Imidazopyridazine IL-17 inhibitor compounds

Abstract

The present application relates to a compound of the formula: [Formula 1] TIFF2024536869000482.tif26128[where, R 1 , R 2 , R 3 , and R 4 or a pharma- ceutically acceptable salt thereof, as well as methods of making and using the compounds disclosed herein to treat or ameliorate syndromes, disorders, and / or diseases mediated by IL-17.

Description

[Technical Field]

[0001] (Claim the benefit of a provisional application) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 248,566, filed September 27, 2021, U.S. Provisional Patent Application No. 63 / 273,422, filed October 29, 2021, and U.S. Provisional Patent Application No. 63 / 367,546, filed July 1, 2022.

[0002] (Reference to electronically submitted sequence listing) This application contains a Sequence Listing that has been submitted electronically as a Sequence Listing in ST.26 XML format with the file name "PRD4156WOPCT1_SL," created on July 1, 2022, and having a size of 3 KB. This submitted Sequence Listing is a part of the present specification and is incorporated by reference herein in its entirety.

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

[0004] Interleukin-17 (IL-17), also known as IL-17A, and CTLA-8 are primarily produced 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 as 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 nonhematopoietic cells (Gaffen, S. Structure and signaling in the IL-17 receptor family. Nat. Rev. Immunol. 2009, 9, 556-567). IL-17A / IL-17R signaling induces de novo gene transcription by inducing NF-kB, C / EBP, and MAPK pathways via the ACT1-TRAF6-TRAF4 complex. This 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, including IL-6, IL-8, G-CSF, TNF-α, and IL-1β, which recruit and activate lymphocytes to sites of injury or inflammation and maintain a pro-inflammatory state.

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

[0006] In the case of psoriasis: IL-17A mRNA and / or protein levels are elevated in the lesional skin and blood of patients with psoriasis and correlate with disease severity. IL-17A directly synergizes with other cytokines (such as TNFα, IFNγ, or IL-22) in keratinocytes, triggering a self-amplifying inflammatory response in the skin and leading to the formation of psoriatic plaques. Blockade of IL-17A with antibodies against IL-17A or IL-23 resulted in a complete reversal of molecular and clinical disease features in the majority of psoriasis patients, highlighting the important role of IL-17A and IL-17-producing T cells in the immunopathogenesis of psoriasis. (Hawkes et al., Psoriasis Pathogenesis and the Development of Novel Targeted Immune Therapies. J Allergy Clin Immunol. 2017, 140(3):645-653). The development and approval of IL-17 monoclonal antibodies, such as secukinumab, ixekizumab, and brodalumab, and their transformative efficacy against psoriasis, demonstrate 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 induces the transcription of several PsA-associated genes, including receptor activator of nuclear factor κB ligand (RANKL). RANKL induces the differentiation of osteoclast precursor cells into activated osteoclasts, leading to bone resorption and subsequent joint deformity in PsA (Adamopoulos I. and Mellins E. Nature reviews Rheumatology 2015;11:189-94). PsA joints are enriched in IL-17+CD8+ T cells, and levels of this T cell subset correlate with disease activity (Menon B. et al., Arthritis & Rheumatology 2014;66:1272-81). Synovial fibroblasts isolated from patients with PsA also contain elevated IL-17R expression ex vivo and secrete increased IL-6, CXCL8, and MMP3 compared with patients with osteoarthritis. Secukinumab and ixekizumab are both FDA-approved drugs for PsA. In matched-adjusted indirect comparison analyses, secukinumab was associated with higher ACR20 / 50 / 70 response rates than anti-TNFα antibodies in patients with active PsA (Mease P. et al., Eur. J. Rheumatol. 2019 Jul 1;6(3):113-121; Strand V. et al., J. Comp. Eff. Res. 2019,8(7):497-510; Nash P. et al., Rheumatol. Ther. 2018,5(1):99-122). In a recent head-to-head study, ixekizumab was superior to adalimumab in achieving simultaneous improvement in joint and skin disease (ACR50 and PASI100) in patients with PsA and inadequate response to conventional synthetic disease-modifying antirheumatic drugs (Mease, P. et al. Ann Rheum Diss 2020;79:123-131). By attacking the same target, IL-17A small molecule inhibitor compounds may exhibit similar or better efficacy than biologics, where small molecules are generally thought to have better tissue penetration.

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

[0009] In the case of ankylosing spondylitis (AS): Various studies have reported an increase in IL-17A and Th17, as well as other cells that produce IL-17, in AS blood samples (Wendling D. et al., Joint Bone Spine. 2007; 74: 304-305; Shen H. et al., Arthritis Rheum. 2009; 60(6): 1647-56; Zhang L. et al., PLoS One. 2012; 7(4): e31000; Jansen D. et al., Rheumatology (Oxford). 2015 Apr; 54(4): 728-735). In situ analysis of AS spines has revealed an increase in IL-17A-producing cells in the bone of the facet (articular process) joints (Appel H. et al., Arthritis Res. Ther. 2011;13(3):R95). Two leading IL-17A-neutralizing antibodies, secukinumab and ixekizumab, both approved by the FDA for AS, have demonstrated efficacy over placebo, even in anti-TNF inadequate responders. In contrast, anti-IL-23 p40 and anti-IL-23 p19 biologics failed to demonstrate beneficial effects (Deodhar A. et al., Arthritis Rheumatol. 2019, 71(2):258-270; Baeten D. et al., Ann. Rheum. Dis. 2018, 77(9):1295-1302), indicating differential 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] Hidradenitis suppurativa (HS): Increased levels of IL-17 and IL-17-producing T helper cells have been reported in skin lesions of HS patients, and molecular proteomics and gene expression data indicate that the IL-23 / Th17 pathway is upregulated in HS lesions (Schlapbach C. et al., J. Am. Acad. Dermatol. 2011;65(4):790; Kelly G. et al., British J. Dermatol. 2015 Dec;173(6):1431-9; Moran B. et al., J. Invest. Dermatol. 2017;137(11):2389; Thomi R. et al., JAMA Dermatol. 2018;154(5):592). Seven out of nine (78%) patients with moderate to severe HS achieved HiSCR in an open-label pilot study with secukinumab (Prussick L. et al., British J. Dermatol. 2019 Sep;181(3):609-611), and further clinical trials with anti-IL-17 mAbs in HS are ongoing.

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

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

[0013] In the case of vitiligo: Many studies in vitiligo patients have demonstrated increased frequencies of Th17 cells and higher levels of IL-17 in both the circulation and lesions, which positively correlate with disease duration, severity, and activity (Singh R. et al., Autoimmun. Rev. 2016, Apr;15(4):397-404). Mouse studies have demonstrated that vitiligo loss correlates with higher IL-17 expression / secretion, which regulates vitiligo development (Eby J. et al., Pigment Cell & Melanoma Res. 2014 Nov;27(6):1075-85).

[0014] In multiple sclerosis (MS), IL-17 expression is increased in PBMCs, cerebrospinal fluid (CSF), and brain lesions and cells from MS patients (Lock, C. et al., Nat. Med. 2002, 8:500-508; Matusevicius, D. et al., Mult. Scler. 1999, 5:101-104; Tzartos, J. et al., Am. J. Pathol. 2008, 172:146-155). IL-17-producing T cells are abundant in active MS lesions (Tzartos, J. et al., Am. J. Pathol. 2008, 172:146-155; Willing A. et al., J. Immunol. 2018, 200(3):974-982). IL-17A levels are elevated in the CSF of patients with relapsing-remitting MS (RRMS), and in vitro data suggest that IL-17A in combination with IL-6 reduced tight junction-related gene expression and disrupted monolayer integrity in blood-brain barrier (BBB) ​​cell lines, correlating with the CSF / serum albumin index, a measure of BBB dysfunction, highlights the potential importance of targeting IL-17A in preserving BBB integrity in RRMS (Setiadi AF et al., J Neuroimmunol. 2019, 332:147-154). Secukinumab has shown promising initial results in a proof-of-concept study in MS patients (Havrdova, E. et al., J Neurol. 2016, 263:1287-1295).

[0015] In asthma: IL-17 expression is increased in the lungs, sputum, bronchoalveolar lavage fluid, and serum of patients with asthma, and the severity of airway hyperresponsiveness is positively correlated with IL-17 expression levels (Chakir J. et al., J. Allergy Clin. Immunol. 2003, 111(6):1293-8). IL-17 has been reported to increase in asthmatic airways and induce human bronchial fibroblasts to produce cytokines (Molet S. et al., J. Allergy Clin. Immunol. 2001, 108(3):430-8). Anti-IL-17 antibodies regulate airway responsiveness, inflammation, tissue remodeling, and oxidative stress in a chronic mouse asthma model (Camargo LdN. et al., Front Immunol. 2018;8:1835, dos Santos T. et al., Front. Physiol. 2018,9:1183).

[0016] In chronic obstructive pulmonary disease (COPD), increased Th17 cells were observed in patients with COPD compared with current smokers and healthy subjects without COPD, and an inverse correlation between Th17 cells and lung function was found (Vargas-Rojas M. et al., Respir. Med. 2011 Nov;105(11):1648-54). In three recent human COPD studies, gene expression profiles in bronchial epithelium showed that higher IL-17 signature expression was associated with a lack of response to inhaled corticosteroids, suggesting the existence of COPD subgroups that could benefit from IL-17 inhibitor therapy (Christenson S. et al., J. Clin. Invest. 2019;129(1):169-181).

[0017] In the case of uveitis, IL-17 promotes the release of inflammatory mediators from retinal pigment epithelial cell lines and disrupts retinal pigment epithelial barrier function (Chen Y. et al., PLoS One. 2011;6:e18139). IL-17 levels were elevated in the serum or aqueous humor of patients with uveitis (El-Asrar A. et al., Clin. Immunol. 2011;139(2):177-84; Jawad S. et al., Ocul. Immunol. Inflamm. 2013;21(6):434-9; Kuiper J. et al., Am. J. Ophthalmol. 2011;152(2):177-182). Anti-IL-17 antibodies delayed the onset of ocular inflammation and significantly prevented the development of experimental autoimmune uveitis in rats (Zhang R. et al., Curr. Eye Res. 2009 Apr;34(4):297-303). Analysis of secondary efficacy data from a phase 3 trial of subcutaneous (sc) secukinumab in uveitis suggested beneficial efficacy of secukinumab with reduced use of concomitant immunosuppressive medications (Dick A. et al., Ophthalmology 2013;120(4):777-87). Subsequent studies of intravenous secukinumab in uveitis demonstrated higher efficacy than sc administration, suggesting optimal exposure is required for efficacy, confirming the therapeutic potential of IL-17A inhibition (Letko E. et al., Ophthalmology 2015,122(5),939-948). It has also been reported that ustekinumab, which blocks the IL-23 / IL-17 pathway, successfully treated a patient with non-infectious uveitis who had severe concomitant psoriasis and PsA and who had failed to respond to conventional immunosuppressants (Mugheddu C. et al., Dermatol. Ther. 2017 Sep;30(5);e12527.).

[0018] In multiple myeloma (MM): IL-17A serum levels are significantly higher in MM patients compared with healthy subjects, even in patients with advanced disease (Lemancewicz D. et al., Med. Sci. Monit. 2012;18(1):BR54-BR59). Weekly administration of secukinumab in the SCIDhu model of human myeloma for 4 weeks after initial tumor detection in mice resulted in significant suppression of tumor growth and reduced bone damage compared with 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 IL-17 levels, proliferation of IL-17-producing T cells in peripheral blood, and infiltration of Th17 cells in target organs such as the kidney have been observed in SLE patients (Wong C. et al., Lupus. 2000;9(8):589-593; Wong C. et al., Clinical Immunology. 2008;127(3):385-393; Zhao XF. et al., Mol. Biol. Rep. 2010 Jan;37(1):81-5; Chen X. et al., J. Clin. Immunol. 2010 Mar;30(2):221-5; Xing Q. et al., Rheumatol. Int. 2012 Apr;32(4):949-58). An imbalance between Th17 cells and regulatory T (Treg) cells has been observed in patients with SLE, including those in the quiescent phase (Ma J. et al., Clin. Rheumatol. 2010;29(11):1251-1258; Dolff S. et al., Clin. Immunol. 2011,141(2):197-204). Overexpression of IL-17A using adenovirus increased the severity of lupus nephritis, whereas blocking IL-17A using a neutralizing antibody reduced the severity of lupus nephritis (Wen, Z. et al., PLoS One. 2013,8:e58161). In a phase 2 study, ustekinumab, an anti-IL-12 / 23p40 monoclonal antibody that blocks the IL-23 / IL-17 pathway, demonstrated efficacy in patients with SLE (van Vollenhoven R. et al., Lancet 2018;392:1330-39). Human expression studies, animal models, and clinical trials have shown that IL-17 blockade may be a promising therapeutic strategy for SLE (Koga T. et al., Expert Rev. Clin. Immunol. 2019,15(6)629-637).

[0020] In summary, animal and human studies indicate that IL-17A plays a critical role in the pathogenesis of multiple diseases and / or conditions mentioned above. The importance of targeting IL-17A is demonstrated by the transformative efficacy of injectable IL-17A neutralizing antibodies in patients.

[0021] Despite the advances made with injectable IL-17A antagonist antibodies, there is a long-felt need for the development of oral small molecule IL-17A inhibitors, which have the potential to expand treatment options for many patients without the need for biologics. Additionally, safe and effective small molecule IL-17A inhibitors could offer patients significant advantages over injectable IL-17A neutralizing antibodies, such as convenient dosing regimens and reduced costs, which could ultimately provide effective long-term disease management.

[0022] However, the development of oral small molecule therapeutics remains challenging. For example, no oral small molecule IL-17A inhibitors have yet advanced to late-stage clinical trials, and only two oral small molecule IL-17A inhibitors have advanced to Phase I clinical trials (NCT04586920 and NCT04883333) as of September 28, 2021. Additionally, as of December 2021, one of these clinical trials (NCT04586920) has been suspended for safety review. Summary of the Invention

[0023] Therefore, there is a need for new small molecule IL-17A modulators (eg, inhibitors).

[0024] The present application provides compounds of formula I:

[0025] [ka] [In the formula, R 1 , R 2 , R 3 , and R 4 or a pharmaceutically acceptable salt thereof, wherein each is as defined herein.

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

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

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

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

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

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

[0032] The term "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 described herein by using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof. Such methods include administering therapeutically effective amounts of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof, either simultaneously or sequentially at different times during the course of treatment or as a combination therapy.

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

[0034] The term "therapeutically effective amount" or "effective amount" refers to 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 sought by a researcher, veterinarian, physician, or other clinician, including preventing, treating, or ameliorating the symptoms of the syndrome, disorder, or disease being treated.

[0035] As used herein, "IL-17" or "IL-17A" refers to interleukin 17A, which is also known as IL17, CTLA8, or CTLA-8. Interleukin 17A is a pro-inflammatory cytokine. This cytokine is produced by 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 the nucleic acid sequence in GenBank Accession No. NM_002190.3.

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

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

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

[0039] As used herein, the terms "treat," "treating," or "treatment" of any disease, condition, syndrome, or disorder refer, in one embodiment, to ameliorating the disease, condition, syndrome, or disorder (i.e., slowing or halting or alleviating 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 either physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat," "treating," or "treatment" refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome, or disorder.

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

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

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

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

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

[0045] [ka] and examples, by way of example and not limitation, of spirohexyl groups include:

[0046] [ka] Examples of cycloheptyl groups include, but are not limited to,

[0047] [ka] Examples of cyclooctyl groups include, but are not limited to,

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

[0049] [ka] Also included.

[0050] The term "heterocycle" or "heterocyclyl" refers to a saturated or partially unsaturated ring system having at least one atom other than carbon in the ring system, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. Heterocyclyl groups can, for example, consist of a single ring or multiple rings (e.g., in the form of a spirocyclic or bicyclic ring system). Exemplary heterocycles include, but are not limited to, oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl.

[0051] The term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon within the ring, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. The term "heteroaryl" includes a single aromatic ring having 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.

[0052] The term "halogen" or "halo" refers to bromo (-Br), chloro (-Cl), fluoro (-F), or iodo (-I).

[0053] Where the compounds disclosed herein possess at least one stereocenter, they may accordingly exist as enantiomers or diastereomers, and it is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0054] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0055] "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 "scalic" mixture of enantiomers is a mixture of enantiomers in a ratio other than 1:1.

[0056] When the process for preparing the compounds according to the present invention gives rise to a mixture of stereoisomers, these isomers may be separated by conventional techniques, such as preparative chromatography. The compounds may be prepared in racemic form, or scalicomixtures or individual enantiomers may be prepared either by enantiospecific synthesis or resolution. The compounds may be resolved into their component enantiomers by standard techniques, for example, by 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 may also be resolved by the formation of 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 integrals in H NMR spectra, 1 Rotamers of compounds observable by 1 H NMR may exist.

[0057] Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. Chiral centers of known absolute configuration are designated with the prefixes R and S, assigned by standard sequencing procedures, preceded, if necessary, by the appropriate locant (Pure & Appl. Chem. 45, 1976, 11-30). Certain pairs of enantiomers and diastereomers are presented together in the examples. These enantiomers / diastereomers can be designated and characterized as Enantiomer 1 or Enantiomer 2 (or Diastereomer 1 or Diastereomer 2) in the following synthetic methods. Presentation of stereoisomers in this manner conveys the separate preparation or isolation of the compound as a pure single enantiomer or diastereomer at the specified stereocenter. However, unless otherwise specified, when pure single enantiomers (or diastereomers) are presented in the Examples of this disclosure along with the corresponding pure single enantiomers (or diastereomers), the order in which the chemical structures / IUPAC names are presented does not necessarily correspond to the order in which the Example numbers are listed. As an example, if the R and S enantiomers of a compound are presented side by side under the heading "Example X and Example Y," then unless otherwise specified in the Methods and Characterizations below, Example X can be either the R or S enantiomer, and Example Y is the opposite enantiomer, regardless of the order in which the IUPAC names or chemical structures of the compounds are presented.

[0058] A particular example is (R * ) or (S * ) and chemical structures represented or displayed as (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, but the absolute configuration of that stereocenter has not been established. * A compound designated as (R) or (S) refers to a compound that is a single isomer pure at that stereocenter, having either the (R) or (S) absolute configuration; *A compound designated as (R) or (S) refers to a compound that is a pure single isomer at that stereocenter, having either the (R) or (S) absolute configuration. For example, 4-cyclopropyl-N-((S-(4,4-difluorocyclohexyl)(7-(((R * )-5-Fluoro-5-methyl-2-oxotetrahydropyrimidin-1(2H-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide:

[0059] [ka] It refers to a compound that is either

[0060] Pseudo-asymmetric stereocenters are treated similarly to chiral centers but are given the lower case symbol r or s (Angew. Chem. Int. Ed. Engl. 1982, 21, 567-583).

[0061] During any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved using conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene & P. ​​G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. These protecting groups may be removed at a subsequent convenient stage using methods known in the art.

