with 20% IPA in CHCl3 (15 mL x 3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound as an off-white solid, which was used without further purification.

[0426] Working Example Example 1 N-((S)-(7-((R * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxamide

[0427] [ka]

[0428] Example 2 N-((S)-(7-((S * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxamide

[0429] [ka]

[0430] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)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 re-purified by preparative HPLC (XBridge C18, 10%-100% MeCN / NH4OH in water (20 mM)) to give Example 2 as a colorless solid. 1 H NMR(500MHz,DMSO-d6)δ 9.20(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,2H),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)δ 9.19(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,4H),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] + Actual value: 651.3.

[0431] Example 3 N-((S)-(7-((S)-cyclopropyl((R * )-4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)isonicotinamide

[0432] [ka]

[0433] Example 4 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

[0434] [ka]

[0435] 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), 21.2×250 mm, 30:70 i-PrOH / CO2 followed by CHIRALCEL OD-H, 30×250 mm, 9:91 i-PrOH(0.3% i-PrNH2) / CO2) to give a pair of diastereomers. The first eluting isomer was Example 3 and the second eluting isomer was Example 4. Example 3: 1 H NMR(600MHz,DMSO-d6)δ 9.09(d,J=9.0Hz,1H),8.87(d,J=6.9Hz,1H),8.76(d,J=7.6Hz,1H),8.74-8.70(m,1H),7.85(s,1H),7.83(s,1H),7.81(dd,J= 1.5,5.1Hz,1H),7.04(d,J=6.9Hz,1H),5.17(t,J=8.6Hz,1H),4.36-4.18(m,1H),3.89(q,J=11.4Hz,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=6.9Hz,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: 1H NMR(600MHz,DMSO-d6)δ 9.09(d,J=8.8Hz,1H),8.87(d,J=7.1Hz,1H),8.77(d,J=7.6Hz,1H),8.72(d,J=5.1Hz,1H),7.85(s,1H),7.83(s,1H),7.81(dd,J=1 .7,5.1Hz,1H),7.05(d,J=6.9Hz,1H),5.17(t,J=8.6Hz,1H),4.33-4.16(m,1H),3.89(q,J=11.4Hz,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=6.9Hz,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] + Actual value: 661.2.

[0436] Example 5 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

[0437] [ka]

[0438] Example 6 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

[0439] [ka]

[0440] 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-H 2×25 cm / 15% (2:1) heptane:IPA / CO2, 100 bar, 70 mL / min) to give two products (Examples 5 and 6), each a 1:1 mixture of two diastereomers. The first eluting material was Example 5 and the second eluting material was Example 6. Example 5: 1 H NMR(600MHz,DMSO-d6)δ 8.89(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=1.1 Hz,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: 1H NMR(600MHz,DMSO-d6)δ 8.87(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] + Actual value: 610.3.

[0441] Example 7 N-((S)-(7-((S)-cyclopropyl((S * )-4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isoxazole-4-carboxamide

[0442] [ka]

[0443] Example 8 N-((S)-(7-((S)-cyclopropyl((R * )-4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isoxazole-4-carboxamide

[0444] [ka]

[0445] N-((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isoxazole-4-carboxamide (Intermediate 51) was purified by SFC using a chiral stationary phase (CHIRALCEL OD-H, 5 μm, 250×30 mm, 91% CO 2 , 9% IPA (with 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. Both isomers were further purified by preparative HPLC (XBridge® Prep, 5 μM, C18 OBD™, 50×100 mm, 0-100% acetonitrile / water (with 20 mM NH4OH)). The product containing fractions were lyophilized to a white powder. Example 7: 1 H NMR(500MHz,DMSO-d6)δ 9.51(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),1.92-1.70(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: 1H NMR(500MHz,DMSO-d6)δ 9.51(s,1H),8.87(d,J=6.9Hz,1H),8.82-8.72(m,2H),7.81(s,1H),7.04(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] + Actual value: 665.3.

[0446] Example 9 3-Cyclopropyl-N-((S)-(7-((S)-cyclopropyl((S * )-4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)isoxazole-4-carboxamide

[0447] [ka]

[0448] Example 10 3-Cyclopropyl-N-((S)-(7-((S)-cyclopropyl((R * )-4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)isoxazole-4-carboxamide

[0449] [ka]

[0450] 3-Cyclopropyl-N-((1S)-(7-((1S)-cyclopropyl(4,4,4-trifluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)isoxazole-4-carboxamide (Intermediate 50) was purified by SFC using a chiral stationary phase (CHIRALCEL OD-H, 5 μm, 250×30 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)δ 9.36(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=7.0H) z,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,1H),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),1.3 5-1.18(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: 1H NMR(500MHz,DMSO-d6)δ 9.36(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] + Actual value: 609.3.