[0062] Furthermore, within the scope of the present invention, particularly when reference is made to the compounds of the present disclosure or pharmaceutically acceptable salts thereof, any element is intended to include all isotopes and isotopic mixtures of that element, whether occurring in nature or synthetically produced, in either natural abundance or 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) A group represented by alkyl includes not only -CH but also CD, not only CHCH but also CDCD, etc. Similarly, references to carbon and oxygen include, within their scope, respectively: 12 C. 13 C, and 14 C, and 15 O, and 16 O, and 17 O, and 18 These isotopes may be radioactive or non-radioactive. Radiolabeled compounds of the present disclosure include: 3 H, 11 C. 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 The radioisotope may comprise a radioisotope selected from the group including Br. Preferably, the radioisotope is 3 H, 11 C, and 18 It is selected from the group F.

[0063] Compounds of the Disclosure The present application provides compounds of formula I:

[0064] [ka] [In the formula, R 1 but,

[0065] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when m is 2, two geminal R 1a The groups, together with the carbon atoms to which they are attached, form a spiro C (3~5) forming a cycloalkyl, R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~7) Cycloalkyl (wherein the C (3~7) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m1, m2, and m3 are independently 0, 1, or 2; R 2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, -C (1~3) Alkyl-OC (3~5) cycloalkyl, or 4- to 6-membered heterocyclyl (wherein the -C (1~3) Alkyl, the -C (3~5) Cycloalkyl, the -C (1~3) Alkyl-OC (1~3) Alkyl, and the -C (1~3)Alkyl-OC (3~5) The cycloalkyl group may be unsubstituted or may contain 1 to 6 R 2a substituted with a group; R 2a is independently at each occurrence fluorine or —CN; R 3 But -C (1~10) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) Alkyl, -C (3~8) Cycloalkyl, or -C (1~3) Alkyl-(C (3~5) Cycloalkyl) 1-2 (each unsubstituted or substituted with 1 to 6 fluorine atoms), R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) Cycloalkyl (wherein the -C (1~6) Alkyl, -OC (1~6) Alkyl, the -C (1~6) Alkyl-OC (1~6) Alkyl, and the -C (0~2) Alkyl-C (3~6) cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3), or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0067] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when m is 2, two geminal R 1a The groups, together with the carbon atoms to which they are attached, form a spiro C (3~5) forming a cycloalkyl, R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~7) Cycloalkyl (wherein the C (3~7) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m1, m2, and m3 are independently 0, 1, or 2; R 2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, -C (1~3) Alkyl-OC (3~5) cycloalkyl, or 4- to 6-membered heterocyclyl (wherein the -C (1~3) Alkyl, the -C (3~5) Cycloalkyl, the -C (1~3) Alkyl-OC(1~3) Alkyl, and the -C (1~3) Alkyl-OC (3~5) The cycloalkyl group may be unsubstituted or may contain 1 to 6 R 2a substituted with a group; R 2a is independently at each occurrence fluorine or —CN; R 3 But -C (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) Alkyl, -C (3~8) Cycloalkyl, or -C (1~3) Alkyl-(C (3~5) Cycloalkyl) 1-2 (each unsubstituted or substituted with 1 to 6 fluorine atoms), R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) Cycloalkyl (wherein the -C (1~6) Alkyl, -OC (1~6) Alkyl, the -C (1~6) Alkyl-OC (1~6) Alkyl, and the -C (0~2) Alkyl-C (3~6) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

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

[0069] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~7) Cycloalkyl (wherein the C (3~7) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m1, m2, and m3 are independently 0, 1, or 2; R 2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) Cycloalkyl (wherein the -C (1~3) Alkyl, the -C (3~5) Cycloalkyl, the -C (1~3) Alkyl-OC (1~3) Alkyl, and the -C (1~3) Alkyl-OC (3~5) The cycloalkyl group may be unsubstituted or may contain 1 to 6 R 2asubstituted with a group; R 2a is independently at each occurrence fluorine; R 3 But -C (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, or -C (3~8) cycloalkyl, each unsubstituted or substituted with 1 to 6 fluorine atoms; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) Cycloalkyl (wherein the -C (1~6) Alkyl, -OC (1~6) Alkyl, the -C (1~6) Alkyl-OC (1~6) Alkyl, and the -C (0~2) Alkyl-C (3~6) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

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

[0071] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C(3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when m is 2, two geminal R 1a The groups, together with the carbon atoms to which they are attached, form a spiro C (3~5) forming a cycloalkyl, R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~7) Cycloalkyl (wherein the C (3~7) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m1, m2, and m3 are independently 0, 1, or 2; R 2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, -C (1~3) Alkyl-OC (3~5) cycloalkyl, or 4- to 6-membered heterocyclyl (wherein the -C (1~3) Alkyl and the -C (3~5) Cycloalkyl is unsubstituted or has 1 to 6 R 2a substituted with a group; R 2a is independently at each occurrence fluorine or —CN; R 3 But -C (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5)Cycloalkyl-C (1~3) Alkyl, -C (3~8) Cycloalkyl, or -CH(C (3~5) cycloalkyl)2, each of which is unsubstituted or substituted with 1 to 6 fluorine atoms; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) Cycloalkyl (wherein the -C (1~6) Alkyl, -OC (1~6) Alkyl, the -C (1~6) Alkyl-OC (1~6) Alkyl, and the -C (0~2) Alkyl-C (3~6) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

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

[0073] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b each occurrence independently represents a halo or -C (1~3)Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~7) Cycloalkyl (wherein the C (3~7) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m1, m2, and m3 are independently 0, 1, or 2; R 2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, R 3 But -C (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, or -C (3~8) cycloalkyl, each unsubstituted or substituted with 1 to 6 fluorine atoms; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) Cycloalkyl (wherein the -C (1~6) Alkyl, -OC (1~6) Alkyl, the -C (1~6) Alkyl-OC (1~6) Alkyl, and the -C (0~2) Alkyl-C (3~6)Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

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

[0075] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when m is 2, two geminal R 1a groups taken together with the carbon atoms to which they are attached form a spirocyclopropyl; R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m1, m2, and m3 are independently 0, 1, or 2; R 2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, -C (1~3)Alkyl-OC (3~5) cycloalkyl, or 4- to 6-membered heterocyclyl (wherein the -C (1~3) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and the -C (3~5) Cycloalkyl is unsubstituted or substituted with one -CN group; R 3 But -C (1~6) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl, -C (1~3) Alkyl-OC (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (3~5) Cycloalkyl-CH3, -C (5~6) Cycloalkyl, or -CH(C (3~5) cycloalkyl)2, each of which is unsubstituted or substituted with 1 to 6 fluorine atoms; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But -C (1~4) Alkyl, -OC (1~4) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl or -C (0~2) Alkyl-C (3~4) Cycloalkyl (wherein the -C (1~4) Alkyl, -OC (1~4) Alkyl, the -C (1~4) Alkyl-OC (1~4) Alkyl, and the -C (0~2) Alkyl-C (3~4) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

[0076] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0077] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m1, m2, and m3 are independently 0, 1, or 2; R 2 But, H, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, R 3 But -C (1~6) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl, -C (1~3) Alkyl-OC (3~5) cycloalkyl, or cyclohexyl (each unsubstituted or substituted with 1 to 6 fluorine atoms); R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4aBut -C (1~4) Alkyl, -OC (1~4) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl or -C (0~2) Alkyl-C (3~4) Cycloalkyl (wherein the -C (1~4) Alkyl, -OC (1~4) Alkyl, the -C (1~4) Alkyl-OC (1~4) Alkyl, and the -C (0~2) Alkyl-C (3~4) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

[0078] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0079] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when m is 2, two geminal R 1a groups taken together with the carbon atoms to which they are attached form a spirocyclopropyl; R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C(3~5) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m1, m2, and m3 are independently 0, 1, or 2; R 2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, -C (1~3) Alkyl-OC (3~5) cycloalkyl, or tetrahydropyranyl (wherein the -C (1~3) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and the -C (3~5) Cycloalkyl is unsubstituted or substituted with one -CN group; R 3 -C substituted with 2-3 fluorine atoms (5~6) Alkyl, -C substituted with two fluorine atoms (5~6) cycloalkyl,

[0080] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3; R 3e and R 3f are each independently H or -CH3; R 3g is H or -CF3, R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But -C (1~4) Alkyl, -OC (1~4) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl or -C(0~2) Alkyl-C (3~4) Cycloalkyl (wherein the -C (1~4) Alkyl, -OC (1~4) Alkyl, the -C (1~4) Alkyl-OC (1~4) Alkyl, and the -C (0~2) Alkyl-C (3~4) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

[0081] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0082] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m1, m2, and m3 are independently 0, 1, or 2; R 2 But, H, -C (3~5)Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, R 3 is replaced by one -CF3 (1~5) Alkyl,

[0083] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But -C (1~4) Alkyl, -OC (1~4) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl or -C (0~2) Alkyl-C (3~4) Cycloalkyl (wherein the -C (1~4) Alkyl, -OC (1~4) Alkyl, the -C (1~4) Alkyl-OC (1~4) Alkyl, and the -C (0~2) Alkyl-C (3~4) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

[0084] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0085] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m1, m2, and m3 are independently 0, 1, or 2; R 2 But, H, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, R 3 but,

[0086] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But -C (1~4) Alkyl, -OC(1~4) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl or -C (0~2) Alkyl-C (3~4) Cycloalkyl (wherein the -C (1~4) Alkyl, -OC (1~4) Alkyl, the -C (1~4) Alkyl-OC (1~4) Alkyl, and the -C (0~2) Alkyl-C (3~4) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

[0087] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0088] [ka] and R 1a is independently at each occurrence -CH3, -CH2F, -CHF2, -CF3, or -C (3~4) cycloalkyl, or when m1 is 2, two geminal R 1a groups taken together with the carbon atoms to which they are attached form a spirocyclopropyl; R 1b is independently at each occurrence fluoro, -CH, -CHF, -CHF, -CF, or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m1 and m2 are independently 0, 1, or 2; R2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, -C (1~3) Alkyl-OC (3~5) cycloalkyl, or tetrahydropyranyl (wherein the -C (1~3) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and the -C (3~5) Cycloalkyl is unsubstituted or substituted with one -CN group; R 3 -C substituted with 2-3 fluorine atoms (5~6) Alkyl, -C substituted with two fluorine atoms (5~6) cycloalkyl,

[0089] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3; R 3e and R 3f are each independently H or -CH3; R 3g is H or -CF3, R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But -C (1~4) Alkyl, -OC (1~4) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl or -C (0~2) Alkyl-C (3~4) Cycloalkyl (wherein the -C (1~4) Alkyl, -OC (1~4) Alkyl, the -C (1~4) Alkyl-OC (1~4) Alkyl, and the -C(0~2) Alkyl-C (3~4) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

[0090] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0091] [ka] and R 1b is independently at each occurrence fluoro, -CH, -CHF, -CHF, -CF, or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m2 is 0, 1, or 2; R 2 But, H, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, R 3 is replaced by one -CF3 (1~5) Alkyl,

[0092] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But -C (1~4) Alkyl, -OC (1~4) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl or -C (0~2) Alkyl-C (3~4) Cycloalkyl (wherein the -C (1~4) Alkyl, -OC (1~4) Alkyl, the -C (1~4) Alkyl-OC (1~4) Alkyl, and the -C (0~2) Alkyl-C (3~4) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

[0093] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0094] [ka] and R 1b is independently at each occurrence fluoro, -CH, -CHF, -CHF, -CF, or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), n is 1 or 2, m2 is 0, 1, or 2; R 2 But, H, -C (3~5) Cycloalkyl, -C(1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, R 3 but,

[0095] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3; R 4 is unsubstituted or has 1 to 2 R 4a is a 5-membered heteroaryl substituted with a group; R 4a But -C (1~4) Alkyl, -OC (1~4) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl or -C (0~2) Alkyl-C (3~4) Cycloalkyl (wherein the -C (1~4) Alkyl, -OC (1~4) Alkyl, the -C (1~4) Alkyl-OC (1~4) Alkyl, and the -C (0~2) Alkyl-C (3~4) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

[0096] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0097] [ka] and R1b is independently at each occurrence fluoro, or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3) Cycloalkyl (wherein the C (3) cycloalkyl is unsubstituted or substituted with 1 to 2 fluorine atoms), n is 1 or 2, m2 is 0, 1, or 2; R 2 But, H, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) is cycloalkyl, R 3 -C substituted with 2-3 fluorine atoms (5~6) Alkyl, -C substituted with two fluorine atoms (5~6) cycloalkyl,

[0098] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3; R 3e and R 3f are each independently H or -CH3; R 3g is H or -CF3, R 4 but,

[0099] [ka] and R 4a But -C (1~4) Alkyl, -OC (1~4) Alkyl, -C (1~4) Alkyl-OC (1~4)Alkyl or -C (0~2) Alkyl-C (3~4) Cycloalkyl (wherein the -C (1~4) Alkyl, -OC (1~4) Alkyl, the -C (1~4) Alkyl-OC (1~4) Alkyl, and the -C (0~2) Alkyl-C (3~4) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

[0100] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0101] [ka] and R 1b is independently at each occurrence fluoro, or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3) Cycloalkyl (wherein the C (3) cycloalkyl is unsubstituted or substituted with 1 to 2 fluorine atoms), n is 1 or 2, m2 is 0, 1, or 2; R 2 is H, cyclopropyl, -CH2OCH3, or -CH2-O-cyclopropyl; R 3 -C substituted with 2-3 fluorine atoms (5~6) Alkyl, -C substituted with two fluorine atoms (5~6) cycloalkyl, or

[0102] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3; R 4 but,

[0103] [ka] and R 4a is methyl, ethyl, isopropyl, -CD2CD3, -CHF2, -CF3, -CH2CH2CF3, -OCH3, -OCH2CHF2, -CH2OCHF2, cyclopropyl, or -CH2-cyclopropyl.

[0104] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when m is 2, two geminal R 1a The groups together with the carbon atom to which they are attached form a spirocyclopropyl.

[0105] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a each occurrence independently represents -C which is unsubstituted or substituted with 1 to 5 fluorine atoms; (1~3) alkyl, or when m1 is 2, two geminal R 1a The groups together with the carbon atom to which they are attached form a spirocyclopropyl.

[0106] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1ais independently at each occurrence -CH3, -CH2F, -CHF2, -CF3, or -C (3~4) cycloalkyl, or when m1 is 2, two geminal R 1a The groups together with the carbon atom to which they are attached form a spirocyclopropyl.

[0107] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a is independently at each occurrence -CH3, -CH2F, -CHF2, or -CF3, or when m1 is 2, two geminal R 1a The groups together with the carbon atom to which they are attached form a spirocyclopropyl.

[0108] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) The alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms.

[0109] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) It is cycloalkyl.

[0110] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a is independently at each occurrence -CH3, -CH2F, -CHF2, -CF3, or -C (3~4) It is cycloalkyl.

[0111] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R1a each occurrence independently represents -C which is unsubstituted or substituted with 1 to 5 fluorine atoms; (1~3) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence, -C (3~5) In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein m is 2 and two geminal R 1a The groups together with the carbon atom to which they are attached form a spirocyclopropyl.

[0112] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1b each occurrence independently represents a halo or -C (1~3) alkyl, or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) Cycloalkyl is unsubstituted or substituted with 1 to 5 fluorines.

[0113] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) Cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms.

[0114] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1b is independently at each occurrence fluoro, -CH, -CHF, -CHF, -CF, or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) Cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms.

[0115] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1b is independently at each occurrence fluoro, -CH, -CHF, -CHF, -CF, or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3) Cycloalkyl (wherein the C (3) Cycloalkyl is unsubstituted or substituted with 1 to 2 fluorine atoms.

[0116] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1b is independently at each occurrence fluoro, or when n is 2, two R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3) Cycloalkyl (wherein the C (3) Cycloalkyl is unsubstituted or substituted with 1 to 2 fluorine atoms.

[0117] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, where n is 1. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, where n is 2.

[0118] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein m1 is 0, 1, or 2. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein m1 is 0. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein m2 is 0, 1, or 2. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein m3 is 0.

[0119] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein m1 is 0, 1, or 2, m2 is 0, 1, or 2, and m3 is 0. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein m1 is 0, m2 is 0, 1, or 2, and m3 is 0.

[0120] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0121] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when m is 2, two geminal R 1a The groups, together with the carbon atoms to which they are attached, form a spiro C (3~5) forming a cycloalkyl, R 1b each occurrence independently represents a halo or -C (1~3)Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; m1, m2, and m3 are independently 0, 1, or 2.

[0122] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0123] [ka] and R 1a is independently at each occurrence -CH3, -CH2F, -CHF2, or -CF3, or when m1 is 2, two geminal R 1a groups taken together with the carbon atoms to which they are attached form a spirocyclopropyl; R 1b is independently at each occurrence fluoro, -CH3, -CH2F, -CHF2, -CF3; m1, m2, and m3 are independently 0, 1, or 2.

[0124] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0125] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b each occurrence independently represents a halo or -C (1~3)Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; m1, m2, and m3 are independently 0, 1, or 2.

[0126] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0127] [ka] and R 1a is independently at each occurrence -CH3, -CH2F, -CHF2, -CF3, or -C (3~4) is cycloalkyl, R 1b is independently at each occurrence fluoro, —CH3, —CH2F, —CHF2, or —CF3; m1, m2, and m3 are independently 0, 1, or 2.

[0128] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0129] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when m is 2, two geminal R 1a The groups, together with the carbon atoms to which they are attached, form a spiro C (3~5) forming a cycloalkyl, R 1beach occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; m1 and m2 are independently 0, 1, or 2.

[0130] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0131] [ka] and R 1a is independently at each occurrence -CH3, -CH2F, -CHF2, or -CF3, or when m1 is 2, two geminal R 1a groups taken together with the carbon atoms to which they are attached form a spirocyclopropyl; R 1b is independently at each occurrence fluoro, -CH3, -CH2F, -CHF2, -CF3; m1 and m3 are independently 0, 1, or 2.

[0132] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0133] [ka] and R 1b is independently at each occurrence fluoro, -CH3, -CH2F, -CHF2, -CF3; m2 is 0, 1, or 2.

[0134] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0135] [ka] and R 1b is independently at each occurrence fluoro, -CH3, -CH2F, -CHF2, -CF3; m2 is 0, 1, or 2.

[0136] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0137] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms) or two adjacent R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~7) Cycloalkyl (wherein the C (3~7) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), m1, m2-1, m2-2, and m3 are independently 0, 1, or 2.

[0138] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R1 but,

[0139] [ka] and R 1a is independently at each occurrence -CH3, -CH2F, -CHF2, -CF3, or -C (3~4) is cycloalkyl, R 1b is independently at each occurrence fluoro, -CH3, -CH2F, -CHF2, -CF3, or two adjacent R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), m1, m2-1, m2-2, and m3 are independently 0, 1, or 2.

[0140] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0141] [ka] and R 1a independently for each occurrence, -C (1~3) Alkyl or -C (3~5) Cycloalkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R 1b each occurrence independently represents a halo or -C (1~3) Alkyl (wherein the -C (1~3) alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms) or two adjacent R 1b The groups, together with the carbon atoms to which they are attached, form a fused C(3~7) Cycloalkyl (wherein the C (3~7) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), m1, m2-1, and m2-2 are independently 0, 1, or 2.

[0142] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0143] [ka] and R 1a is independently at each occurrence -CH3, -CH2F, -CHF2, -CF3, or -C (3~4) is cycloalkyl, R 1b is independently at each occurrence fluoro, -CH3, -CH2F, -CHF2, -CF3, or two adjacent R 1b The groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), m1, m2-1, and m2-2 are independently 0, 1, or 2.

[0144] In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R 1 but,

[0145] [ka] and R 1b is independently at each occurrence fluoro, -CH3, -CH2F, -CHF2, -CF3, or two adjacent R 1bThe groups, together with the carbon atoms to which they are attached, form a fused C (3~5) Cycloalkyl (wherein the C (3~5) cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), m2-1 and m2-2 are independently 0, 1, or 2.

[0146] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 but,

[0147] [ka] is.

[0148] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 but,

[0149] [ka] is.

[0150] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 but,

[0151] [ka] is.

[0152] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 but,

[0153] [ka] is.

[0154] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 but,

[0155] [ka] is.

[0156] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 but,

[0157] [ka] is.

[0158] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 but,

[0159] [ka] is.

[0160] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 but,

[0161] [ka] is.

[0162] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C(1~3) Alkyl-OC (3~5) Cycloalkyl (wherein the -C (1~3) Alkyl, the -C (3~5) Cycloalkyl, the -C (1~3) Alkyl-OC (1~3) Alkyl, and the -C (1~3) Alkyl-OC (3~5) The cycloalkyl group may be unsubstituted or may contain 1 to 6 R 2a substituted with a group).

[0163] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, -C (1~3) Alkyl-OC (3~5) cycloalkyl, or 4- to 6-membered heterocyclyl (wherein the -C (1~3) Alkyl and the -C (3~5) Cycloalkyl is unsubstituted or has 1 to 6 R 2a substituted with a group).

[0164] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, -C (1~3) Alkyl-OC (3~5) cycloalkyl, or 4- to 6-membered heterocyclyl (wherein the -C (1~3) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and the -C (3~5) Cycloalkyl is unsubstituted or substituted with one -CN group.

[0165] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 But, H, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, -C (1~3) Alkyl-OC (3~5) cycloalkyl, or tetrahydropyranyl (wherein the -C (1~3) The alkyl is unsubstituted or substituted with 1 to 6 fluorine atoms, and the -C (3~5) Cycloalkyl is unsubstituted or substituted with one -CN group.

[0166] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 But, H, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl or -C (1~3) Alkyl-OC (3~5) It is cycloalkyl.

[0167] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is H. In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted or substituted with 1 to 6 fluorine atoms, (1~3) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted or substituted with one -CN group; (3~5) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 But -C (1~3) Alkyl-OC (1~3)In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 But -C (1~3) Alkyl-OC (3~5) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 4- to 6-membered heterocyclyl.

[0168] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 but,

[0169] [ka] is.

[0170] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is H, cyclopropyl, —CH2OCH2CH3, —CH2OCH3, or —CH2-O-cyclopropyl.

[0171] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is H, cyclopropyl, —CH2OCH3, or —CH2-O-cyclopropyl.

[0172] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is H. In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is tetrahydropyranyl.

[0173] In some embodiments, disclosed herein are compounds of formula Ia:

[0174] [ka] or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2aIn some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2a But it is -CN.

[0176] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~10) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) Alkyl, -C (3~8) Cycloalkyl, or -CH(C (3~5) cycloalkyl)2 (each unsubstituted or substituted with 1 to 6 fluorine atoms).

[0177] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~8) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) Alkyl, -C (3~8) Cycloalkyl, or -CH(C (3~5) cycloalkyl)2 (each unsubstituted or substituted with 1 to 6 fluorine atoms).

[0178] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~7) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC(3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) Alkyl, -C (3~8) Cycloalkyl, or -CH(C (3~5) cycloalkyl)2 (each unsubstituted or substituted with 1 to 6 fluorine atoms).

[0179] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) Alkyl, -C (3~8) Cycloalkyl, or -CH(C (3~5) cycloalkyl)2 (each unsubstituted or substituted with 1 to 6 fluorine atoms).

[0180] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (5~6) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl, -C (1~3) Alkyl-OC (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (3~5) Cycloalkyl-CH3, -C (5~6) Cycloalkyl, or -CH(C (3~5) cycloalkyl)2 (each unsubstituted or substituted with 1 to 6 fluorine atoms).

[0181] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3-C substituted with 2-3 fluorine atoms (5~6) Alkyl, -C (1~6) Alkyl-OC (1~5) Alkyl-CF3, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-CF3, -C substituted with two fluorine atoms (5~6) Cycloalkyl, or -CH(C (3~5) cycloalkyl)2.

[0182] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 -C substituted with 2-3 fluorine atoms (5~7) Alkyl, -C (1~6) Alkyl-OC (1~5) Alkyl-CF3, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-CF3, -C substituted with two fluorine atoms (5~6) Cycloalkyl, or -CH(C (3~5) cycloalkyl)2.

[0183] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, or -C (3~8) and cycloalkyl (each unsubstituted or substituted with 1 to 6 fluorine atoms).

[0184] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~6) Alkyl, -C(1~6) Alkyl-OC (1~6) Alkyl or -C (1~6) Alkyl-OC (3~5) and cycloalkyl (each unsubstituted or substituted with 1 to 6 fluorine atoms).

[0185] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~6) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl, -C (1~3) Alkyl-OC (3~5) cycloalkyl, or cyclohexyl (each unsubstituted or substituted with 1 to 6 fluorine atoms).

[0186] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~6) Alkyl, -C (1~4) Alkyl-OC (1~4) alkyl, or cyclohexyl (each unsubstituted or substituted with 1 to 6 fluorine atoms).

[0187] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~6) Alkyl, -C (1~6) Alkyl-OC (1~5) alkyl-CF3, or cyclohexyl (wherein the -C (1~6) The alkyl is substituted with 1 to 3 fluorine atoms, and the cyclohexyl is substituted with 2 fluorine atoms).

[0188] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~5) Alkyl, -C (1~6) Alkyl-OC(1~5) alkyl-CF3, or cyclohexyl (wherein the -C (1~5) The alkyl is substituted with one -CF3, and the cyclohexyl is substituted with two fluorine atoms).

[0189] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~6) Alkyl-OC (1~5) alkyl-CF3 or cyclohexyl, where the cyclohexyl is substituted with two fluorine atoms.

[0190] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with 1 to 6 fluorine atoms, (1~6) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with 2 to 3 fluorine atoms, (5~6) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is replaced by one -CF3 (1~5) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is replaced by one -CF3 (5) It is alkyl.

[0191] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with 1 to 6 fluorine atoms, (1~6) Alkyl-OC (1~6)In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~6) Alkyl-OC (1~5) It is alkyl-CF3.

[0192] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with 1 to 6 fluorine atoms, (1~6) Alkyl-OC (3~5) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with 1 to 6 fluorine atoms, (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 But -C (1~6) Alkyl-OC (3~5) It is cycloalkyl-CF3.

[0193] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with 1 to 6 fluorine atoms, (3~8) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with two fluorine atoms; (5~6) In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is a cyclohexyl substituted with two fluorine atoms.

[0194] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with 1 to 6 fluorine atoms, (1~3) Alkyl-(C (3~5) Cycloalkyl) 1-2 In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 But -CH(C (3~5) cycloalkyl)2.

[0195] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 -C substituted with 2-3 fluorine atoms (5~6) Alkyl, -C substituted with two fluorine atoms (5~6) cycloalkyl,

[0196] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3; R 3e and R 3f are each independently H or -CH3; R 3g is H or -CF3.

[0197] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 -C substituted with 2-3 fluorine atoms (5~6) Alkyl, -C substituted with two fluorine atoms (5~6) cycloalkyl, or

[0198] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3.

[0199] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is replaced by one -CF3 (1~5) Alkyl,

[0200] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3.

[0201] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is replaced by one -CF3 (1~5) Alkyl or

[0202] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3.

[0203] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0204] [ka] and R 3a , R3b , R 3c , and R 3d are each independently H or -CH3.

[0205] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0206] [ka] and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3.

[0207] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0208] [ka] and R 3e and R 3f are each independently H or -CH3; R 3g is H or -CF3.

[0209] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is replaced by one -CF3 (1~5) It is alkyl.

[0210] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0211] [ka] is.

[0212] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0213] [ka] is.

[0214] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0215] [ka] is.

[0216] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0217] [ka] is.

[0218] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0219] [ka] is.

[0220] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0221] [ka] is.

[0222] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0223] [ka] is.

[0224] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0225] [ka] is.

[0226] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0227] [ka] is.

[0228] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0229] [ka] is.

[0230] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0231] [ka] is.

[0232] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0233] [ka] is.

[0234] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0235] [ka] is.

[0236] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0237] [ka] is.

[0238] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0239] [ka] is.

[0240] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0241] [ka] is.

[0242] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0243] [ka] is.

[0244] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0245] [ka] is.

[0246] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0247] [ka] is.

[0248] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0249] [ka] is.

[0250] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0251] [ka] is.

[0252] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0253] [ka] is.

[0254] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0255] [ka] is.

[0256] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0257] [ka] is.

[0258] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0259] [ka] is.

[0260] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0261] [ka] is.

[0262] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0263] [ka] is.

[0264] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0265] [ka] is.

[0266] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 but,

[0267] [ka] is.

[0268] In some embodiments, disclosed herein are compounds of formula Ib:

[0269] [ka] or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, disclosed herein are compounds of formula Ib-1:

[0271] [ka] or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, disclosed herein are compounds of formula Ic:

[0273] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3.

[0274] In some embodiments, disclosed herein are compounds of formula Ic-1:

[0275] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3.

[0276] In some embodiments, disclosed herein are compounds of formula Ic-2:

[0277] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 3a, R 3b , R 3c , and R 3d are each independently H or -CH3.

[0278] In some embodiments, disclosed herein are compounds of formula Id:

[0279] [ka] or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, disclosed herein are compounds of formula Id-1:

[0281] [ka] or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, disclosed herein are compounds of formula Id-2:

[0283] [ka] or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 But one or two R 4a and 5-membered heteroaryl substituted with a group.

[0285] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from O and N, wherein the 5-membered heteroaryl is unsubstituted or contains 1 to 2 R 4a substituted with a group).

[0286] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, or oxadiazolyl (each of which is unsubstituted or has 1 to 2 R 4a In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, triazolyl, isoxazolyl, or oxadiazolyl (each of which is unsubstituted or contains 1 to 2 R 4a In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl or oxadiazolyl (each of which is unsubstituted or contains 1 to 2 R 4a substituted with a group).

[0287] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazoyl, 1,2,5-oxadiazolyl, or 1,3,4-oxadiazolyl (each of which is unsubstituted or has one to two R 4a In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, or 1,2,5-oxadiazolyl (each of which is unsubstituted or contains 1 to 2 R 4a In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4is pyrazolyl or 1,2,5-oxadiazolyl (each of which is unsubstituted or contains 1 to 2 R 4a (substituted with a group).

[0288] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0289] [ka] is.

[0290] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0291] [ka] is.

[0292] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0293] [ka] is.

[0294] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0295] [ka] is.

[0296] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4a But -C(1~4) Alkyl, -OC (1~4) Alkyl, -C (1~4) Alkyl-OC (1~4) Alkyl or -C (0~2) Alkyl-C (3~4) Cycloalkyl (wherein the -C (1~4) Alkyl, -OC (1~4) Alkyl, the -C (1~4) Alkyl-OC (1~4) Alkyl, and the -C (0~2) Alkyl-C (3~4) Cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.

[0297] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4a But -C (1~6) Alkyl, -OC (1~6) Alkyl or -C (0~2) Alkyl-C (3~6) and cycloalkyl (each unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH, -CD, -CDCD, -CHF, -CHF, and -CF). In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4a But -C (1~4) Alkyl, -OC (1~4) Alkyl or -C (0~2) Alkyl-C (3~4) and cycloalkyl (each unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3).

[0298] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4a But -C (1~6) Alkyl or -C (0~2)Alkyl-C (3~6) and cycloalkyl (each unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH, -CD, -CDCD, -CHF, -CHF, and -CF). In some embodiments, disclosed herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4a But -C (1~4) Alkyl or -C (0~2) Alkyl-C (3~4) and cycloalkyl (each unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3).

[0299] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4a is methyl, ethyl, isopropyl, -CD2CD3, -CHF2, -CF3, -CH2CH2CF3, -OCH3, -OCH2CHF2, -CH2OCHF2, cyclopropyl, or -CH2-cyclopropyl.

[0300] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4a is methyl, isopropyl, -CD2CD3, -CH2CH2CF3, -OCH2CHF2, -CH2OCHF2, cyclopropyl, or -CH2-cyclopropyl.

[0301] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4a is methyl, ethyl, isopropyl, -CHF2, -CF3, -OCH3, or cyclopropyl.

[0302] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4a is methyl, isopropyl, or cyclopropyl.

[0303] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0304] [ka] is.

[0305] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0306] [ka] is.

[0307] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0308] [ka] is.

[0309] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0310] [ka] is.

[0311] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0312] [ka] is.

[0313] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0314] [ka] is.

[0315] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0316] [ka] is.

[0317] In some embodiments, disclosed herein are compounds of Formula I′ or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0318] [ka] is.

[0319] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0320] [ka] is.

[0321] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0322] [ka] is.

[0323] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0324] [ka] is.

[0325] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0326] [ka] is.

[0327] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0328] [ka] is.

[0329] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0330] [ka] is.

[0331] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0332] [ka] is.

[0333] In some embodiments, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 but,

[0334] [ka] is.

[0335] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, which are deuterated isotopes containing 1 to 30 deuterium atoms. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, which are deuterated isotopes containing 1 to 15 deuterium atoms. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, which are deuterated isotopes containing 1 to 7 deuterium atoms.

[0336] In some embodiments, disclosed herein are compounds of Formula I having a structure as shown in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, and Table 1F, or a pharmaceutically acceptable salt thereof.

[0337] [Table 1-1]

[0338] [Table 1-2]

[0339] [Table 2-1]

[0340] [Table 2-2]

[0341] [Table 3]

[0342] [Table 4-1]

[0343] [Table 4-2]

[0344] [Table 5-1]

[0345] [Table 5-2]

[0346] [Table 6-1]

[0347] [Table 6-2]

[0348] In some embodiments, disclosed herein is a method for treating a psoriasis-associated rhombolytic disorder comprising:

[0349] [ka]

[0350] [ka] or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, disclosed herein is a method for treating a psoriasis-associated rhombolytic disorder comprising:

[0352] [ka]

[0353] [ka] or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, disclosed herein is a method for treating a psoriasis-associated rhombolytic disorder comprising:

[0355] [ka] or a pharmaceutically acceptable salt thereof.

[0356] In some embodiments, disclosed herein is a method for treating a psoriasis-associated rhombolytic disorder comprising:

[0357] [ka] or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, disclosed herein is a method for treating a psoriasis-associated rhombolytic disorder comprising:

[0359] [ka]

[0360] [ka] or a pharmaceutically acceptable salt thereof.

[0361] In some embodiments, disclosed herein is a compound having the following structure:

[0362] [ka] or a pharmaceutically acceptable salt thereof.

[0363] In some embodiments, disclosed herein is a compound having the following structure:

[0364] [ka] or a pharmaceutically acceptable salt thereof.

[0365] In some embodiments, disclosed herein is a compound having the following structure:

[0366] [ka] or a pharmaceutically acceptable salt thereof.

[0367] In some embodiments, disclosed herein is a compound having the following structure:

[0368] [ka] or a pharmaceutically acceptable salt thereof.

[0369] In some embodiments, disclosed herein is a compound having the following structure:

[0370] [ka] or a pharmaceutically acceptable salt thereof.

[0371] In some embodiments, disclosed herein is a compound having the following structure:

[0372] [ka] or a pharmaceutically acceptable salt thereof.

[0373] In some embodiments, disclosed herein is a compound having the following structure:

[0374] [ka] or a pharmaceutically acceptable salt thereof.

[0375] In some embodiments, disclosed herein is a compound having the following structure:

[0376] [ka] or a pharmaceutically acceptable salt thereof.

[0377] In some embodiments, disclosed herein is a compound having the following structure:

[0378] [ka] or a pharmaceutically acceptable salt thereof.

[0379] In some embodiments, disclosed herein is a compound having the following structure:

[0380] [ka] or a pharmaceutically acceptable salt thereof.

[0381] In some embodiments, disclosed herein is a compound having the following structure:

[0382] [ka] or a pharmaceutically acceptable salt thereof.

[0383] In some embodiments, disclosed herein is a compound having the following structure:

[0384] [ka] or a pharmaceutically acceptable salt thereof.

[0385] In some embodiments, disclosed herein is a compound having the following structure:

[0386] [ka] or a pharmaceutically acceptable salt thereof.

[0387] In some embodiments, disclosed herein is a compound having the following structure:

[0388] [ka] or a pharmaceutically acceptable salt thereof.

[0389] In some embodiments, disclosed herein is a compound having the following structure:

[0390] [ka] or a pharmaceutically acceptable salt thereof.

[0391] In some embodiments, disclosed herein is a compound having the following structure:

[0392] [ka] or a pharmaceutically acceptable salt thereof.

[0393] In some embodiments, disclosed herein is a compound having the following structure:

[0394] [ka] or a pharmaceutically acceptable salt thereof.

[0395] In some embodiments, disclosed herein is a compound having the following structure:

[0396] [ka] or a pharmaceutically acceptable salt thereof.

[0397] In some embodiments, disclosed herein is a compound having the following structure:

[0398] [ka] or a pharmaceutically acceptable salt thereof.

[0399] In some embodiments, disclosed herein is a compound having the following structure:

[0400] [ka] or a pharmaceutically acceptable salt thereof.

[0401] In some embodiments, disclosed herein is a compound having the following structure:

[0402] [ka] or a pharmaceutically acceptable salt thereof.

[0403] In some embodiments, disclosed herein is a compound having the following structure:

[0404] [ka] or a pharmaceutically acceptable salt thereof.

[0405] In some embodiments, disclosed herein is a compound having the following structure:

[0406] [ka] or a pharmaceutically acceptable salt thereof.

[0407] In some embodiments, disclosed herein is a compound having the following structure:

[0408] [ka] or a pharmaceutically acceptable salt thereof.

[0409] In some embodiments, disclosed herein are compounds of Formula I having the structure shown in Table 2A, Table 2B, Table 2C, Table 2D, and Table 2E, or a pharmaceutically acceptable salt thereof.