[0451] Example 11 Transformer - (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

[0452] [ka]

[0453] Example 12 Transformer - (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

[0454] [ka]

[0455] 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), 21.2×250 mm, 5 μm, 20:80 i-PrOH / CO2) to give a pair of diastereomers. The first eluting isomer was Example 11 and the second eluting isomer was Example 12. Example 11: 1 H NMR(500MHz,CDCl3)δ 8.35(d,J=6.9Hz,1H),7.41(s,1H),6.90(d,J=6.9Hz,1H),6.85-6.78(m,2H),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: 1H NMR(500MHz,CDCl3)δ 8.35(d,J=6.9Hz,1H),7.43(s,1H),7.30(d,J=8.8Hz,1H),7.04(d,J=7.9Hz,1H),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),2.60-2.45(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] + Actual value: 604.2.

[0456] Example 13 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

[0457] [ka]

[0458] The title compound was prepared as described in the synthesis of intermediate 37, using 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 23 h instead of 2 h, and the crude residue was purified by preparative HPLC (XBridge C18, 40%-100% MeCN / NH4OH in water (20 mM)) followed by SFC using a chiral stationary phase (CHIRALCEL OD-H, 21.2×250 mm, 5 μm, 20:80 MeOH / CO2) to give the title compound as a white solid. 1H NMR(500MHz,CDCl3)δ 8.33(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),2.5 0-2.46(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,3H),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] + Actual value: 605.2.

[0459] Example 14 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

[0460] [ka]

[0461] 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-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, 21.2×250 mm, 5 μm, 15:85 MeOH / CO2) to give the title compound as a cream-colored 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] + Actual value: 605.3.

[0462] Example 15 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

[0463] [ka]

[0464] The title compound was prepared as described in the synthesis of intermediate 37, 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 an additional aliquot of 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid (12 mg, 0.07 mmol) pre-stirred with EDCI (13 mg, 0.07 mmol), HOBt (9 mg, 0.07 mmol), DIPEA (13 μL, 0.08 mmol) and ACN (0.2 mL) was added after 3 h. 1 H NMR(400MHz,CDCl3)δ 8.33(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=2.5Hz,1H),2.8 2-2.69(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] + Actual value: 617.3.

[0465] Example 16 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

[0466] [ka]

[0467] 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 an additional aliquot of 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid (12 mg, 0.07 mmol) pre-stirred with EDCI (13 mg, 0.07 mmol), HOBt (9 mg, 0.07 mmol), DIPEA (13 μL, 0.08 mmol) and ACN (0.2 mL) was added after 3 h. 1H NMR(400MHz,CDCl3)δ 8.33(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),2.62-2.5 1(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] + Actual value: 617.2.

[0468] Example 17 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

[0469] [ka]

[0470] Example 18 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-isopropyl-1H-1,2,4-triazole-5-carboxamide

[0471] [ka]

[0472] 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 2×15 cm, 12% IPA (with 0.3% NPA)) in CO2 at 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)δ 8.90(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),2.36-2.28(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,1H),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)δ 8.89(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] + Actual value: 611.3.

[0473] Example 19 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

[0474] [ka]

[0475] Example 20 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

[0476] [ka]

[0477] 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 2×15 cm, 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)δ 8.90(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] + Found value: 623.3. Example 19: 1H NMR(500MHz,DMSO-d6)δ 8.90(d,J=7.0Hz,1H),8.87(d,J=9.1Hz,1H),8.78(d,J=7.8Hz,1H),8.11(s,1H),7.85(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,1H),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),1.69-1.59(m,1 H),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] + Actual value: 623.3.

[0478] Example 21 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

[0479] [ka]

[0480] 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 (51 mg, 0.35 mmol, Intermediate 40). The resulting mixture was stirred at 0° C. for 45 min, then removed from the ice bath and allowed to warm to room temperature over 19 h. The mixture was then cooled to 0° C. and quenched with water. EtOAc (20 mL) was then added and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL) and the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (XBridge C18, 40%-100% MeCN / NH4OH in water (20 mM)) to give the title compound as a cream-colored solid. 1 H NMR(400MHz,CDCl3)δ 8.35(d,J=6.9Hz,1H),7.70(d,J=8.9Hz,1H),7.47(s,1H),6.90(d,J=6.9Hz,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] + Actual value: 578.2.

[0481] Example 22 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

[0482] [ka]

[0483] 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)δ 8.35(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,3 H),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] + Actual value: 578.2.

[0484] Example 23 N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide

[0485] [ka]

[0486] 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. 1 H NMR(400MHz,CDCl3)δ 8.35(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,3H),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 value: 570.1.

[0487] Example 24 3-Cyclopropyl-N-((S)-(7-((R)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)isoxazole-4-carboxamide

[0488] [ka]

[0489] The title compound was prepared as described in the synthesis of intermediate 37, using 3-cyclopropyl-1,2-oxazole-4-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. 1 H NMR(500MHz,CDCl3)δ 8.76(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,1 H),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] + Actual value: 603.2.