[0410] [Table 7-1]

[0411] [Table 7-2]

[0412] [Table 8-1]

[0413] [Table 8-2]

[0414] [Table 9-1]

[0415] [Table 9-2]

[0416] [Table 10-1]

[0417] [Table 10-2]

[0418] [Table 10-3]

[0419] [Table 11]

[0420] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration (e.g., a tablet or capsule).

[0421] In some embodiments, disclosed herein is a pharmaceutical composition made by mixing a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0422] In some embodiments, disclosed herein is a process for making a pharmaceutical composition, the process comprising mixing a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0423] III. Therapeutic Use The present application is also directed to a method for treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0424] 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 pharmaceutically acceptable salt thereof.

[0425] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0426] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriasis.

[0427] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

[0428] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

[0429] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0430] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.

[0431] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.

[0432] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

[0433] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is vitiligo.

[0434] In some embodiments, disclosed herein are methods for treating or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is multiple sclerosis.

[0435] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

[0436] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is asthma.

[0437] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is uveitis.

[0438] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disorder.

[0439] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is multiple myeloma.

[0440] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).

[0441] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg QD.

[0442] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg BID.

[0443] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0444] In some embodiments, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0445] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0446] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof, 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.

[0447] In some embodiments, disclosed herein are methods for treating or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, and ankylosing spondylitis.

[0448] In some embodiments, disclosed herein are methods of modulating IL-17 activity in a mammal by administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof.

[0449] Also disclosed herein is a method for inhibiting the production of interleukin-17, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0450] IV. Combination Therapy The compounds of formula I or pharmaceutically acceptable salts thereof, compositions thereof, or medicaments thereof may also be used in combination with one or more additional therapeutic agents.

[0451] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, and immunosuppressive agents.

[0452] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of anti-TNF-alpha agents such as infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), etanercept (Enbrel®), thalidomide (Immunoprin®), lenalidomide (Revlimid®), and pomalidomide (Pomalyst® / Imnovid®), anti-p40 antibody agents such as ustekinumab (Stelara®), and anti-p19 antibody agents such as guselkumab (Tremfya®), tildrakizumab (Ilumya™ / Ilumetri), risankizumab (Skyrizi™), and mirikizumab.

[0453] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof, in combination therapy with one or more additional therapeutic agents, such as an anti-inflammatory agent, an immunomodulatory agent, or an immunosuppressant, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus.

[0454] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof, in combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents or immunosuppressants, wherein the syndrome, disorder, or disease is psoriasis, psoriatic arthritis, or ankylosing spondylitis. In some embodiments, the IL-17-mediated inflammatory syndrome, disorder, or disease is psoriasis. In some embodiments, the IL-17-mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis. In some embodiments, the IL-17-mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0455] Dosing regimen When used as IL-17A modulators, the compounds disclosed herein can 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, in a single daily dose or divided daily doses. In some embodiments, the dosage is about 5 mg to 400 mg. In some embodiments, the dosage is about 10 mg to 300 mg. In some embodiments, the dosage is about 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 300, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0456] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 10 mg to 300 mg QD. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 20 mg to 200 mg QD. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 50 mg to 100 mg QD.

[0457] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 10 mg to 300 mg BID. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 20 mg to 200 mg BID. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered in an effective amount within a dosage range of about 50 mg to 100 mg BID.

[0458] The dosage will be affected by factors such as the route of administration, the health, weight, and age of the recipient, the frequency of treatment, and the presence of concurrent unrelated treatments.

[0459] It is also clear to those skilled in the art that the therapeutically effective amount of the compound of the present invention or its pharmaceutical composition varies depending on the desired effect.Therefore, the optimal dosage can be easily determined by those skilled in the art and varies depending on the specific compound used, the administration method, the strength of the preparation, and the progression of the disease state.In addition, factors related to the specific subject being treated, including the subject's age, weight, diet, and administration time, will require adjusting the dosage to an appropriate therapeutic level.Therefore, the above dosage is an example of an average case.Of course, there may be individual cases in which a larger or smaller dosage range is effective, and such cases are also within the scope of the present invention.

[0460] pharmaceutically acceptable salts Pharmaceutically acceptable acidic / anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinolate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodine ... Examples of suitable acid salts include, but are not limited to, methyl nitrate, methyl sulfate, mucoate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, diacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide. Examples of suitable organic or inorganic acids include, but are not limited to, hydroiodic acid, perchloric acid, sulfuric acid, phosphoric acid, propionic acid, glycolic acid, methanesulfonic acid, hydroxyethanesulfonic acid, oxalic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, saccharinic acid, and trifluoroacetic acid.

[0461] Pharmaceutically acceptable basic / cationic salts include, but are not limited to, aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethane, or "TRIS"), ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH, NHOH, N-methyl-D-glucamine, piperidine, potassium, potassium t-butoxide, potassium hydroxide (aqueous), procaine, quinine, sodium, sodium carbonate, sodium 2-ethylhexanoate, sodium hydroxide, triethanolamine, or zinc.

[0462] Pharmaceutical Composition The compound of Formula I or its pharmaceutically acceptable salt can be formulated into a pharmaceutical composition containing any known pharmaceutically acceptable carrier.Exemplary carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antibacterial and antifungal agent, and isotonicity agent.Exemplary excipients that can also be components of the formulation include fillers, binders, disintegrants, and lubricants.

[0463] Pharmaceutically acceptable salts of the compounds of Formula I include conventional non-toxic salts or quaternary ammonium salts formed from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecyl sulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate, and tartrate. Base salts include ammonium salts, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with organic bases such as dicyclohexylamino salts, and salts with amino acids such as arginine. In addition, basic nitrogen-containing groups may be quaternized, for example, with alkyl halides.

[0464] The pharmaceutical compositions of the present invention can be administered by any means that achieves their intended purpose. Examples include parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular administration. Alternatively, or in parallel, administration may be oral. 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, dextrose solutions, isotonic carbohydrate solutions, and cyclodextrin inclusion complexes.

[0465] Also disclosed herein is a method of making a pharmaceutical composition, comprising mixing a pharmaceutically acceptable carrier with any of the compounds of Formula I, or a pharmaceutically acceptable salt thereof. Additionally, the present application includes a pharmaceutical composition made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention. [Example]

[0466] abbreviation The following abbreviations may be used throughout this specification and application: Å Angstrom Ac Acetyl ACN Acetonitrile ATM atmosphere Boc tert-butoxycarbonyl br Broad Bu butyl CDI 1,1'-carbonyldiimidazole Cp cyclopentadienyl δ NMR chemical shift in parts per million downfield from standard d double line d day DCC N,N'-dicyclohexylcarbodiimide DCM dichloromethane DCE Dichloroethane Dess-Martin Periodinane 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DIBAL Diisobutylaluminum hydride DIPA Diisopropylamine DIPEA N,N-Diisopropylethylamine (Hunig's base) DMAP 4-(dimethylamino)pyridine DMSO dimethyl sulfoxide EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride ESI electrospray ionization Et Ethyl EtOAc ethyl acetate g grams h time Hantsch ester Diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate HOBt 1-hydroxybenzotriazole HPLC High Pressure Liquid Chromatography Hz Hertz IPA Isopropanol J Coupling Constant (NMR Spectroscopy) L liters LC liquid chromatography LED Light Emitting Diode m millimeter or multiple lines m / z mass-to-charge ratio M + Parent molecular ion M molar concentration (moles / liter) Me methyl MeCN acetonitrile min MOM methoxymethyl μ Micro MS mass spectrometry N normality (equivalent concentration) NMP 1-methyl-2-pyrrolidone NMR nuclear magnetic resonance PPTS Pyridinium p-toluenesulfonate Rochelle Salt Potassium Sodium Tartrate Tetrahydrate rt room temperature RuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate s single line SFC Supercritical Fluid Chromatography spt septet t triple line T3P 1-Propanephosphonic anhydride TEA Triethylamine Tf Trifluoromethanesulfonic acid TFA trifluoroacetic acid TFE 2,2,2-trifluoroethan-1-ol THF tetrahydrofuran TLC thin layer chromatography TMP 2,2,6,6-Tetramethylpiperidine TMS trimethylsilyl

[0467] In some embodiments, provided herein are processes and intermediates disclosed herein that are useful for preparing the disclosed compounds or pharmaceutically acceptable salts thereof.

[0468] [ka]

[0469] Scheme 1 Compounds of Formula I can be prepared according to Scheme 1. Compound AI can be converted to compound A-II through a series of reactions known as "urea-forming conditions." This can be accomplished by reacting the amine present in compound AI with an activated aminoalcohol precursor, such as 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl trifluoromethanesulfonate. The adduct formed from this reaction is then subjected to hydrazine in a solvent such as ethanol. The resulting diamine can then be cyclized using CDI or triphosgene and DIPEA in a solvent such as THF or DCM to give compound A-II. Alternatively, compound A-II can be prepared by reacting the amine present in compound AI via a three-step process. Compound AI is first reacted with a suitably protected aminoaldehyde, such as 2-(1-(1,3-dioxoisoindolin-2-yl)cyclopropyl)acetaldehyde, in the presence of a reducing agent, such as NaCNBH3, in a solvent such as methanol, with or without an additive such as acetic acid, to give a secondary amine adduct (structure not shown). This adduct is then subjected to hydrazine in a solvent such as ethanol in step 2 to give a diamine (structure not shown). Finally, in step 3, this diamine can be treated with CDI or triphosgene and DIPEA in a solvent such as THF or DCM to give compound A-II. Compound A-II is treated with an acid, such as TFA, in a solvent such as DCM to give compound A-III. These conditions are referred to herein as "Boc deprotection conditions." The reaction of amine A-III with a carboxylic acid (R 4 Amide bond formation between amine A-III and a carboxylic acid chloride (RCOH) can be achieved by using a coupling agent such as HATU, EDCI, or 2-chloro-1-methylpyridinium iodide in the presence of a base such as DIPEA or TEA in a solvent such as DMF, MeCN, or DCM, with or without an additive such as HOBt, to give compounds of Formula I. Alternatively, amide bond formation can be achieved by coupling amine A-III with a carboxylic acid chloride (RCOH) in the presence or absence of an additive such as DIPEA or DMAP in a solvent such as ACN, DCM, or THF.4 COCl) to give compounds of formula I. Additionally, amine A-III can be treated with an N-hydroxysuccinic acid ester in the presence of a reagent such as DIPEA in a solvent such as acetonitrile to give compounds of formula I. Alternatively, amide bond formation can be achieved by converting amine A-III to an ester (R 4 CO2R 4aa (In the formula, R 4aa Ga-C (1~6) This can be achieved by treatment with a reagent such as 2-(2-(2-methyl-2-propanol)-1-yl)-(2-methyl-2-propanol)) which is an alkyl group to provide compounds of formula I.

[0470] [ka]

[0471] Scheme 2 Amides AI can also be prepared as shown in Scheme 2. Vinylated intermediates A-IV can be converted to compounds AV by a two-step sequence: 1) halogenation using a reagent such as potassium trifluoro(vinyl)boranide and a catalyst such as RuPhos Pd G3 in a solvent such as 1,4-dioxane, and 2) oxidative cleavage of the olefin prepared in the previous step using reagents such as K2OsO4·2H2O and NaIO4 in a solvent such as 1,4-dioxane and water. Sulfinimine formation can be achieved using a reagent such as 2-methylpropane-2-sulfinamide in the presence of CuSO4 or Cs2CO3 in a solvent such as DCM to give compounds A-VI. 2 Addition of a suitable nucleophile, such as M (where M is Li, MgCl, or MgBr), to sulfinimine A-VI provides the corresponding sulfinamine (structure not shown), which is deprotected using a reagent such as HCl in a solvent such as 1,4-dioxane to provide amine AI.

[0472] [ka]

[0473] Scheme 3 Urea A-VII can be prepared by several methods, two of which are depicted in Scheme 3. Method 1: Aldehyde AV can be treated with a diamine such as 2,2-difluoropropane-1,3-diamine dihydrochloride under reductive amination conditions such as NaCNBH in a solvent such as methanol in the presence of an additive such as acetic acid, followed by treatment with a reagent such as triphosgene or CDI in a solvent such as DCM or THF to afford the corresponding cyclic urea A-VII. Method 2: In a two-step procedure, aldehyde AV is subjected to reductive amination conditions with a monoprotected diamine such as tert-butyl (S)-(1-aminopropan-2-yl)carbamate using NaCNBH in a solvent such as methanol in the presence of an additive such as acetic acid. In a second step, the adduct resulting from the first step is treated with a reagent such as potassium tert-pentoxide in a solvent such as tert-amyl alcohol to afford urea A-VII. Compound A-VII can be converted to a compound of formula I using the methods described in Scheme 1 for the conversion of compound A-II to a compound of formula I.

[0474] [ka]

[0475] Scheme 4 Intermediate A-III may be prepared as shown in Scheme 4. Treatment of sulfinimide A-VIII with an appropriate radical precursor such as diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and 1,3-dioxoisoindolin-2-yl 2-cyclopropoxypropanoate in the presence of an amine base such as DIPEA in a solvent such as DMSO under 450 nm light provides the corresponding sulfinamide (structure not shown). Subsequent deprotection of the sulfinamide with a reagent such as HCl in a solvent such as 1,4-dioxane provides amine A-III.

[0476] [ka]

[0477] Scheme 5 Amines A-IIIa can be prepared as shown in Scheme 5. Aldehydes BI can be reacted with Treatment with (S)-(-)-2-methyl-2-propanesulfinamide in the presence of a reagent such as CuSO4 and a solvent such as DCM affords the corresponding sulfinimine (structure not shown). The sulfinimine is then reacted with a reagent such as 3-[1-(trifluoromethyl)cyclopropyl]propanoic acid and a base such as LDA in a solvent such as THF to afford compound B-II. Compound B-II can be converted to compound B-III via a two-step process. First, compound B-II is treated with N-hydroxyphthalimide in the presence of a reagent such as DCC using an additive such as DMAP in a solvent such as DCM. The second step of this process is reduction of the dioxoisoindoline substituent using a reagent such as Hantzsch's ester in the presence of a base such as DIPEA in a solvent such as DMSO. Subsequent deprotection of sulfinamine B-III with a reagent such as HCl in a solvent such as 1,4-dioxane affords amine A-IIIa.

[0478] Intermediate 1: 2-Fluoro-2-methylpropane-1,3-diamine dihydrochloride

[0479] [ka]

[0480] Step A: 2-Fluoro-2-methylmalonamide. Diethyl 2-fluoromalonate (2.00 g, 11.2 mmol) and anhydrous THF (40 mL) were added in one portion to a nitrogen-purged 250 mL three-necked round-bottom flask charged with t-BuOK (13.5 mL, 13.5 mmol, 1 M THF solution), and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was treated with MeI (0.840 mL, 13.5 mmol) via syringe over 1 min, and the resulting mixture was stirred at room temperature for an additional 1 h. The mixture was then treated with ammonia (60 mL, 7 M MeOH solution) in one portion, and the reaction mixture was stirred at room temperature for an additional 16 h. The reaction mixture was then concentrated to dryness to give a white solid. The solid was washed with HO (40 mL) and dried under vacuum to give 2-fluoro-2-methylmalonamide (80% yield) as a white solid.

[0481] Step B: 2-Fluoro-2-methylpropane-1,3-diamine dihydrochloride. 2-Fluoro-2-methylmalonamide (1.2 g, 9.0 mmol, Step A) and THF (15 mL) were added to an oven-dried, nitrogen-purged 100 mL three-necked round-bottom flask, which was then cooled to 0 °C in an ice / water bath. The mixture was treated dropwise over 10 min with BH3·THF (45 mL, 45 mmol) using a constant pressure addition funnel. The reaction mixture was stirred at 50 °C for 3 h and then treated in small portions with MeOH (5.0 mL) over 5 min. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction mixture was then concentrated to dryness, and the residue was dissolved in MeOH (20 mL) and HCl (5 mL, 4 M in MeOH). The resulting mixture was stirred at room temperature for an additional 0.5 h, filtered, and the filter cake was dried under vacuum to give 2-fluoro-2-methylpropane-1,3-diamine dihydrochloride (62% yield) as a white solid.

[0482] Intermediate 2: 1-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(cyclopropyl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0483] [ka]

[0484] Step A: tert-butyl ((S)-(7-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. To a solution of tert-butyl ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (100 mg, 0.23 mmol) and 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl trifluoromethanesulfonate (172 mg, 0.46 mmol) in acetonitrile (1.2 mL) was added DIPEA (44 μL, 0.25 mmol), and the reaction mixture was heated at 50° C. for 18 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by silica gel chromatography (0-100% EtOAc (containing 10% MeOH) / hexanes) to give the title compound (81% yield).

[0485] Step B: tert-Butyl ((S)-(7-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. To a solution of tert-butyl ((S)-(7-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (500 mg, 0.76 mmol, Step A) in 3.8 mL of EtOH was added hydrazine monohydrate (110 μL, 2.28 mmol). The reaction mixture was warmed to 35°C and stirred for 18 h, at which point a thick slurry formed. The reaction mixture was cooled in an ice bath, filtered, washed with 10 mL of ice-cold EtOH, and the filtrate was concentrated to give the title compound, which was used in the next step without further purification (assumed 100% yield).

[0486] Step C: tert-Butyl ((S)-(7-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. To a stirred solution of tert-butyl ((S)-(7-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (0.76 mmol, theoretically, Step B) in THF (12 mL) was added CDI (185 mg, 1.14 mmol) and the reaction mixture was stirred at 60° C. for 18 hours. The reaction mixture was cooled to room temperature and treated with 3M aqueous NaOH (2 mL) with stirring for 10 minutes, then diluted with brine and the layers were separated. The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated. This material was purified by silica gel chromatography (0-100% EtOAc (with 10% MeOH) / hexanes) to give the title compound (77% yield).

[0487] Step D: 1-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(cyclopropyl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. A vial was charged with tert-butyl ((S)-(7-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (153 mg, 0.28 mmol, Step C) and TFA (2 mL, 26.13 mmol). The reaction was stirred at room temperature for 2 hours and then concentrated. The resulting oil was dissolved in DCM and quenched by carefully adding 0.5 M aqueous NaOH until the pH of the solution was above pH 7. The aqueous layer was washed with DCM. The combined organic phases were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to give the title compound (assumed 100% yield), which was used without further purification.

[0488] Intermediate 3: 1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0489] [ka]

[0490] Step A: tert-Butyl ((S)-(7-((S)-1-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. To an oven-dried, N2-flushed flask was added tributyl(methoxymethyl)stannane (1.41 g, 4.22 mmol) and THF (20.1 mL). The flask was cooled (-78 °C) and n-butyllithium (1.76 mL, 4.22 mmol, 2.4 M in hexane) was added dropwise. After an additional 15 min at −78 °C, the reaction mixture was treated dropwise with a solution of tert-butyl ((S)-(7-((E)-(((R)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (1.00 g, 2.01 mmol) in THF (5 mL). After stirring for an additional 2 h at −78 °C, the reaction mixture was quenched with EtOH (0.35 mL), allowed to warm to room temperature, and diluted with saturated aqueous NaHCO and EtOAc. The layers were separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (40–100% acetone / hexanes) to afford the title compound (39% yield) as the second-eluting isomer.