[0490] Example 25 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

[0491] [ka]

[0492] 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. The mixture was stirred at 40° C. for 23 h instead of 2 h. 1 H NMR(500MHz,CDCl3)δ 8.73(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] + Actual value: 655.2.

[0493] Example 26 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)isoxazole-4-carboxamide

[0494] [ka]

[0495] The title compound was prepared as described in the synthesis of Intermediate 37 using 3-(3,3,3-trifluoropropyl)isoxazole-4-carboxylic acid (Intermediate 34) instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. 1 H NMR(500MHz,CDCl3)δ 8.76(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),2.81-2. 69(m,2H),2.67-2.53(m,3H),2.49-2.45(m,2H),2.33-2.24(m,2H),2.19-1.97(m,4H),1.84-1.63(m ,3H),1.55-1.47(m,1H),1.37-1.29(m,1H),1.22-1.15(m,1H),0.64-0.58(m,3H),0.54-0.48(m,1H). MS(ESI)m / z:[M+H] + Actual value: 659.2.

[0496] Example 27 3-Cyclopropyl-N-((S)-(7-((S)-cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)isoxazole-4-carboxamide

[0497] [ka]

[0498] 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 3-cyclopropyl-1,2-oxazole-4-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. 1 H NMR(500MHz,CDCl3)δ 8.75(s,1H),8.35(d,J=6.9Hz,1H),7.47(s,1H),7.13(d,J=8.6Hz,1H),6.90(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] + Actual value: 603.2.

[0499] Example 28 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

[0500] [ka]

[0501] 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 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. 1 H NMR(500MHz,CDCl3)δ 8.73(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] + Actual value: 655.2.

[0502] Example 29 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)isoxazole-4-carboxamide

[0503] [ka]

[0504] 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 3-(3,3,3-trifluoropropyl)isoxazole-4-carboxylic acid (Intermediate 34) instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. 1 H NMR(500MHz,CDCl3)δ 8.76(s,1H),8.36(d,J=6.9Hz,1H),7.46(s,1H),6.96(d,J=8.6Hz,1H),6.92(d,J=6.9Hz,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),2.81-2.71(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),1.81-1.6 4(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] + Actual value: 659.2.

[0505] Example 30 N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-3-(3,3,3-trifluoropropyl)isoxazole-4-carboxamide

[0506] [ka]

[0507] 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 using 3-(3,3,3-trifluoropropyl)isoxazole-4-carboxylic acid (intermediate 34) instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. The mixture was stirred at 40° C. for 4.5 hours instead of 2 hours. 1 H NMR(500MHz,CDCl3)δ 8.77(s,1H),8.37(d,J=6.9Hz,1H),7.46(s,1H),7.05(d,J=8.4Hz,1H),6.93(d,J=7.0 Hz,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),1.54-1. 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] + Actual value: 651.2.

[0508] Example 31 N-((S)-(7-((S)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxamide

[0509] [ka]

[0510] To a vial with a stir bar was placed N-((S)-(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 minutes and then EDCI (33 mg, 0.17 mmol) and Hunig's base (0.042 mL, 0.25 mmol) were added and the reaction was stirred at 40° C. for 30 minutes. 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 concentrated to give a glassy solid. The crude material was purified by FCC (0-100% (10% MeOH in EtOAc) / Hexanes). The product containing fractions were concentrated, taken up in minimal MeCN:water and lyophilized to give the title compound as a white powder. 1H NMR(500MHz,DMSO-d6)δ 8.88(d,J=7.0Hz,1H),8.71(d,J=7.6Hz,1H),8.41(d,J=9.0Hz,1H),8.19(s,1H),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] + Actual value: 609.3.

[0511] Example 32 N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide

[0512] [ka]

[0513] 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 using 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid instead of 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid. The material was further purified by preparative HPLC (XBridge® Prep, 5 μM, C18 OBD™, 50×100 mm, 0-100% acetonitrile / water (containing 20 mM NH4OH)) to provide the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.97-8.81(m,2H),8.72(d,J=7.8Hz,1H),8.10(s,1H),7.84(s,1H),7.06(d,J=7.0 Hz,1H),5.10(t,J=8.6Hz,1H),4.52-4.37(m,2H),4.28(dd,J=7.8,8.8Hz,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] + Actual value: 609.2.

[0514] Example 33 N-((S)-(7-((S)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxamide

[0515] [ka]

[0516] 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. The material was further purified by preparative HPLC (XBridge® Prep, 5 μM, C18 OBD™, 50×100 mm, 0-100% acetonitrile / water (containing 20 mM NH4OH)) to provide the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.94-8.83(m,2H),8.72(d,J=7.8Hz,1H),8.10(s,1H),7.84(s,1H),7.06(d,J=7.0 Hz,1H),5.10(t,J=8.5Hz,1H),4.51-4.36(m,2H),4.30(dd,J=8.0,8.6Hz,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] + Actual value: 609.3.