[0491] Step B: tert-butyl ((S)-(7-((S)-1-amino-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound was prepared by the procedure of ((R)-1-(7-((S *Prepared as described for the synthesis of intermediate 9 using tert-butyl ((S)-(7-((S)-1-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step A) instead of tert-butyl (((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate to afford the title compound (100% yield) as a white foam.

[0492] Step C: tert-butyl ((S)-(4,4-difluorocyclohexyl)(7-((S)-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. The title compound was prepared as described for Step A of the synthesis of Intermediate 2 using tert-butyl ((S)-(7-((S)-1-amino-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step B) instead of tert-butyl ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate to afford the title compound (84% yield).

[0493] Step D: tert-Butyl ((S)-(7-((S)-1-((3-amino-2,2-difluoropropyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound was prepared as described for Step B of the synthesis of Intermediate 2 using tert-butyl ((S)-(4,4-difluorocyclohexyl)(7-((S)-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (Step C) instead of tert-butyl ((S)-(7-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate to afford the title compound (86% yield).

[0494] Step E: tert-Butyl ((S)-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound was prepared as described for Step C of the synthesis of Intermediate 2 using tert-butyl ((S)-(7-((S)-1-((3-amino-2,2-difluoropropyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step D) instead of tert-butyl ((S)-(7-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate to afford the title compound (100% yield).

[0495] Step F: 1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. The title compound was prepared as described for Step D of the synthesis of Intermediate 2, using tert-butyl ((S)-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step E) instead of tert-butyl ((S)-(7-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate and adding DCM (2 mL) as a co-solvent to afford the title compound (93% yield), which was used without further purification.

[0496] Intermediate 4: (R)-(1-(7-chloroimidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)tert-butylcarbamate

[0497] [ka] In an oven-dried round-bottom flask, 5-chloropyridazin-3-amine (4.45 g, 34.3 mmol), (S)-(4-(dimethyl(oxo)-λ)- 6A mixture of tert-butyl 1-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)butan-2-yl)carbamate (12.7 g, 32.6 mmol), chlorocyclopentadienylbis(triphenylphosphine)ruthenium(II) (630 mg, 0.868 mmol), sodium trifluoromethanesulfonate (313 mg, 1.82 mmol), and 4 Å molecular sieves (8.9 g) was charged. Anhydrous toluene (110 mL) was added under a N atmosphere, and the reaction was then heated to 90° C. for 24 hours. The mixture was allowed to cool to room temperature and then filtered through diatomaceous earth (e.g., Celite®). The filter cake was washed with EtOAc, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% EtOAc / hexanes) to afford the title compound in 28% yield.

[0498] Intermediate 5: (R)-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)-1-(7-vinylimidazo[1,2-b]pyridazin-2-yl)ethyl)carbamate tert-butyl

[0499] [ka] To a solution of (R)-(1-(7-chloroimidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)tert-butylcarbamate (4.05 g, 9.58 mmol, Intermediate 4) and potassium vinyltrifluoroborate (1.93 g, 14.4 mmol) in 1,4-dioxane (33 mL) was added a solution of tribasic potassium phosphate (6.10 g, 28.7 mmol) in HO (5 mL). The mixture was degassed with a N sparge for 10 min, after which RuPhos Pd G3 (200 mg, 0.239 mmol) was added, the vessel was sealed with a Teflon septum, and the reaction mixture was heated to 100 °C for 2 h. The mixture was then concentrated under reduced pressure, diluted with HO, and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0500] Intermediate 6: (R)-(1-(7-formylimidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)tert-butylcarbamate

[0501] [ka] To a well-stirred mixture of (R)-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)-1-(7-vinylimidazo[1,2-b]pyridazin-2-yl)ethyl) tert-butylcarbamate (3.97 g, 9.58 mmol, Intermediate 5) and potassium osmate(VI) dihydrate (88 mg, 0.24 mmol) in 1,4-dioxane (12 mL) was added a suspension of sodium periodate (8.20 g, 38.3 mmol) in HO (11 mL). The reaction was stirred at room temperature for 3 hours and then filtered through diatomaceous earth (e.g., Celite®). The filter cake was washed with EtOAc, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-100% EtOAc / hexanes) to provide the title compound in 69% yield.

[0502] Intermediate 7: tert-butyl ((R)-1-(7-((E)-(((R)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0503] [ka] A mixture of (R)-(1-(7-formylimidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)tert-butylcarbamate (2.75 g, 6.60 mmol, Intermediate 6), (R)-2-methylpropane-2-sulfinamide (1.12 g, 9.25 mmol), and CsCO (3.01 g, 9.25 mmol) in CHCl (21 mL) was stirred at room temperature for 16 hours, then filtered through diatomaceous earth (e.g., Celite®), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-100% EtOAc / hexanes) to provide the title compound in 87% yield.

[0504] Intermediate 8:((R)-1-(7-((S *)-1-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate tert-Butyl

[0505] [ka] A solution of tributyl(methoxymethyl)stannane (948 mg, 2.83 mmol) in THF (10 mL) was cooled to −78° C., after which n-butyllithium (1.8 mL, 1.6 M in hexanes, 2.8 mmol) was added dropwise. The reaction was stirred for 20 minutes, after which a solution of tert-butyl ((R)-1-(7-((E)-(((R)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (700 mg, 1.35 mmol, Intermediate 7) in THF (5 mL) was added slowly over 10 minutes. The reaction was stirred at −78° C. for 2.5 hours, after which it was quenched with EtOH (0.24 mL) and allowed to warm to room temperature. To this mixture was added saturated aqueous NaHCO3 (1.5 mL) and potassium fluoride (1.3 g, 11 mmol, 50 w / w% on diatomaceous earth (e.g., Celite®). The resulting suspension was stirred for 16 h, after which the solids were filtered off and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography (10-100% EtOAc / hexanes) afforded the title compound in 17% yield.

[0506] Intermediate 9:((R)-1-(7-((S * )-1-amino-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate tert-butyl

[0507] [ka] ((R)-1-(7-((S * To a solution of tert-butyl 2-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (126 mg, 0.223 mmol, Intermediate 8) in EtOAc (1 mL) was added HCl (0.11 mL, 0.45 mmol, 4 M solution in 1,4-dioxane). The reaction was stirred at room temperature for 4.5 hours, after which HCl (0.055 mL, 0.23 mmol, 4 M solution in 1,4-dioxane) was added. The reaction was stirred at room temperature for 30 minutes, after which it was diluted with HO (5 mL). The resulting solution was washed twice with 3:2 hexane / EtOAc, and these extracts were discarded. NaCO (71 mg) was added to adjust the pH of the aqueous mixture. The resulting solution was extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound in 68% yield.

[0508] Intermediate 10:((R)-1-(7-((S * )-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate tert-Butyl

[0509] [ka]

[0510] Process A:((R)-1-(7-((S * )-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate tert-butyl. ((R)-1-(7-((S *To a stirred solution of tert-butyl 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (70 mg, 0.15 mmol, Intermediate 9) and 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl trifluoromethanesulfonate (113 mg, 0.303 mmol) in acetonitrile (0.8 mL) was added DIPEA (29 μL, 0.17 mmol). The reaction mixture was heated at 50° C. for 36 h. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure, and diluted with HO. The mixture was extracted twice with EtOAc, and the combined organic extracts were then washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0511] Process B:((R)-1-(7-((S * )-1-((3-amino-2,2-difluoropropyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate tert-butyl ((R)-1-(7-((S * To a solution of tert-butyl 2-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (104 mg, 0.152 mmol, Step A) in EtOH (1.5 mL) was added hydrazine monohydrate (120 μL, 1.85 mmol). The reaction mixture was heated to 50° C. and stirred for 2 h, at which point a thick slurry formed. The reaction mixture was diluted with HO and extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0512] Process C:((R)-1-(7-((S * )-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate tert-butyl ((R)-1-(7-((S * To a stirred solution of tert-butyl 2-((3-amino-2,2-difluoropropyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (84 mg, 0.15 mmol, Step B) in THF (3 mL) was added CDI (74 mg, 0.46 mmol) and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was then cooled to room temperature and then quenched with HO. The mixture was diluted with EtOAc, washed with 0.05 M aqueous HCl and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0513] Intermediate 11:1-((S * )-1-(2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one hydrochloride

[0514] [ka] HCl (0.76 mL, 3.0 mmol, 4 M solution in 1,4-dioxane) was added to ((R)-1-(7-((S *To the resulting solution was added tert-butyl 2-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (84 mg, 0.15 mmol, Intermediate 10). The reaction was stirred at room temperature for 45 minutes, then diluted with MeOH and concentrated under reduced pressure. The residue was dissolved in MeCN and then concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0515] Intermediate 12: Tributyl(cyclopropoxymethyl)stannane

[0516] [ka] To a reaction vial containing NaH (0.500 g, 12.5 mmol, 60% in mineral oil) under N was added DMF (40 mL). The resulting suspension was cooled to 0 °C, and then cyclopropanol (0.789 mL, 12.5 mmol) was added dropwise. The reaction was stirred at this temperature for 10 minutes, after which tributyl(iodomethyl)stannane (3.32 mL, 10.0 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 1 hour, then quenched with HO and diluted with 5% aqueous LiCl. The resulting mixture was extracted with CHCl (3 × 25 mL), and then the combined organics were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-20% EtOAc / hexanes) afforded the title compound in 100% yield.

[0517] Intermediate 13: tert-butyl ((S)-(7-((S)-1-(((R)-tert-butylsulfinyl)amino)-2-cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0518] [ka] A solution of tributyl(cyclopropoxymethyl)stannane (800 mg, 2.22 mmol, Intermediate 12) in THF (10 mL) was cooled to −78° C., after which n-butyllithium (1.4 mL, 1.6 M in hexanes, 2.2 mmol) was added dropwise. The reaction was stirred for 20 minutes, after which a solution of tert-butyl ((S)-(7-((E)-(((R)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (525 mg, 1.06 mmol) in THF (5 mL) was added slowly over 10 minutes. The reaction was stirred at −78° C. for 30 minutes, after which it was quenched with EtOH (0.19 mL) and allowed to warm to room temperature. The resulting mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-60% acetone / hexane (containing 0.1% TEA)) to give the title compound in 48% yield. The stereochemistry was assigned by Mosher ester analysis of intermediate 14.

[0519] Intermediate 14: tert-butyl ((S)-(7-((S)-1-amino-2-cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0520] [ka] To a solution of tert-butyl ((S)-(7-((S)-1-(((R)-tert-butylsulfinyl)amino)-2-cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (300 mg, 0.527 mmol, Intermediate 13) in EtOAc (3.5 mL) was added HCl (0.33 mL, 1.3 mmol, 4 M in 1,4-dioxane). The reaction was stirred at room temperature for 1 h and then diluted with HO. The resulting solution was washed twice with hexanes, and these extracts were discarded. The pH of the aqueous mixture was adjusted by adding 3 M aqueous NaOH (0.7 mL), followed by extraction three times with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound, which was used without further purification. The stereochemistry was assigned by Mosher ester analysis.

[0521] Intermediate 15: tert-butyl ((S)-(7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0522] [ka]

[0523] Step A: tert-butyl ((S)-(7-((S)-2-cyclopropoxy-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. To a stirred solution of tert-butyl ((S)-(7-((S)-1-amino-2-cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (245 mg, 0.527 mmol, Intermediate 14) and 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl trifluoromethanesulfonate (354 mg, 0.949 mmol) in acetonitrile (2.6 mL) was added DIPEA (138 μL, 0.791 mmol). The reaction mixture was heated at 55° C. for 16 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. Purification by silica gel chromatography (10-100% (10% MeOH in EtOAc) / hexanes) afforded the title compound in 55% yield.

[0524] Step B: tert-Butyl ((S)-(7-((S)-1-((3-amino-2,2-difluoropropyl)amino)-2-cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. To a solution of tert-butyl ((S)-(7-((S)-2-cyclopropoxy-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (0.20 g, 0.29 mmol, Step A) in 3 mL of EtOH was added hydrazine monohydrate (220 μL, 2.9 mmol). The reaction mixture was heated to 50° C. and stirred for 2 h, at which point a thick slurry formed. The reaction mixture was diluted with EtOAc, then washed with 5% aqueous LiCl and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound in 92% yield.

[0525] Step C: tert-butyl ((S)-(7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. A stirred solution of tert-butyl ((S)-(7-((S)-1-((3-amino-2,2-difluoropropyl)amino)-2-cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (150 mg, 0.27 mmol, Step B) and DIPEA (116 μL, 0.671 mmol) in CHCl (5 mL) was cooled to 0 °C, after which a solution of triphosgene (32 mg, 0.11 mmol) in CHCl (0.5 mL) was added. The reaction was stirred at 0 °C for 15 min and then quenched with HO and 2 M aqueous HCl (0.67 mL, 1.3 mmol). The resulting mixture was extracted three times with CH2Cl2, then the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0526] Intermediate 16: 1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-cyclopropoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one hydrochloride

[0527] [ka] The title compound was synthesized by the reaction of ((R)-1-(7-((S *

[0082] Prepared as described for the synthesis of intermediate 11, using tert-butyl ((S)-(7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (intermediate 15) instead of tert-butyl ((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. 1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-cyclopropoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one hydrochloride (1.12 g, 1.87 mmol) was dissolved in 50 mL of EtOAc and 30 mL of saturated aqueous NaHCO solution, followed by 3M 1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-cyclopropoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one hydrochloride was converted to 1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-cyclopropoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (hereafter referred to as Intermediate 16A) by adding aqueous NaOH to adjust the pH of the solution to pH 11. The layers were separated, and the aqueous layer was further extracted with EtOAc (4 x 25 mL). The organic layers were combined, washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to dryness to give Intermediate 16A (99% yield) as a white solid.

[0528] Intermediate 17: tert-butyl (R)-(1-(7-(((3-amino-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0529] [ka] To a flask charged with a solution of tert-butyl (R)-(1-(7-formylimidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (72 mg, 0.173 mmol, Intermediate 6) and 2,2-difluoropropane-1,3-diamine dihydrochloride (63.3 mg, 0.346 mmol) in DCM (6 mL) was added triethylamine (0.121 mL, 0.865 mmol). The reaction was stirred at room temperature until the solids dissolved and then heated to 40 °C. After 1 h, the reaction was cooled to room temperature and MeOH (1 mL), sodium cyanoborohydride (65.2 mg, 1.04 mmol), and AcOH (0.040 mL, 0.692 mmol) were added, and the resulting mixture was stirred at room temperature. After 1 h, LCMS analysis showed that all of the tert-butyl (R)-(1-(7-formylimidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate was consumed. The mixture was concentrated under reduced pressure and diluted with saturated aqueous NaHCO and CHCl. ​​The resulting mixture was extracted twice with CHCl. ​​The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0530] Intermediate 18: tert-butyl (R)-(1-(7-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0531] [ka] To a solution of tert-butyl (R)-(1-(7-(((3-amino-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (84.1 mg, 0.165 mmol, Intermediate 17) in THF (4.3 mL) was added CDI (84.1 mg, 0.519 mmol). The resulting mixture was heated to 65° C. After 75 minutes, LCMS analysis indicated that all of the tert-butyl (R)-(1-(7-(((3-amino-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate was consumed. The mixture was cooled to room temperature and quenched with 1 M aqueous NaOH (1.5 mL). The mixture was then concentrated under reduced pressure and partitioned between saturated aqueous NaHCO and EtOAc. The aqueous layer was further extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (10-100% (10% MeOH in EtOAc) / hexanes) afforded the title compound in 67% yield (62.4 mg).

[0532] Intermediate 19: (R)-1-((2-(1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0533] [ka] To a mixture of tert-butyl (R)-(1-(7-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (62.4 mg, 0.116 mmol, Intermediate 18) in CHCl (21 mL) was added 2,2,2-trifluoroacetic acid (0.18 mL, 2.33 mmol) and the resulting mixture was stirred at room temperature. After 20 minutes, LCMS analysis showed that all of the tert-butyl (R)-(1-(7-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate was consumed. The mixture was diluted with EtOAc (2 mL) and washed twice with saturated aqueous NaHCO. The aqueous layer was then washed with a 4:1 mixture of DCM / IPA. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0534] Intermediate 20: (S)-1-((2-(amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0535] [ka]

[0536] Step A: (S)-tert-Butyl ((7-(((3-amino-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. A solution of tert-butyl (S)-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (300 mg, 0.761 mmol), 2,2-difluoropropane-1,3-diamine dihydrochloride (418 mg, 2.28 mmol), and triethylamine (0.742 mL, 5.32 mmol) in DCM (8.6 mL) was stirred at room temperature. After 2 h, acetic acid (0.261 mL, 4.56 mmol) and MeOH (1.5 mL) were added. After an additional 5 min, sodium cyanoborohydride (167 mg, 2.65 mmol) was added, and the heterogeneous reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (30 mL), and saturated aqueous sodium bicarbonate (30 mL) and 3 M aqueous sodium hydroxide (30 mL) were added. The layers were separated, and the aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give a gum that was used directly in the next step without further purification.

[0537] Step B: tert-Butyl (S)-((7-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. tert-Butyl (S)-((7-(((3-amino-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (0.76 mmol, theoretical) prepared in Step A was diluted with THF (10 mL) and treated with CDI (370 mg, 2.28 mmol). The resulting mixture was stirred at room temperature for 45 minutes. The reaction mixture was then diluted with THF (90 mL) and warmed to 60° C. for 45 minutes. The reaction mixture was cooled to room temperature and treated with 3 M aqueous sodium hydroxide (3 mL). After stirring at room temperature for 1 h, the reaction mixture was diluted with brine (20 mL) and the layers were separated. The organic layer was washed with 0.1 M aqueous HCl (2 × 10 mL) and brine (2 × 10 mL), dried over anhydrous MgSO4, filtered, and concentrated to give a gum, which was used directly in the next step without further purification.

[0538] Step C: (S)-1-((2-(amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. To a cooled (0° C.) solution of tert-butyl (S)-((7-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (500 mg) prepared in Step B in 3.7 mL of DCM was added TFA (3.7 mL, 48 mmol). After stirring at 0° C. for 1.5 hours, the reaction mixture was concentrated to dryness and then diluted with EtOAc (20 mL), brine (30 mL), 3 M aqueous sodium hydroxide (5 mL), and saturated aqueous sodium bicarbonate (3 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×20 mL) and DCM (6×15 mL). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (88.3% yield over three steps) as a yellow film, which was used without further purification.