[0517] Example 34 N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxamide

[0518] [ka]

[0519] 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. 1 H NMR(500MHz,DMSO-d6)δ 8.88(d,J=7.0Hz,1H),8.72(d,J=7.6Hz,1H),8.41(d,J=9.1Hz,1H),8.19(s,1H),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] + Actual value: 609.3.

[0520] Example 35 N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)-3-fluoroimidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0521] [ka]

[0522] 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 using 1-isopropyl-1H-pyrazole-5-carboxylic acid instead of 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid. 1 H NMR(500MHz,DMSO-d6)δ 8.81(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),1.65-1.57(m,1 H),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] + Actual value: 614.3.

[0523] Example 36 3-Cyclopropyl-N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)isoxazole-4-carboxamide

[0524] [ka]

[0525] 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 using 3-cyclopropylisoxazole-4-carboxylic acid instead of 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid. 1 H NMR(500MHz,DMSO-d6)δ 9.36(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),1.34-1.2 4(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] + Actual value: 595.2.

[0526] Example 37 3-Cyclopropyl-N-((S)-(7-((S)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)isoxazole-4-carboxamide

[0527] [ka]

[0528] The title compound was prepared as described in the synthesis of Example 31, using 3-cyclopropylisoxazole-4-carboxylic acid instead of 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid. 1 H NMR(500MHz,DMSO-d6)δ 9.35(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,1H),7.04(d,J=7.0 Hz,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] + Actual value: 595.3.

[0529] Example 38 N-((S)-(7-((S * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0530] [ka]

[0531] Example 39 N-((S)-(7-((R *)-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0532] [ka]

[0533] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)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), 25×2 cm; 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)δ 8.87(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,1H),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: 1H NMR(500MHz,DMSO-d6)δ 8.86(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),2.8 8-2.76(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] + Actual value: 664.2.

[0534] Example 40 N-((S)-(7-((S * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[0535] [ka]

[0536] Example 41 N-((S)-(7-((R * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[0537] [ka]

[0538] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)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, 25×2 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 H NMR(500MHz,DMSO-d6)δ 8.88(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] + Found value: 651.1. Example 41: 1 H NMR(500MHz,DMSO-d6)δ 8.87(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,1H),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]+ Actual value: 651.1.

[0539] Example 42 N-((S)-(7-((S * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide

[0540] [ka]

[0541] Example 43 N-((S)-(7-((R * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide

[0542] [ka]

[0543] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)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, 25×2 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: 1H NMR(500MHz,DMSO-d6)δ 8.88(d,J=6.9Hz,1H),8.73(d,J=7.6Hz,1H),7.99(d,J=9.2Hz,1H),7.91(d,J=2.4H z,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)δ 8.88(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),1.9 2-1.65(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] + Actual value: 650.3.

[0544] Example 44 N-((S)-(7-((S * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[0545] [ka]

[0546] Example 45 N-((S)-(7-((R * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[0547] [ka]

[0548] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)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, 25×2 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)δ 8.86(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=8.6Hz,1H),4.3 0-4.22(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: 1H NMR (500MHz, DMSO-d6) δ 8.86(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] + Actual value: 568.3.

[0549] Example 46 N-((S)-(7-((S * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0550] [ka]

[0551] Example 47 N-((S)-(7-((R * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0552] [ka]

[0553] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)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), 25×2 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 H NMR(600MHz,DMSO-d6)δ 8.88(d,J=6.9Hz,1H),8.74-8.70(m,2H),7.81(s,1H),7.50(d,J=2.0Hz,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] + Found value: 596.3. Example 47: 1 H NMR(500MHz,DMSO-d6)δ 8.87(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,1H),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] + Actual value: 596.3.

[0554] Example 48 N-((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)isonicotinamide

[0555] [ka]

[0556] 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 using 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. The mixture was stirred at 40° C. for 21 hours instead of 2 hours. 1 H NMR(500MHz,CDCl3)δ 8.76-8.70(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] + Actual value: 647.2.

[0557] Example 49 N-((S)-(7-((S * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0558] [ka]

[0559] Example 50 N-((S)-(7-((R * )-Cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0560] [ka]

[0561] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)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, 25×3 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: 1H NMR (400MHz, DMSO-d6) δ 8.86(d,J=6.8Hz,1H),8.73(d,J=7.7Hz,1H),8.40-8.28(m,2H),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) δ 8.86(d,J=6.7Hz,1H),8.72(d,J=7.7Hz,1H),8.40-8.27(m,2H),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] + Actual value: 650.3.

[0562] Example 51 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

[0563] [ka]

[0564] Example 52 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

[0565] [ka]

[0566] 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) was added TCFH (80 mg, 0.28 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (30 mg, 0.24 mmol) and 1-methylimidazole (0.1 mL, 1.25 mmol) and the resulting mixture was stirred at room temperature for 30 min. The mixture was then poured into water (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 exposed silica, 0.2% / 98% / 2% NH4OH / DCM / MeOH). This material was further purified by achiral SFC (AMINO 6 mm, 250×21.2 mm, 12:88 MeOH (0.3% i-PrNH2) / CO2) followed by SFC using a chiral stationary phase (Whelk-O1(S,S), 21.2×250 mm, 5 mm, 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)d 8.35(d,J=6.9Hz,1H),7.70(d,J=9.0Hz,1H),7.47(s,1H),6.91(d,J=6.9Hz,1H),6.87(d,J=7. 8Hz,1H),5.21(dd,J=9.0,7.8Hz,1H),4.62(t,J=8.2Hz,1H),2.60(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] + Found value: 564.2. Example 52: 1 H NMR(500MHz,CDCl3)d 8.34(d,J=6.9Hz,1H),7.70(d,J=9.0Hz,1H),7.47(s,1H),6.91(d,J=6.9Hz,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] + Actual value: 564.2.

[0567] Example 53 N-((S)-(7-((R)-cyclopropyl(2-((S * )-2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methylisoxazole-3-carboxamide

[0568] [ka]

[0569] Example 54 N-((S)-(7-((R)-cyclopropyl(2-((R * )-2,2-difluorocyclopropyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methylisoxazole-3-carboxamide

[0570] [ka]

[0571] Examples 53 and 54 were 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)-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-(2,2-difluorocyclopropyl)acetamide (Intermediate 59) and using 4-methylisoxazole-3-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. A pure mixture of diastereomers (Examples 53 and 54) was separated by SFC using a chiral stationary phase (Whelk-O1(S,S), 21.2×250 mm, 5 mm, 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: 1H NMR(400MHz,CDCl3)δ 8.33(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: 1 H NMR(400MHz,CDCl3)δ 8.33(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] + Actual value: 563.2.

[0572] Example 55 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

[0573] [ka]

[0574] Example 56 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

[0575] [ka]

[0576] Examples 55 and 56 were 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)-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-(2,2-difluorocyclopropyl)acetamide (Intermediate 59) 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 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), 21.2×250 mm, 5 mm, 25:75 i-PrOH (0.3% i-PrNH2) / CO2). The first eluting isomer was Example 56, and the second eluting isomer was Example 55. Example 55: 1H NMR(400MHz,CDCl3)δ 8.33(d,J=6.9Hz,1H),8.13(d,J=9.3Hz,1H),7.85(s,1H),7.47(s,1H),6.90(dd,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: 1 H NMR(400MHz,CDCl3)δ 8.33(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),2.4 2-2.34(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,4H),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] + Actual value: 603.2.

[0577] Example 57 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)isoxazole-4-carboxamide

[0578] [ka]

[0579] Example 58 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)isoxazole-4-carboxamide

[0580] [ka]

[0581] Examples 57 and 58 were 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)-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-(2,2-difluorocyclopropyl)acetamide (Intermediate 59) and using 3-(trifluoromethyl)isoxazole-4-carboxylic acid instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. Examples 57 and 58 were separated by SFC using a chiral stationary phase (Whelk-O1(S,S), 21.2×250 mm, 5 mm, 15:85 EtOH / CO2). The second eluting diastereomer (Example 57) was re-purified by SFC using a chiral stationary phase (Whelk-O1(S,S), 21.2×250 mm, 5 mm, 15:85 EtOH / CO2). The first eluting isomer was Example 58 and the second eluting isomer was Example 57. Example 57: 1H NMR(400MHz,CDCl3)δ 9.03-8.96(m,1H),8.36(d,J=6.9Hz,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),1.61-1.5 0(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] + Found value: 617.2. Example 58: 1 H NMR(400MHz,CDCl3)δ 9.01-8.95(m,1H),8.36(d,J=6.9Hz,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),1.67-1.6 4(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] + Actual value: 617.2.

[0582] Example 59 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

[0583] [ka]

[0584] To a solution of 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-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, 30×75 mm, 3 mm, 40-70% ACN / water (0.05% NH4OH+10 mM NH4HCO3)) to give the title compound. 1 H NMR(400MHz,CDCl3)d 8.34(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,1H),4.60(t ,J=8.4Hz,1H),2.65-2.53(m,5H),2.04(d,J=2.4Hz,10H),1.83-1.66(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] + Actual value: 572.2.