[0539] Intermediate 21: 1-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-methyltetrahydropyrimidin-2(1H)-one

[0540] [ka]

[0541] Step A: tert-butyl ((1S)-(7-(((3-((tert-butoxycarbonyl)amino)-2-methylpropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound was synthesized in a manner similar to Step A of Intermediate 20, using tert-butyl (3-amino-2-methylpropyl)carbamate instead of 2,2-difluoropropane-1,3-diamine dihydrochloride.

[0542] Step B: tert-Butyl ((1S)-(4,4-difluorocyclohexyl)(7-((5-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. tert-Butyl ((1S)-(7-(((3-((tert-butoxycarbonyl)amino)-2-methylpropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (0.76 mmol, theoretically, Step A) was diluted with THF (10 mL), treated with potassium tert-pentoxide (1.5 mL, 2 M solution in tert-amyl alcohol), and warmed to 60° C. After 2.5 h, the reaction mixture was cooled to room temperature, treated with 1 M aqueous HCl (5 mL), and diluted with EtOAc (30 mL), brine (30 mL), and saturated aqueous NaHCO (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organics were dried over anhydrous NaSO, filtered, and concentrated to dryness to give an oil that was used in the next step without further purification.

[0543] Step C: 1-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-methyltetrahydropyrimidin-2(1H)-one. The title compound was prepared as described for Step C of the synthesis of Intermediate 20 using tert-butyl ((1S)-(4,4-difluorocyclohexyl)(7-((5-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (Step B) instead of tert-butyl (S)-((7-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate to give the title compound (312 mg), which was used without further purification.

[0544] Intermediate 22: (S)-1-((2-(amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-1,3-diazepan-2-one

[0545] [ka]

[0546] Step A: (S)-tert-butyl((7-(((4-aminobutyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound was synthesized in a manner similar to Step A of Intermediate 20, using 1,4-diaminobutane instead of 2,2-difluoropropane-1,3-diamine dihydrochloride.

[0547] Step B: tert-butyl (S)-((4,4-difluorocyclohexyl)(7-((2-oxo-1,3-diazepan-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. The title compound was synthesized in a manner similar to Step B of Intermediate 20, using tert-butyl (S)-((7-(((4-aminobutyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step A) instead of tert-butyl (S)-((7-(((3-amino-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.

[0548] Step C: (S)-1-((2-(amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-1,3-diazepan-2-one. The title compound was synthesized in a manner similar to Step C of Intermediate 20, using tert-butyl (S)-((4,4-difluorocyclohexyl)(7-((2-oxo-1,3-diazepan-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (Step B) instead of (S)-1-((2-(amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one to provide the title compound, which was used without further purification.

[0549] Intermediate 23: (S)-1-((2-(amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-dimethyltetrahydropyrimidin-2(1H)-one

[0550] [ka]

[0551] Step A: (S)-tert-butyl((7-(((3-amino-2,2-dimethylpropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound was synthesized in a manner similar to Step A of Intermediate 20, using 2,2-dimethylpropane-1,3-diamine instead of 2,2-difluoropropane-1,3-diamine dihydrochloride.

[0552] Step B: tert-butyl (S)-((4,4-difluorocyclohexyl)(7-((5,5-dimethyl-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. The title compound was synthesized in a manner similar to Step B of Intermediate 20, using tert-butyl (S)-((7-(((3-amino-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step A) instead of tert-butyl (S)-((7-(((3-amino-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.

[0553] Step C: (S)-1-((2-(amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-dimethyltetrahydropyrimidin-2(1H)-one. The title compound was synthesized in a manner similar to Step C of Intermediate 20 using tert-butyl (S)-((4,4-difluorocyclohexyl)(7-((5,5-dimethyl-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (Step B) instead of tert-butyl (S)-((7-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate to provide the title compound, which was used without further purification.

[0554] Intermediate 24: (S)-1-((2-(amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)tetrahydropyrimidin-2(1H)-one

[0555] [ka]

[0556] Step A: (S)-tert-butyl((7-(((3-aminopropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound was synthesized in a manner similar to Step A of Intermediate 20, using 1,3-diaminopropane instead of 2,2-difluoropropane-1,3-diamine dihydrochloride.

[0557] Step B: tert-butyl (S)-((4,4-difluorocyclohexyl)(7-((2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. The title compound was synthesized in a manner similar to Step B of Intermediate 20, using tert-butyl (S)-((7-(((3-aminopropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step A) instead of tert-butyl (S)-((7-(((3-amino-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.

[0558] Step C: (S)-1-((2-(amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)tetrahydropyrimidin-2(1H)-one. The title compound was synthesized in a manner similar to Step C of Intermediate 20 using tert-butyl (S)-((4,4-difluorocyclohexyl)(7-((2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (Step B) instead of tert-butyl (S)-((7-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate to provide the title compound, which was used without further purification.

[0559] Intermediate 25:1-((S * )-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-ethoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one hydrochloride

[0560] [ka]

[0561] Step A. Tributyl(ethoxymethyl)stannane The title compound was prepared as described for the synthesis of intermediate 12 using ethanol instead of cyclopropanol (86% yield).

[0562] Process B.((S)-(7-((S * tert-Butyl)-1-(((R)-tert-butylsulfinyl)amino)-2-ethoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound was prepared in a manner similar to the synthesis of Intermediate 13 (56% yield) using tributyl(ethoxymethyl)stannane (Step A) instead of tributyl(cyclopropoxymethyl)stannane.

[0563] Process C.((S)-(7-((S * )-1-amino-2-ethoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl) tert-butyl carbamate. The title compound was prepared by substituting ((S)-(7-((S-1-(((R)-tert-butylsulfinyl)amino)-2-cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate for tert-butyl ((S)-(7-((S *Prepared as described for the synthesis of Intermediate 14 using tert-butyl 2-(((R)-tert-butylsulfinyl)amino)-2-ethoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step B) and used without further purification.

[0564] Process D.((S)-(7-((S) * )-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-ethoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl) tert-butyl carbamate. The title compound was prepared by replacing ((S)-(7-((S)-1-amino-2-cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate with ((S)-(7-((S * Prepared as described for the synthesis of intermediate 15 using tert-butyl)-1-amino-2-ethoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step C) (60% yield).

[0565] Process E.1-((S * )-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-ethoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one hydrochloride. The title compound was prepared by the procedure of ((R)-1-(7-((S * )-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl) tert-butylcarbamate instead of ((S)-(7-((S *Prepared as described for the synthesis of intermediate 11 using tert-butyl 1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-ethoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step D) (92% yield).

[0566] Intermediate 26: 2,5-dioxopyrrolidin-1-yl 1-isopropyl-1H-pyrazole-5-carboxylate

[0567] [ka]

[0568] Step A. 1-Isopropyl-1H-pyrazole-5-carbonyl chloride. A round-bottom flask was charged with 1-isopropyl-1H-pyrazole-5-carboxylic acid (1 g, 6.5 mmol) and DCM (13 mL) and cooled to 0° C. under a nitrogen atmosphere. To the solution was added oxalyl chloride (1.1 mL, 13.0 mmol), followed by DMF (0.05 mL, 0.65 mmol), dropwise. The reaction was stirred while slowly warming to room temperature. When gas evolution ceased, the reaction was concentrated under reduced pressure to give a yellow oil, which was then dissolved in 12 mL of dry DCM and stored as a 2 M solution.

[0569] Step B. 2,5-dioxopyrrolidin-1-yl 1-isopropyl-1H-pyrazole-5-carboxylate. A round-bottom flask was charged with N-hydroxysuccinimide (1.1 g, 9.7 mmol), DCM (25 mL), and DIPEA (16 mL, 6.5 mmol) and cooled to 0 °C under a nitrogen atmosphere. To the solution was added 1-isopropyl-1H-pyrazole-5-carbonyl chloride solution (13 mL, 6.5 mmol, 2 M in DCM, Step A). ​​The solution was allowed to warm to room temperature with stirring for 1 hour. The solution was washed with water, then brine, dried over anhydrous MgSO4, filtered, and concentrated. The isolated material was purified by silica gel chromatography (0-100% EtOAc (containing 10% MeOH) / hexanes) to afford the title compound as an off-white solid.

[0570] Intermediate 27: 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl-1,1,3,3-d4 trifluoromethanesulfonate

[0571] [ka] Step AN - Benzyl-2,2-difluoro-3,3-d2-3-hydroxypropanamide. A flask was charged with methyl 3-(benzylamino)-2,2-difluoro-3-oxopropanoate (2 g, 8.2 mmol), MeOH (42 mL), and cooled to 0 °C. To the cold solution was added sodium borodeuteride (860 mg, 20.6 mmol) in small portions. The reaction was stirred at 0 °C for 1 hour and then quenched by the addition of water (15 mL). The reaction was concentrated to remove MeOH. The resulting solution was further diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organics were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give N-benzyl-2,2-difluoro-3,3-d2-3-hydroxypropanamide as a white solid:

[0572] [ka] (100% yield) was obtained and used without further purification.

[0573] Step B. 3-(Benzylamino)-2,2-difluoropropan-1,1,3,3-d4-1-ol. A flask was charged with N-benzyl-2,2-difluoro-3,3-d2-3-hydroxypropanamide (7.7 g, 35.5 mmol, Step A) and THF (230 mL). Boron trifluoride diethyl etherate (18.8 mL, 46.5 wt%, 70.9 mmol) was added portionwise to the reaction. The reaction mixture was then heated to reflux and stirred for 1 hour. The reaction mixture was cooled to room temperature and quenched by careful addition of MeOH (50 mL). The resulting mixture was stirred for 30 minutes and then concentrated to dryness. Ethyl acetate was added to the resulting white solid, and the remaining solid was removed by filtration. The filtrate was concentrated to provide the title compound, which was used without further purification.

[0574] Step C. 3-Amino-2,2-difluoropropan-1,1,3,3-d4-1-ol. A flask was charged with 3-(benzylamino)-2,2-difluoropropan-1,1,3,3-d4-1-ol (7.1 g, 34.3 mmol, Step B), MeOH (690 mL), Pd / C (3.7 g, 3.4 mmol, 10 wt% Pd), and ammonium formate (21.7 g, 343.9 mmol). The reaction was warmed to 60° C. and stirred for 3 hours. The reaction was cooled to room temperature and filtered through a pad of diatomaceous earth (e.g., Celite®), and the solid was washed with ethyl acetate. The combined organic layers were concentrated to give an off-white solid, which was used directly in the next step.

[0575] Step D. 2-(2,2-Difluoro-3-hydroxypropyl-1,1,3,3-d4)isoindoline-1,3-dione. A flask was charged with 3-amino-2,2-difluoropropan-1,1,3,3-d4-1-ol (3.6 g, 34.4 mmol, Step C), N-carbethoxyphthalimide (8.7 g, 39.6 mmol), THF (86 mL), and DIPEA (23.7 mL, 137 mmol). The reaction mixture was then heated to 60° C. for 12 hours. The reaction mixture was cooled to room temperature and concentrated to dryness. Water (250 mL) was added to the resulting residue and stirred for 30 minutes, during which time a solid formed. The solid was collected by filtration and dried under reduced pressure overnight to give the title compound as a white powder (59% yield over Steps B, C, and D).

[0576] Step E: 3-(1,3-Dioxoisoindolin-2-yl)-2,2-difluoropropyl-1,1,3,3-d4 trifluoromethanesulfonate. A flask was charged with 2-(2,2-difluoro-3-hydroxypropyl-1,1,3,3-d4)isoindoline-1,3-dione (1.5 g, 5.9 mmol, Step D), DCM (20 mL), and pyridine (0.53 mL, 6.6 mmol), and trifluoromethanesulfonic anhydride (1.1 mL, 6.3 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes and then quenched by the addition of water (5 mL). The resulting layers were separated, and the aqueous layer was further extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give an off-white solid in 50% yield.

[0577] Intermediate 28: 1-((S)-1-(2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one-4,4,6,6-d4

[0578] [ka]

[0579] Step A: tert-butyl ((R)-1-(6-chloro-7-((S)-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl-1,1,3,3-d4)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. A flask was charged with tert-butyl ((R)-1-(7-((S)-1-amino-2-methoxyethyl)-6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (484 mg, 0.98 mmol, Intermediate 48), 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl-1,1,3,3-d4 trifluoromethanesulfonate (458 mg, 1.2 mmol, Intermediate 27), MeCN (3.5 mL), and DIPEA (0.33 mL, 1.9 mmol). The resulting reaction mixture was stirred at 60° C. for 48 hours. The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified by silica gel chromatography (0-100% ethyl acetate (with 10% MeOH):hexanes) to afford the title compound (71%) as a white solid.

[0580] Step B: tert-butyl ((R)-1-(7-((S)-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl-1,1,3,3-d4)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. A vial was charged with tert-butyl ((R)-1-(6-chloro-7-((S)-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl-1,1,3,3-d4)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (450 mg, 0.62 mmol, Step A), 2-methyl-2-butanol (20 mL), 2,2,2-trifluoroethanol (10 mL), Pd / C (381 mg, 10 wt% Pd), and ammonium formate (1.3 g, 21.7 mmol). The vial was warmed to 90° C., stirred for 1 hour, and then cooled to room temperature. The reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®) and the solid was washed with ethanol. The combined organic layers were concentrated to give the title compound (100%) as a yellow solid.

[0581] Step C: tert-butyl ((R)-1-(7-((S)-1-((3-amino-2,2-difluoropropyl-1,1,3,3-d4)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. A flask was charged with a stir bar, tert-butyl ((R)-1-(7-((S)-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl-1,1,3,3-d4)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (435 mg, 0.63 mmol, Step B), ethanol (3.3 mL), and hydrazine monohydrate (0.42 mL, 6.3 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was then partitioned between water and ethyl acetate, the layers were separated, and the aqueous layer was further extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a glassy solid (71%).

[0582] Step D: tert-butyl ((R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl-4,4,6,6-d4)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. A flask was charged with tert-butyl ((R)-1-(7-((S)-1-((3-amino-2,2-difluoropropyl-1,1,3,3-d4)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (241 mg, 0.43 mmol, Step C), THF (8.6 mL), CDI (209 mg, 1.3 mmol), and DIPEA (0.22 mL, 1.3 mmol). The reaction was warmed to 60° C. and stirred for 1 hour. The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The layers were separated and the aqueous phase was further extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, concentrated, and purified by silica gel chromatography (0-100% ethyl acetate (with 10% MeOH):hexanes) to afford the title compound (45%) as a glassy solid.

[0583] Step E: 1-((S)-1-(2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one-4,4,6,6-d4. A flask was charged with tert-butyl ((R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl-4,4,6,6-d4)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (105 mg, 0.18 mmol, Step D) and TFA (1 mL). The reaction was stirred at room temperature for 5 minutes and then concentrated. The residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a yellow solid (100%).

[0584] Intermediate 29: tert-butyl ((S)-(7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl-4,4,6,6-d4)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0585] [ka] The title compound was prepared by using 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl-1,1,3,3-d4 trifluoromethanesulfonate (Intermediate 27) instead of 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl trifluoromethanesulfonate and ((R)-1-(7-((S *Prepared as described for intermediate 10 using tert-butyl ((S)-(7-((S)-1-amino-2-cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (intermediate 14) instead of tert-butyl ((S)-1-amino-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (30% yield).

[0586] Intermediate 30: 1-((S)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-cyclopropoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one-4,4,6,6-d4

[0587] [ka] The title compound was prepared by the reaction of ((R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl-4,4,6,6-d4)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate with tert-butyl ester ((S)-(7- Prepared as described for step B of intermediate 28 using tert-butyl ((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl-4,4,6,6-d4)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (intermediate 29) (71% yield).

[0588] Intermediate 31: 2,5-dioxopyrrolidin-1-yl 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylate

[0589] [ka]

[0590] Step A: 4-Cyclopropyl-1,2,5-oxadiazole-3-carbonyl chloride. A flask was charged with 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (200 mg, 1.3 mmol) and DCM (2.5 mL) and cooled to 0 °C. Oxalyl chloride (0.22 mL, 2.6 mmol) and 1 drop of DMF were then added. The resulting mixture was stirred for 1 hour while warming to room temperature. The mixture was concentrated to give a yellow oil, which was used without further purification.

[0591] Step B: 2,5-dioxopyrrolidin-1-yl 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylate. The residue from Step A was dissolved in DCM (3.2 mL) and cooled to 0 °C. To the solution was added N-hydroxysuccinimide (231 mg, 1.9 mmol) and DIPEA (0.34 mL, 1.9 mmol). The reaction was stirred for 1 hour while warming to room temperature. The reaction was quenched by the addition of water (3 mL) and the layers were separated. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. This material was purified by silica gel chromatography (0-100% ethyl acetate (with 10% MeOH) / hexanes) to afford the title compound (40% yield) as a clear oil.

[0592] Intermediate 32: (R,E)-N-(5-(((tert-butylsulfinyl)imino)methyl)-6-chloropyridazin-3-yl)pivalamide

[0593] [ka]

[0594] Step A: N-(6-chloropyridazin-3-yl)pivalamide. To a stirred solution of 6-chloropyridazin-3-amine (350 g, 2.70 mol) and pyridine (427 g, 5.40 mol) in DCM (5000 mL) was added 2,2-dimethylpropanoyl chloride (814 g, 6.75 mol) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The mixture was basified to pH 7-8 using saturated aqueous NaHCO3, and the resulting mixture was extracted with DCM (3 × 3 L). The combined organic layers were washed with brine (1 × 2 L) and water (1 × 2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by trituration with petroleum ether (2 L). The precipitated solid was collected by filtration to give the title compound in 87% yield.

[0595] Step B: N-(6-chloro-5-iodopyridazin-3-yl)pivalamide. To a stirred solution of TMPMgCl.LiCl (6.8 L, 6.8 mol) was added dropwise a solution of N-(6-chloropyridazin-3-yl)pivalamide (560 g, 2.62 mol, Step A) in THF (5.0 L) at −60° C. under a nitrogen atmosphere. The resulting mixture was stirred at −55° C. for 2.5 hours under a nitrogen atmosphere, after which a solution of iodine (998 g, 3.93 mol) in THF (3.0 L) was added dropwise at −60° C. The resulting mixture was stirred at −55° C. for an additional hour, after which the reaction was quenched by the addition of saturated NH4Cl (aq) (2 L) at −40° C. The resulting mixture was extracted with EtOAc (3 × 3 L), and the combined organic layers were washed with saturated aqueous NaSO (1 × 2 L) and brine (1 × 2 L), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% EtOAc / petroleum ether) to give the title compound in 69% yield.