[0585] Example 60 N-((S)-(7-((R)-cyclopropyl((S)-4,4-difluoro-3-methylbutanamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide

[0586] [ka]

[0587] The title compound was prepared as described in the synthesis of Intermediate 37, using 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 (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 using (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 × 75 mm, 3 mm, 40-70% ACN / water (0.05% NH4OH + 10 mM NH4HCO3)) to give the title compound. 1 H NMR (400MHz, CDCl3) δ 8.37(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] + Actual value: 566.4.

[0588] Example 61 N-((S)-(7-((R)-cyclopropyl(2-((1r,3S)-3-fluorocyclobutyl)acetamido)methyl)imidazo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide

[0589] [ka]

[0590] The title compound was prepared as described in the synthesis of Intermediate 37, using 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 (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 using 2-((1r,3s)-3-fluorocyclobutyl)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 × 75 mm, 3 mm, 35-65% ACN / water (0.05% NH4OH + 10 mM NH4HCO3)) to give the title compound. 1 H NMR(400MHz,CDCl3)d 8.37(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,1H),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] +Actual value: 560.4.

[0591] Example 62 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

[0592] [ka]

[0593] The title compound was prepared as described for the synthesis of intermediate 37, using 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (CAS1083246-26-7) instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. The solution was stirred at room temperature for 30 min instead of 2 h at 40° C. The crude material was purified by preparative HPLC (Boston Green ODS, 150×30 mm, 5 mm, 10-40% ACN / water (0.05% NH4OH)) to give the title compound. 1 H NMR(400MHz,DMSO-d6)d 9.50(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),0.99-0.93(m,2H),0.57-0.43(m,3H),0.43-0.35(m,1H). MS(ESI)m / z:[M+H] + Actual value: 604.2.

[0594] Example 63 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)isoxazole-3-carboxamide

[0595] [ka]

[0596] The title compound was prepared as described for the synthesis of Intermediate 37, using 4-(2,2,2-trifluoroethyl)isoxazole-3-carboxylic acid (Intermediate 68) instead of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid and DCM instead of ACN. The solution was stirred at room temperature for 30 min instead of 2 h at 40° C. The crude material was purified by preparative HPLC (Boston Green ODS, 150×30 mm, 5 mm, 10-40% ACN / water (0.05% NH4OH)) to give the title compound. 1 H NMR(400MHz,DMSO-d6)d 9.20-9.11(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] + Actual value: 645.4.

[0597] In vitro biological data IL-17A (FLAG-tagged):IL-17RA (His-tagged) binding disruption Eu-HTRF assay An antibody against the FLAG tag of IL-17A (SEQ ID NO:1) is labeled with an HTRF donor chromophore (Europium-cryptate). IL-17A exists as a dimer and is "locked" into this quaternary structure by the formation of an intramolecular disulfide bridge spanning the loop. 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). An antibody against the His tag of the IL-17RA chimera is labeled with an HTRF acceptor chromophore ("D2"). Fluorescence resonance energy transfer (FRET) depends on the proximity of the donor chromophore to the acceptor, and FRET is reduced / eliminated when binding between IL-17A and IL-17RA is disrupted. Thus, this assay allows the evaluation of the effect of compounds on binding of IL-17A and IL-17RA by monitoring donor vs. acceptor fluorescence intensity. The assay is performed as follows:

[0598] 40 nL of 2-fold serially diluted compound solution for a total of 22 dilution points is added to each well of a 1536-well, white, low volume, non-binding plate (Greiner #782904), then 2 μL of FLAG-tagged IL-17A at 2x the final concentration (2.5 nM) in a solution of PBS + 0.01% Triton-X100 is added to each well. The assay plate is briefly centrifuged and then incubated at room temperature for 1 hour. A mixture solution containing 2x 5 nM 10HISxIL-17RA, 2x 2.5 nM Eu-anti-FLAG (CISBIO), 2x 5 nM D2-anti-HIS (CISBIO) is prepared in PBS + 0.01% Triton-X100 + 200 mM potassium fluoride (Sigma 60238) and 2 μL of the mixture is added to each well of the assay plate. The plate is briefly centrifuged and then incubated at room temperature for 2 hours. The HTRF intensities at donor (620 nm) and acceptor (665 nm) wavelengths are measured using a BMG Pherastar. The ratio of the intensities at the two wavelengths is calculated and plotted against compound concentration, and the data is fitted to a one-site competition model to determine the IC of the compounds. 50 Request.

[0599] IL-17A acts directly on keratinocytes through binding to the dimeric receptor IL-17RA / RC, promoting the production of multiple inflammatory mediators known to be elevated in psoriatic lesional tissue. IL-17A small molecule inhibitors that block the interaction between IL-17A and IL-17R can block IL-17A signaling in target cells such as keratinocytes. The functional activity of compounds is evaluated for their effect on IL-17A-induced G-CSF production in human normal keratinocytes (NHK).

[0600] NHK assay Adult normal human keratinocytes are cultured in Keratinocyte Growth Medium (Lonza) in flasks to approximately 90% confluence, after which the cells are transferred to 384-well plates at a density of 3000-4000 cells / well. Recombinant human IL-17A (Gibco PHC9174) is pre-incubated with titrated compounds or DMSO for 1 h at room temperature and then added to the cell culture plate. The final concentration of IL-17A is 5 ng / mL and DMSO is 0.2% in culture medium containing 5% FBS. The cells are cultured / treated for 24 h at 37 °C. The supernatant is collected and G-CSF production is measured by HTRF technique using a human G-CSF kit (CisBio). G-CSF concentrations are extrapolated from the standard curve and IC was calculated using GraphPad Prism. 50 Cell viability is also assessed using a CellTiter-Glo kit (Promega) and the effect of compounds on cell viability is compared to a DMSO control.

[0601] If compounds were tested multiple times, the ICs shown 50 The value is a simple average of the measured values.

[0602] [Table 5-1]

[0603] [Table 5-2]

[0604] The foregoing specification, together with examples given for purposes of illustration, teaches the principles of the invention, but it will be understood that the practice of the invention encompasses all ordinary modifications, adaptations and / or alterations that come within the scope of the following claims and equivalents thereof.

[0605] All documents cited are incorporated herein by reference.

[0606] SEQ ID NO:1 Name:IL-17A-Flag MATGSRTSLLLAFGLLCLPWLQEGSAGSDYKDDDDKGSGSGSLEVLFQGPGITIPRNPGCPNSEDKNFPRTVMVNLNIHNRNTNTNPKRSSDYYNRSTSPWNLHRNEDPERYPSVIWEAQCRHLGCINADGNVDYHMNSVPIQQEILVLRREPPHCPNSFRLEKILVSVGCTCVTPIVHHVQ

[0607] SEQ ID NO:2 Name:IL-17RA MKFLVNVALVFMVVYISYIYALRLLDHRALVCSQPGLNCTVKNSTCLDDSWIHPRNLTPSSPKDLQIQLHFAHTQQGDLFPVAHIEWTLQTDASILYLEGAELSVLQLNTNERLCVRFEFLSKLRHHHRRWRFTFSHFVVDPDQEYEVTVHHLPKPIPDGD PNHQSKNFLVPDCEHARMKVTTPCMSSGSLWDPNITVETLEAHQLRVSFTLWNESTHYQILLTSFPHMENHSCFEHHIPAPRPEEFHQRSNVTLTLRNLKGCCRHQVQIQPFFSSCLNDCLRHSATVSCPEMPDTPEPIPDYMPLWGSGGHHHHHHHHHH * The present invention includes the following embodiments. [Claim 1] Formula I: [ka] [In the formula, R 1 -C (1~6) Alkyl or -C (0~3) Alkyl C (3~6) is cycloalkyl, Said-C (1~6) Alkyl and the -C (0~3) Alkyl C (3~6) Cycloalkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R 2 -C (3~5) is cycloalkyl, R 3 -C (0~1) Alkyl C (3~6) cycloalkyl, (0~1) Alkyl C (3~6) Cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 4 -C (3~4) cycloalkyl or 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S; Said C (3~4) Cycloalkyl is unsubstituted or has 1 to 3 R 4a is substituted with a group, The 5- to 6-membered heteroaryl is unsubstituted or has one or two R 4b is substituted with a group, Each R 4a The group is an unsubstituted -C (1~4) -C substituted with alkyl or 1 to 6 fluorine atoms (1~4) independently selected from alkyl, Each R 4b The group is -C (0~2) Alkyl C (3~4) Cycloalkyl or -C (1~5) alkyl, (0~2) Alkyl C (3~4) Cycloalkyl and -C (1~5) Alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R 5 is H or F, During the ceremony, R 4 Ga-C (3~4) When cycloalkyl, the compound of formula I has formula Ia:

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Claims

1. Formula I: 【Chemistry 1】 [In the formula, R １ is -C （１～６） Alkyl or -C （０～３） Alkyl C （３～６） is cycloalkyl, Said-C （１～６） Alkyl and the -C （０～３） Alkyl C （３～６） cycloalkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R ２ is -C （３～５） is cycloalkyl, R ３ is -C （０～１） Alkyl C （３～６） cycloalkyl, and said -C （０～１） Alkyl C （３～６） cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R ４ is -C （３～４） cycloalkyl or a 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S; Said C （３～４） Cycloalkyl is unsubstituted or has 1 to 3 R ４ａ is substituted with a group, The 5- to 6-membered heteroaryl is unsubstituted or has one or two R ４ｂ is substituted with a group, Each R ４ａ The group is an unsubstituted -C （１～４） Alkyl or -C substituted with 1 to 6 fluorine atoms （１～４） independently selected from alkyl, Each R ４ｂ The group is -C （０～２） Alkyl C （３～４） Cycloalkyl or -C （１～５） alkyl, （０～２） Alkyl C （３～４） Cycloalkyl and -C （１～５） Alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R ５ is H or F, During the ceremony, R ４ Ga-C （３～４） When cycloalkyl, the compound of formula I has formula Ia: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