[0596] Step C: N-(6-chloro-5-formylpyridazin-3-yl)pivalamide. To a stirred solution of N-(6-chloro-5-iodopyridazin-3-yl)pivalamide (607 g, 1.79 mol, Step B) in THF (6.0 L) was added 60% NaH dispersion in mineral oil (93.0 g, 2.32 mol) in small portions at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere, and isopropylmagnesium chloride-lithium chloride complex (1.99 L, 2.59 mol) was added dropwise at −60° C. The resulting mixture was stirred at −55° C. for an additional 1.5 hours, after which a solution of dimethylformamide (653 g, 8.94 mol) in THF (700 mL) was added dropwise at −60° C. The resulting mixture was stirred at room temperature for an additional hour and then quenched by the addition of saturated aqueous NH4Cl (2 L) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 3 L). The combined organic layers were washed with brine (1 x 2 L) and water (1 x 2 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound, which was used without further purification.

[0597] Step D: (R,E)—N-(5-(((tert-Butylsulfinyl)imino)methyl)-6-chloropyridazin-3-yl)pivalamide. To a stirred solution of N-(6-chloro-5-formylpyridazin-3-yl)pivalamide (372 g, 1.54 mol, Step C) and (R)-2-methylpropane-2-sulfinamide (243 g, 2.00 mol) in DCM (2.20 L) was added potassium bisulfate (272 g, 2.00 mol) in small portions at room temperature. The resulting mixture was stirred overnight at room temperature and then quenched with water (2 L) at room temperature. The mixture was extracted with DCM (3×1.5 L), and the combined organic layers were washed with water (1×1 L), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc / petroleum ether) to give the title compound in 60% yield over two steps.

[0598] Intermediate 33: N-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)-6-chloropyridazin-3-yl)pivalamide

[0599] [ka] To a stirred solution of magnesium (47.4 g, 1.95 mol) in THF (360 mL) was added dibromoethane (13.7 g, 74.0 mmol) dropwise under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere, and additional dibromoethane (60.0 g, 222 mmol) was added. The reaction mixture was then heated to 40°C, and mercuric chloride (4.72 g, 17.4 mmol) was added portionwise, and the reaction mixture was stirred at room temperature for an additional 20 minutes. A solution of MOMBr (22.1 g, 177 mmol) in toluene (30 mL) was then added dropwise at room temperature and stirred for an additional 20 minutes. The reaction mixture was then cooled to -15°C, followed by the dropwise addition of additional MOMBr (200 g, 1.60 mol) in toluene (270 mL), and the resulting mixture was stirred at -15°C for 40 minutes. To the mixture was added LiCl (74.0 g, 1.74 mol) in small portions, and the resulting mixture was stirred at −15° C. for 30 min. To the mixture was added (R,E)-N-(5-(((tert-butylsulfinyl)imino)methyl)-6-chloropyridazin-3-yl)pivalamide (60.0 g, 174 mmol, Intermediate 32) in THF (360 mL) dropwise at −20° C. The resulting mixture was stirred at −10° C. for an additional 30 min. The reaction was quenched by the addition of saturated NH4Cl(aq) (5 L) at 0° C. The mixture was extracted with EtOAc (3 × 2 L), and the combined organic layers were washed with water (1 × 2 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc / petroleum ether), reverse phase chromatography, and elution with hexane. Sequential purification by flash chromatography (40%) MeCN / water (0.1% NH4HCO3) and chiral SFC (chiral ART Cellulose-SC, 5 μm, 5 × 25 cm, 30% MeOH / CO2) afforded the title compound as the second-eluting isomer in 21% yield.

[0600] Intermediate 34: N-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2-cyclopropoxyethyl)-6-chloropyridazin-3-yl)pivalamide

[0601] [ka] The title compound was synthesized in a manner similar to Intermediate 13 using (R,E)-N-(5-(((tert-butylsulfinyl)imino)methyl)-6-chloropyridazin-3-yl)pivalamide (Intermediate 32) instead of tert-butyl ((S)-(7-((E)-(((R)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The product was purified by silica gel chromatography (0-80% EtOAc / petroleum ether), preparative HPLC (Xtimate C18, 10 μm, 40 × 150 mm, 35-65% MeCN / water (containing 0.05% aqueous NH3 (10 mM NH4HCO3)) and chiral SFC (DAICEL CHIRALPAK AD, 10 μm, 30 × 250 mm, 10% EtOH (containing 0.1% aqueous ammonia) / CO2) to give the title compound in 6% yield as the second-eluting fraction.

[0602] Intermediate 35: (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0603] [ka]

[0604] Step A: (S)—N-(5-(1-amino-2-methoxyethyl)-6-chloropyridazin-3-yl)pivalamide. To a stirred solution of N-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)-6-chloropyridazin-3-yl)pivalamide (Intermediate 33, 8.00 g, 20.5 mmol) in EtOAc (102 mL) was added a solution of HCl in 1,4-dioxane (4 M, 20.5 mL, 81.9 mmol) at room temperature. After 5 h, the reaction mixture was diluted with hexane (150 mL) and water (200 mL). The layers were separated, and the organic layer was extracted with aqueous HCl (0.05 M, 2×50 mL). The combined aqueous layers were diluted with EtOAc (50 mL) and brought to pH 11 with 3 M aqueous NaOH. The layers were separated, and the aqueous layer was extracted with EtOAc (4×50 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated to give the title compound (>99% yield, traces of EtOAc remaining) as a solid, which was used without further purification.

[0605] Step B: (S)—N-(6-chloro-5-(1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)-2-methoxyethyl)pyridazin-3-yl)pivalamide. To a stirred solution of (S)—N-(5-(1-amino-2-methoxyethyl)-6-chloropyridazin-3-yl)pivalamide (5.87 g, 20.6 mmol, Step A) in ACN (68.8 mL) was added DIPEA (5.75 mL, 33.0 mmol) and 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl trifluoromethanesulfonate (10.8 g, 28.9 mmol) under a N atmosphere, and the reaction mixture was heated to 55° C. After 23 h, additional portions of DIPEA (0.90 mL, 5.22 mmol) and 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl trifluoromethanesulfonate (1.60 g, 4.29 mmol) were added, and heating was continued for an additional 72 h. The reaction mixture was concentrated and purified by silica gel chromatography (10-50% acetone / hexanes (containing 0.1 V / V% TEA)) to give the title compound (80%).

[0606] Step C: (S)-2-(3-((1-(6-Amino-3-chloropyridazin-4-yl)-2-methoxyethyl)amino)-2,2-difluoropropyl)isoindoline-1,3-dione. To a stirred solution of (S)—N-(6-chloro-5-(1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)-2-methoxyethyl)pyridazin-3-yl)pivalamide (4.11 g, 8.06 mmol, Step B) in 1,4-dioxane (40 mL) was added aqueous HSO (3 M, 80.6 mL, 242 mmol) and the reaction mixture was heated to 60° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (80 mL) and water (80 mL), cooled to 0° C., and treated with NaHCO (40 g) in small portions with stirring (gas evolution). The reaction mixture was diluted with saturated aqueous NaHCO (100 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (4 x 100 mL) and the combined organic layers were dried over anhydrous NaSO and concentrated to give the title compound (>99% yield, traces of EtOAc remaining) as a solid, which was used without further purification.

[0607] Process D:(S)-N 1 -(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-2,2-difluoropropane-1,3-diamine. To a stirred suspension of (S)-2-(3-((1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)amino)-2,2-difluoropropyl)isoindoline-1,3-dione (3.43 g, 8.06 mmol, Step C) in EtOH (115 mL) was added hydrazine hydrate (1.20 mL, 24.2 mmol) and the reaction mixture was heated to 40° C. for 56 h. The reaction mixture was cooled to 0° C., filtered, and the filter cake was washed with ice-cold EtOH (3×5 mL). The filtrate was evaporated to dryness to give the title compound (98%), which was used without further purification.

[0608] Step E: (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. To a stirred solution of CDI (1.40 g, 8.63 mmol) in a cooled (0° C.) THF (200 mL) was added (S)-N 1 A suspension of -(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-2,2-difluoropropane-1,3-diamine (2.22 g, 7.51 mmol, Step D) in 50 mL of THF was added dropwise over 5 min. After 2 h, the reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was then heated to 60 °C for 6 h. The reaction mixture was cooled to room temperature, evaporated to dryness, and purified by reverse-phase basic HPLC (X-Bridge Prep C18 5 μm column, 50 × 250 mm, 5-100% acetonitrile / water (containing 20 nM NH4OH)). The product-containing fractions were lyophilized to give the title compound (71% yield) as a white solid.

[0609] Intermediate 36: (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-cyclopropoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0610] [ka]

[0611] Step A: (S)—N-(5-(1-amino-2-cyclopropoxyethyl)-6-chloropyridazin-3-yl)pivalamide. The title compound was synthesized in a manner similar to Step A of Intermediate 35 using N-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2-cyclopropoxyethyl)-6-chloropyridazin-3-yl)pivalamide (Intermediate 34) instead of N-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)-6-chloropyridazin-3-yl)pivalamide (99% yield) and was used without further purification.

[0612] Step B: (S)—N-(6-chloro-5-(2-cyclopropoxy-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)ethyl)pyridazin-3-yl)pivalamide. The title compound was synthesized in a manner similar to Step B of Intermediate 35, using (S)—N-(5-(1-amino-2-cyclopropoxyethyl)-6-chloropyridazin-3-yl)pivalamide (Step A) instead of (S)—N-(5-(1-amino-2-methoxyethyl)-6-chloropyridazin-3-yl)pivalamide (78% yield).

[0613] Step C: (S)-2-(3-((1-(6-Amino-3-chloropyridazin-4-yl)-2-cyclopropoxyethyl)amino)-2,2-difluoropropyl)isoindoline-1,3-dione. The title compound was synthesized in a manner similar to Step C of Intermediate 35, using (S)-N-(6-chloro-5-(2-cyclopropoxy-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)ethyl)pyridazin-3-yl)pivalamide (Step B) instead of (S)-N-(6-chloro-5-(1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)-2-methoxyethyl)pyridazin-3-yl)pivalamide (99% yield, used without further purification).

[0614] Process D:(S)-N 1-(1-(6-amino-3-chloropyridazin-4-yl)-2-cyclopropoxyethyl)-2,2-difluoropropane-1,3-diamine. The title compound was synthesized in a manner similar to Step D of Intermediate 35, using (S)-2-(3-((1-(6-amino-3-chloropyridazin-4-yl)-2-cyclopropoxyethyl)amino)-2,2-difluoropropyl)isoindoline-1,3-dione (Step C) instead of (S)-2-(3-((1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)amino)-2,2-difluoropropyl)isoindoline-1,3-dione (99% yield, used without further purification).

[0615] Step E: (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-cyclopropoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. The title compound was prepared by the reaction of (S)-N 1 (S)-N instead of -(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-2,2-difluoropropane-1,3-diamine 1 Synthesized in a manner similar to Step E of Intermediate 35 using -(1-(6-amino-3-chloropyridazin-4-yl)-2-cyclopropoxyethyl)-2,2-difluoropropane-1,3-diamine (Step D) (18% yield).

[0616] Intermediate 37: ((3S,4R)-1-(dimethyl(oxo)-λ 6 tert-Butyl 4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate

[0617] [ka]

[0618] Step A: (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanoic acid. Sodium hydride (3.5 g, 88 mmol, 60% dispersion in mineral oil) was added portionwise to a solution of (R)-1,1,1-trifluoropropan-2-ol (5.0 g, 44 mmol) in DMF (70 mL) at 0°C. The resulting mixture was stirred at room temperature for 30 minutes and then recooled to 0°C. A separate solution of (S)-2-bromopropanoic acid (6.0 g, 40 mmol) in DMF (5 mL) was added at 0°C, and the resulting mixture was allowed to warm to room temperature and stir for 12 hours. The reaction mixture was then poured into ice-cold water (100 mL) and extracted with MTBE (25 mL). The pH of the aqueous layer was adjusted by adding 2 N aqueous HCl (15 mL) until the pH of the mixture reached pH 5-6. The aqueous layer was extracted with MTBE (80 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound in 93% yield as a yellow oil, which was used without further purification.

[0619] Step B: (R)-N-Methoxy-N-methyl-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanamide. A round-bottom flask was charged with (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanoic acid (7.6 g, 41 mmol, Step A), DMF (70 mL), HATU (20 g, 53 mmol), and DIPEA (18 mL, 102 mmol). The mixture was stirred for 5 minutes, after which N,O-dimethylhydroxylamine hydrochloride (6.0 g, 61 mmol) was added. The resulting solution was stirred for 12 hours, after which the reaction was quenched with water (30 mL) and diluted with MTBE (50 mL). The organic layer was separated, and the aqueous layer was extracted with MTBE (80 mL × 2). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (9-17% EtOAc / petroleum ether) to give the title compound as a yellow oil in 58% yield.

[0620] Step C: (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanal. A round-bottom flask was charged with (R)-N-methoxy-N-methyl-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanamide (5.4 g, 24 mmol, Step B) and THF (300 mL), cooled to −78° C., and LAH (4.5 g, 120 mmol) was added portionwise. The resulting mixture was stirred at −78° C. for approximately 1 hour and then quenched dropwise with water (20 mL) at −78° C. Saturated aqueous potassium sodium tartrate solution (120 mL) was added, and the solution was stirred for 30 minutes and then extracted with MTBE (120 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound in 100% yield, which was used without further purification.

[0621] Step D: (S)-2-Methyl-N-((R,E)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide. A round-bottom flask was charged with (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanal (7.4 g, 44 mmol, Step C), THF (250 mL), CuSO (28 g, 174 mmol), (S)-2-methylpropane-2-sulfinamide (7.9 g, 65 mmol), and PPTS (2.2 g, 8.7 mmol), and the resulting mixture was stirred at 30° C. for 16 hours. The suspension was filtered through diatomaceous earth (e.g., Celite®), and the filtrate was concentrated under reduced pressure. The product was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to afford the title compound as a colorless oil in 73% yield.

[0622] Step E: (S)—N-((1R,2R)-1-cyano-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide. A mixture of (S)-2-methyl-N-((R,E)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide (8.7 g, 32 mmol, Step D), TMSCN (5.5 mL, 44 mmol), Sc(OTf) (3.1 g, 6.4 mmol), and 4 Å molecular sieves (5 g) in DCM (100 mL) was stirred at room temperature for 16 h. The reaction was then filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-60 EtOAc / petroleum ether) afforded the title compound as a colorless oil in 79% yield.

[0623] Step F: O-((R)-1,1,1-trifluoropropan-2-yl)-L-threonine hydrochloride. (S)—N-((1R,2R)-1-cyano-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (7.6 g, 25 mmol, Step E) was dissolved in 4 M HCl / 1,4-dioxane solution (120 mL) and water (20 mL). The resulting mixture was stirred at 80° C. for 16 hours. The reaction was then cooled to room temperature and concentrated to dryness to afford the title compound (assumed 100% yield) as a brown oil, which was used without further purification.

[0624] Step G: N-(tert-butoxycarbonyl)-O-((R)-1,1,1-trifluoropropan-2-yl)-L-threonine. A round-bottom flask was charged with O-((R)-1,1,1-trifluoropropan-2-yl)-L-threonine hydrochloride (7.3 g, 25 mmol, Step F), THF (100 mL), and 1 M aqueous NaOH (101 mL) and allowed to stir at room temperature for 0.5 h. Then, BocO (5.5 g, 25 mmol) was added in one portion, and the reaction was allowed to stir at room temperature for 16 h. The reaction mixture was poured into water (100 mL), and the biphasic mixture was extracted with EtOAc (3 × 100 mL). The aqueous layer was then acidified to pH 3-4 with citric acid. The acidic aqueous layer was then extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated under reduced pressure to give the title compound in 88% yield, which was used without further purification.

[0625] Step H: ((3S,4R)-1-(dimethyl(oxo)-λ 6tert-Butyl (-sulfanylidene)-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate. To a suspension of trimethylsulfoxonium iodide (15.5 g, 49.2 mmol) in THF (250 mL) was added a 1 M solution of potassium tert-butoxide in THF (73.7 mL, 73.7 mmol). The mixture was stirred at room temperature for 2 hours. In a separate flask, a solution of N-(tert-butoxycarbonyl)-O-((R)-1,1,1-trifluoropropan-2-yl)-L-threonine (15.5 g, 49.2 mmol, Step G) in THF (250 mL) was cooled to 0 °C and charged with CDI (9.57 g, 59.0 mmol) in one portion. The mixture was stirred at 0 °C for 2 hours. This solution was then added dropwise to the previously prepared solution and stirred at 25°C for 2 hours. The reaction mixture was then poured into water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated to dryness. The product was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) and chiral SFC (DAICEL CHRALPAK AD, 10 μm, 50 x 250 mm, 20% EtOH (containing 0.1% 25% aqueous NH) / CO) to give the title compound in 21% yield as the first-eluting fraction.

[0626] Intermediate 38: ((3S,4R)-1-(dimethyl(oxo)-λ 6 tert-Butyl 4-(((S)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate

[0627] [ka]

[0628] Step A: (R)-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanoic acid. The title compound was synthesized in a manner similar to Step A of Intermediate 37, using (S)-1,1,1-trifluoropropan-2-ol instead of (R)-1,1,1-trifluoropropan-2-ol (80% yield).

[0629] Step B: (R)-N-Methoxy-N-methyl-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanamide. The title compound was synthesized in a manner similar to Step B of Intermediate 37, using (R)-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanoic acid (Step A) instead of (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanoic acid (46% yield).

[0630] Step C: (R)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanal. The title compound was synthesized in a manner similar to Step C of Intermediate 37, using (R)-N-methoxy-N-methyl-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanamide (Step B) instead of (R)-N-methoxy-N-methyl-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanamide (80% yield).

[0631] Step D: (S)-2-Methyl-N-((R,E)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide. The title compound was synthesized in a manner similar to Step D of Intermediate 37, using (R)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propanal (Step C) instead of (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanal (55% yield).

[0632] Step E: (S)—N-((1R,2R)-1-cyano-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide. The title compound was synthesized in a manner similar to Step E of Intermediate 37, using (S)-2-methyl-N-((R,E)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide (Step D) instead of (S)-2-methyl-N-((R,E)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide (91% yield).

[0633] Step F: O-((S)-1,1,1-trifluoropropan-2-yl)-L-threonine hydrochloride. The title compound was synthesized in a manner similar to Step F of Intermediate 37, using (S)-N-((1R,2R)-1-cyano-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (Step E) instead of (S)-N-((1R,2R)-1-cyano-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (assumed 100% yield).

[0634] Step G: N-(tert-butoxycarbonyl)-O-((S)-1,1,1-trifluoropropan-2-yl)-L-threonine. The title compound was synthesized in a manner similar to Step G of Intermediate 37, using O-((S)-1,1,1-trifluoropropan-2-yl)-L-threonine hydrochloride (Step F) instead of O-((R)-1,1,1-trifluoropropan-2-yl)-L-threonine hydrochloride, and was used without further purification.