2. R １ But, -C （１～６） Alkyl or -C （０～３） Alkyl C （３～６） is cycloalkyl, Said-C （１～６） Alkyl and the -C （０～３） Alkyl C （３～６） cycloalkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R ２ But, -C （３～５） is cycloalkyl, R ３ But, -C （０～１） Alkyl C （３～６） cycloalkyl, and said -C （０～１） Alkyl C （３～６） cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R ４ is a 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S; The 5- to 6-membered heteroaryl is unsubstituted or has one or two R ４ｂ is substituted with a group, Each R ４ｂ The group is -C （０～２） Alkyl C （３～４） Cycloalkyl or -C （１～５） alkyl, （０～２） Alkyl C （３～４） Cycloalkyl and -C （１～５） alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; R ５ is H or F; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

3. R ５ is H, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

4. R １ But, -C （１～４） is alkyl, Said-C （１～４） Alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

5. R １ But, C （１～２） Alkyl C （３～５） cycloalkyl, and said -C （１～２） Alkyl C （３～５） cycloalkyl is unsubstituted or substituted with 1 to 3 fluorine atoms; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

6. R １ but, 【Chemistry 4】 2. The compound of claim 1, wherein:

7. R ２ is cyclopropyl, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

8. R ３ but, 【Chemistry 5】 2. The compound of claim 1, wherein:

9. R ４ is pyridinyl, said pyridinyl being unsubstituted or （１～２） is substituted with alkyl, （１～２） 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms.

10. R ４ is unsubstituted or has one or two R ４ｂ pyrazolyl, triazolyl, isoxazolyl, or oxadiazolyl substituted with a group; Each R ４ｂ The group is -C （０～１） Alkyl C （３） Cycloalkyl or -C （１～３） alkyl, （０～１） Alkyl C （３） Cycloalkyl and -C （１～３） Alkyl is unsubstituted or substituted with 1 to 4 fluorine atoms; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

11. R ４ is unsubstituted or has one or two R ４ｂ 2. The compound according to claim 1, which is 1H-pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, isoxazol-4-yl, or 1,2,5-oxadiazolyl substituted with a group, or a pharma- ceutically acceptable salt thereof.

12. R ４ but, 【Chemistry 7A】 2. The compound of claim 1, wherein:

13. R ４ but, 【Chemistry 9】 13. The compound of claim 12, wherein:

14. R ４ but, 【Chemistry 10】 13. The compound of claim 12, wherein:

15. R ４ but, 【Chemistry 12】 13. The compound of claim 12, wherein:

16. R ４ But, -C （３） is cycloalkyl, Said C （３） Cycloalkyl is unsubstituted or has 1 to 3 R ４ａ is substituted with a group, Each R ４ａ The group is an unsubstituted —C （１～２） Alkyl or -C substituted with 1 to 3 fluorine atoms （１～２） independently selected from alkyl, The compound of formula (I) has the formula (Ia): 【Chemistry 13】 is a compound of 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

17.

19. 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 2. The compound of claim 1 selected from:

18. 【Chemical 25A】 18. The compound of claim 17 selected from:

19.

26. 20. The compound of claim 18, wherein:

20. 【Catalogue 27】 20. The compound of claim 18, wherein:

21. 【Catalogue 28】 20. The compound of claim 18, wherein:

22. 【Catalogue 29】 20. The compound of claim 18, wherein:

23. 【Chemical 30】 20. The compound of claim 18, wherein:

24. 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

25. A pharmaceutical composition for treating or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising a compound according to any one of claims 1 to 23 or a pharma- ceutically acceptable salt thereof.

26. 26. The pharmaceutical composition of claim 25, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

27. 27. The pharmaceutical composition of claim 26, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriasis.

28. 27. The pharmaceutical composition of claim 26, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

29. 27. The pharmaceutical composition of claim 26, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

30. 27. The pharmaceutical composition of claim 26, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

31. The pharmaceutical composition of claim 25, wherein the compound, or a pharma- ceutically acceptable salt thereof, is administered orally.

32. The pharmaceutical composition of claim 31, wherein the compound, or a pharma- ceutically acceptable salt thereof, is administered as a tablet or capsule. 【Request 33】 【Chemical 100】 20. The compound of claim 18, wherein:

34. 【Chemical 101】 20. The compound of claim 18, wherein:

35. 【Chemical 102】 20. The compound of claim 18, wherein:

36. 【Chemical 103】 20. The compound of claim 18, wherein:

37. 【Catalogue 104】 20. The compound of claim 18, wherein:

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