[0635] Step H: ((3S,4R)-1-(dimethyl(oxo)-λ 6tert-Butyl -sulfanylidene)-2-oxo-4-(((S)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate. The title compound was synthesized in a manner similar to Step H of Intermediate 37, using N-(tert-butoxycarbonyl)-O-((S)-1,1,1-trifluoropropan-2-yl)-L-threonine (Step G) instead of N-(tert-butoxycarbonyl)-O-((R)-1,1,1-trifluoropropan-2-yl)-L-threonine. The product was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) and chiral SFC (DAICEL CHRALPAK AD, 10 μm, 50 × 250 mm, 15% EtOH (containing 0.1% 25% aqueous NH) / CO) to give the title compound (19% yield) as the first eluting fraction.

[0636] Intermediate 39: tert-butyl ((3S,4R)-1-iodo-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate

[0637] [ka]

[0638] Step A: tert-butyl ((3S,4R)-1-chloro-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate. To an oven-dried round-bottom flask was added anhydrous lithium chloride (120 mg, 2.85 mmol) and ((3S,4R)-1-(dimethyl(oxo)-λ 6tert-Butyl ((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate (400 mg, 1.03 mmol, Intermediate 37) was charged under a N atmosphere. Anhydrous THF (7.2 mL) was added and the reaction was cooled to 0 °C, after which methanesulfonic acid (71.5 μL, 1.01 mmol) was added dropwise. The reaction was maintained at 0 °C for 10 minutes and then heated to 60 °C for 3 hours. The mixture was then cooled to room temperature, diluted with HO, and extracted with 1:1 EtOAc:hexanes. The organic extract was washed with brine, dried over anhydrous NaSO, filtered, and concentrated to give the title compound, which was used without further purification.

[0639] Step B: tert-Butyl ((3S,4R)-1-iodo-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate. A mixture of tert-butyl ((3S,4R)-1-chloro-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate (354 mg, 1.02 mmol, Step A) and NaI (1.53 g, 10.2 mmol) in acetone was stirred at room temperature for 1 hour, then diluted with EtOAc and filtered. The filtrate was washed with saturated aqueous sodium thiosulfate solution, then dried over anhydrous NaSO, filtered, and concentrated to give the title compound, which was used without further purification.

[0640] Intermediate 40: tert-butyl ((3S,4R)-1-iodo-2-oxo-4-(((S)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate

[0641] [ka]

[0642] Step A: tert-butyl ((3S,4R)-1-chloro-2-oxo-4-(((S)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate. The title compound was prepared by the procedure of ((3S,4R)-1-(dimethyl(oxo)-λ 6 -sulfanylidene)-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate tert-butyl ester ((3S,4R)-1-(dimethyl(oxo)-λ 6 Intermediate 39, Step A, was synthesized using tert-butyl 4-(((S)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate (Intermediate 38) in a manner similar to Step A of Intermediate 39, which was used without further purification.

[0643] Step B: tert-Butyl ((3S,4R)-1-iodo-2-oxo-4-(((S)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate. The title compound was synthesized in a manner similar to Step B of Intermediate 39 using tert-butyl ((3S,4R)-1-chloro-2-oxo-4-(((S)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate (Step A) instead of tert-butyl ((3S,4R)-1-chloro-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate and used without further purification.

[0644] Intermediate 41: (1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propan-1-aminium trifluoroacetate

[0645] [ka]

[0646] Step A: tert-Butyl ((1R,2R)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate. An oven-dried round-bottom flask was charged with (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (80 mg, 0.25 mmol, Intermediate 35) and activated 4 Å molecular sieves and DMA (3.3 mL). A separate solution of tert-butyl ((3S,4R)-1-iodo-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate (273 mg, 0.62 mmol, Intermediate 39) in DMA (2 mL) was added, and the reaction was heated to 50° C. under a N atmosphere for 16 hours. The reaction was then cooled to room temperature and filtered through diatomaceous earth (e.g., Celite®). The filtrate was then diluted with 5% LiCl solution, and the aqueous layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)) to provide the title compound in 82% yield.

[0647] Step B: tert-butyl ((1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate. tert-Butyl ((1R,2R)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate (125 mg, 0.203 mmol, Step A) was dissolved in EtOH (15.6 mL) and TFE (10 mL), and ammonium formate (192 mg, 3.05 mmol) and 10 wt% Pd / C (124 mg) were added sequentially. The resulting heterogeneous solution was heated to 85° C. under a N atmosphere for 1 hour. The reaction mixture was then filtered through diatomaceous earth (e.g., Celite®), concentrated under reduced pressure, and used without further purification.

[0648] Step C: (1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propan-1-aminium trifluoroacetate. tert-Butyl ((1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate (118 mg, 0.203 mmol, Step B) was dissolved in DCM (6.6 mL) and cooled to 0° C. Then, TFA (6.5 mL) was added dropwise and the resulting mixture was allowed to stir for 40 minutes. The reaction was then concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0649] Intermediate 42: (1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propan-1-aminium trifluoroacetate

[0650] [ka]

[0651] Step A: tert-butyl ((1R,2R)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate. The title compound was synthesized in a manner similar to Step A of Intermediate 41 using tert-butyl ((3S,4R)-1-iodo-2-oxo-4-(((S)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate (Intermediate 40) instead of tert-butyl ((3S,4R)-1-iodo-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate to afford the title compound in 68% yield after silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)).

[0652] Step B: tert-butyl ((1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate. The title compound was prepared by the reaction of ((1R,2R)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate with tert-butyl ester. Synthesis of tert-butyl 2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate in a manner similar to Step B of Intermediate 41 using tert-butyl 2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-carbamate (Step A) to afford the title compound in 74% yield after silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)).

[0653] Step C: (1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propan-1-aminium trifluoroacetate. The title compound may be prepared by the reaction of ((1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate with tert-butyl ester. Synthesized in a manner similar to Step C of Intermediate 41 using tert-butyl 5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((S)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate (Step B) to provide the title compound, which was used without further purification.

[0654] Intermediate 43: (S)-1-(7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutan-1-aminium trifluoroacetate

[0655] [ka]

[0656] Step A: tert-butyl ((S)-1-(6-chloro-7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate. The title compound was prepared by using (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-cyclopropoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (Intermediate 36) instead of (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one and ((3S,4R)-1-iodo-2-oxo-4-(((R Synthesized in a manner similar to Step A of Intermediate 41 using tert-butyl (S)-(6,6,6-trifluoro-1-iodo-5,5-dimethyl-2-oxohexan-3-yl)carbamate instead of tert-butyl (S)-(6,6,6-trifluoro-1-iodo-5,5-dimethyl-2-oxohexan-3-yl)carbamate to afford the title compound in >99% yield after silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)).

[0657] Step B: tert-butyl ((S)-1-(7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate. The title compound was prepared by the reaction of ((S)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate with tert-butyl ((1R,2R)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate Synthesized in a manner similar to Step B of Intermediate 41 using tert-butyl ((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate (Step A) to provide the title compound, which was used without further purification.

[0658] Step C: (S)-1-(7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutan-1-aminium trifluoroacetate. The title compound was synthesized in a manner similar to Step C of Intermediate 41 using tert-butyl ((S)-1-(7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate (Step B) instead of tert-butyl ((1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate to provide the title compound, which was used without further purification.

[0659] Intermediate 44: 1-((S)-1-(2-((S)-1-amino-4,4,4-trifluoro-3,3-dimethylbutyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0660] [ka]

[0661] Step A. tert-Butyl ((S)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate. To an oven-dried and N-flushed vial was added oven-dried 4 Å molecular sieves (3.5 g), (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (Intermediate 35, 138 mg, 0.43 mmol), (S)-(6,6,6-trifluoro-1-iodo-5,5-dimethyl-2-oxohexan-3-yl) tert-butyl carbamate (910 mg, 2.15 mmol), and dimethylacetamide (9 mL). The reaction mixture was heated (50° C.) and stirred for 72 hours, at which point an additional portion of tert-butyl (S)-(6,6,6-trifluoro-1-iodo-5,5-dimethyl-2-oxohexan-3-yl)carbamate (1.27 g, 3.00 mmol) was added. After an additional 36 hours, a final portion of tert-butyl (S)-(6,6,6-trifluoro-1-iodo-5,5-dimethyl-2-oxohexan-3-yl)carbamate (280 mg, 0.66 mmol) was added, and heating was continued for an additional 36 hours. The reaction mixture was cooled to room temperature, filtered, and the solids were washed with EtOAc (10 mL) and DCM (10 mL). The filtrate was diluted with brine (50 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (2 × 30 mL), saturated aqueous NaSO (1 × 20 mL), and brine (1 × 20 mL). The combined organic layers were dried over anhydrous NaSO, concentrated, and purified by silica gel chromatography (5-60% acetone / hexane (containing 0.1 V / V% TEA)) to give the title compound (48%).

[0662] Step B. tert-Butyl ((S)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate. To a suspension of ammonium formate (194 mg, 3.08 mmol) and 10% Pd / C (126 mg, dry) in EtOH (20 mL) was added tert-butyl ((S)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate (123 mg, 0.21 mmol, Step A). ​​The reaction mixture was attached to a nitrogen bubbler, heated (80° C.), and stirred for 70 minutes. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth (e.g., Celite®), rinsing with EtOH (20 mL). The filtrate was evaporated to dryness and partitioned between saturated aqueous NaHCO (15 mL) and DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (1 x 20 mL). The combined organic layers were dried over anhydrous NaSO and concentrated to give the title compound (99%), which was used without further purification.

[0663] Step C. 1-((S)-1-(2-((S)-1-amino-4,4,4-trifluoro-3,3-dimethylbutyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. The title compound was prepared as described for Step C of the synthesis of Intermediate 20 using tert-butyl ((S)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate (Step B) instead of tert-butyl (S)-((7-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate to afford the title compound (100%), which was used without further purification.

[0664] Intermediate 45: (S)-(1-(dimethyl(oxo)-λ 6 -sulfanylidene)-7,7,7-trifluoro-6,6-dimethyl-2-oxoheptan-3-yl)carbamic acid tert-butyl ester

[0665] [ka]

[0666] Step A: 1,1,1-Trifluoro-4-iodo-2,2-dimethylbutane. To a stirred solution of 4,4,4-trifluoro-3,3-dimethylbutan-1-ol (9.75 g, 62.5 mmol) in DCM (125 mL) was added triphenylphosphine (24.6 g, 93.7 mmol) and imidazole (5.53 g, 81.2 mmol), and the resulting mixture was cooled to 0 °C. Iodine (23.8 g, 93.7 mmol) was then added portionwise, and the mixture was stirred for 24 h, at which point it was quenched with saturated aqueous NaHCO and stirred for 15 min. The organic layer was removed, washed sequentially with half-saturated aqueous NaHCO and brine, dried over anhydrous MgSO, filtered, and concentrated to give a residue. To the residue was added cold hexane (50 mL), and the mixture was stirred vigorously for 10 min, at which point a white precipitate formed. The white solid was removed by filtration through a silica pad and the solid was washed with a second portion of cold hexane. The filtrate was concentrated to give the title compound as a clear, colorless oil (66% yield), which was used without further purification.

[0667] Step B: (2R,5S)-2-Isopropyl-3,6-dimethoxy-5-(4,4,4-trifluoro-3,3-dimethylbutyl)-2,5-dihydropyrazine. To a stirred solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (0.66 g, 3.59 mmol) in THF (7 mL) was added t-BuLi (2.33 mL, 3.95 mmol, 1.7 M in pentane) at −78° C., and the reaction was allowed to stir at −78° C. After 1 h, a solution of 1,1,1-trifluoro-4-iodo-2,2-dimethylbutane (1.05 g, 3.95 mmol, Step A) in THF (6 mL) was added dropwise, and the reaction was stirred at room temperature for 24 h. The reaction was quenched by the addition of aqueous phosphate buffer (50 mL, 0.1 M, pH 7) and diluted with diethyl ether. The organic layer was removed, and the aqueous layer was extracted with diethyl ether (2 × 50 mL). The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated to give an oil. LC / MS of this oil revealed a diastereomeric mixture in an approximately 1.5:1 ratio. This mixture was separated by silica gel chromatography (0-30% ethyl acetate / hexanes) to give the first-eluting isomer (50% yield) as a yellow oil, which was designated the R,S diastereomer. The second-eluting isomer, designated the R,R diastereomer, (2R,5R)-2-isopropyl-3,6-dimethoxy-5-(4,4,4-trifluoro-3,3-dimethylbutyl)-2,5-dihydropyrazine, was isolated in 28% yield.

[0668] Step C: Methyl (S)-2-amino-6,6,6-trifluoro-5,5-dimethylhexanoate. To a stirred solution of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(4,4,4-trifluoro-3,3-dimethylbutyl)-2,5-dihydropyrazine (1.15 g, 3.57 mmol, Step B, first-eluting isomer) in ACN (14.3 mL) was added aqueous HCl (14.3 mL, 1 M) at room temperature. After stirring for 2 h, the reaction mixture was poured into saturated aqueous NaHCO at 0 °C and then extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated to give an oil that was used without further purification.

[0669] Step D: (S)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluoro-5,5-dimethylhexanoate. To a stirred solution of (S)-2-amino-6,6,6-trifluoro-5,5-dimethylhexanoate (810.6 mg, 3.57 mmol, Step C) in DCM (15.1 mL) was added BocO (1.56 g, 7.14 mmol). After 24 h, the reaction was quenched with aqueous HCl (10 mL, 1 M), and the layers were separated. The organic layer was washed with aqueous HCl (10 mL, 1 M), water, brine, dried over anhydrous MgSO, filtered, and concentrated to give an oil that was used in the next step without further purification.

[0670] Step E: (S)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluoro-5,5-dimethylhexanoic acid. To a stirred solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluoro-5,5-dimethylhexanoate (925 mg, 2.83 mmol, Step D) in THF (22.4 mL) was added aqueous LiOH (8.50 mL, 1 M) at 0 °C, and the resulting mixture was stirred for 2 h. The reaction mixture was then acidified to pH 2 using aqueous HCl (1 M). The mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO 4 , filtered, and concentrated to give a clear oil, which was used in the next step without further purification.

[0671] Step F: (S)-(1-(dimethyl(oxo)-λ 6tert-Butyl (-sulfanylidene)-7,7,7-trifluoro-6,6-dimethyl-2-oxoheptan-3-yl)carbamate. To a suspension of trimethylsulfoxonium chloride (0.581 g, 4.52 mmol) in THF (7 mL) was added t-BuOK solution (4.24 mL, 4.24 mmol, 1 M THF solution), and the resulting solution was stirred for 2 h. Separately, to a solution of (S)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluoro-5,5-dimethylhexanoic acid (885 mg, 2.83 mmol, Step E) in THF (7 mL) cooled to 0 °C, CDI (550 mg, 3.39 mmol) was added, and the resulting mixture was stirred at 0 °C for 2 h. This mixture was then added via cannula to the suspension from the trimethylsulfoxonium chloride, and the resulting mixture was stirred at room temperature. After 2 hours, the reaction mixture was filtered through diatomaceous earth (eg, Celite®), concentrated, and purified by silica gel chromatography (0-100% ethyl acetate / hexanes) to afford the title compound (56% yield) as a white foam.

[0672] Intermediate 46: (S)-(7,7,7-trifluoro-1-iodo-6,6-dimethyl-2-oxoheptan-3-yl)carbamate tert-butyl

[0673] [ka]

[0674] Step A: (S)-(1-chloro-7,7,7-trifluoro-6,6-dimethyl-2-oxoheptan-3-yl) tert-butylcarbamate. The title compound was prepared by the procedure of ((3S,4R)-1-(dimethyl(oxo)-λ 6 -sulfanylidene)-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate tert-butyl ester 6Synthesized in a manner similar to Step A of Intermediate 39 using tert-butyl (7,7,7-trifluoro-6,6-dimethyl-2-oxoheptan-3-yl)carbamate (Intermediate 45) which was used without further purification.

[0675] Step B: tert-butyl (S)-(7,7,7-trifluoro-1-iodo-6,6-dimethyl-2-oxoheptan-3-yl)carbamate. The title compound was synthesized in a manner similar to Step B of Intermediate 39, using tert-butyl (S)-(1-chloro-7,7,7-trifluoro-6,6-dimethyl-2-oxoheptan-3-yl)carbamate (Step A) instead of tert-butyl ((3S,4R)-1-chloro-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate, and was used without further purification.

[0676] Intermediate 47: 1-((S)-1-(2-((S)-1-amino-5,5,5-trifluoro-4,4-dimethylpentyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0677] [ka]

[0678] Step A: ((S)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)carbamate tert-butyl. The title compound was synthesized in a manner similar to Step A of Intermediate 44, using (S)-(7,7,7-trifluoro-1-iodo-6,6-dimethyl-2-oxoheptan-3-yl)carbamate tert-butyl (Intermediate 46) instead of (S)-(6,6,6-trifluoro-1-iodo-5,5-dimethyl-2-oxohexan-3-yl)carbamate tert-butyl to afford the title compound (20% yield) as a brown oil.

[0679] Step B: ((S)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)carbamate tert-butyl. The title compound was synthesized in a manner similar to Step B of Intermediate 44 using tert-butyl ((S)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)carbamate (Step A) instead of tert-butyl ((S)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate to afford the title compound as a brown oil, which was used without further purification.

[0680] Step C: 1-((S)-1-(2-((S)-1-amino-5,5,5-trifluoro-4,4-dimethylpentyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. The title compound was synthesized in a manner similar to Step C of Intermediate 44 using tert-butyl ((S)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)carbamate (Step B) instead of tert-butyl ((S)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate to afford the title compound as a yellow oil, which was used without further purification.

[0681] Intermediate 48: tert-butyl ((R)-1-(7-((S)-1-amino-2-methoxyethyl)-6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0682] [ka]

[0683] Step A: (S)—N-(5-(1-amino-2-methoxyethyl)-6-chloropyridazin-3-yl)pivalamide. To a stirred solution of N-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)-6-chloropyridazin-3-yl)pivalamide (8.00 g, 20.5 mmol, Intermediate 33) in EtOAc (102 mL) was added a solution of HCl in 1,4-dioxane (4 M, 20.5 mL, 81.9 mmol) at room temperature. After 5 h, the reaction mixture was diluted with hexane (150 mL) and water (200 mL). The layers were separated, and the organic layer was extracted with aqueous HCl (0.05 M, 2×50 mL). The combined aqueous layers were diluted with EtOAc (50 mL), and the pH of the solution was adjusted to pH 11 using 3 M aqueous NaOH. The layers were separated and the aqueous layer was extracted with EtOAc (4 x 50 mL). The combined organic layers were dried over anhydrous NaSO and concentrated to give the title compound (>99% yield, traces of EtOAc were present) as a solid, which was used without further purification.

[0684] Step B: (S)—N-(6-chloro-5-(1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)pyridazin-3-yl)pivalamide. To a stirred solution of (S)—N-(5-(1-amino-2-methoxyethyl)-6-chloropyridazin-3-yl)pivalamide (1.17 g, 4.07 mmol, Step A) and isobenzofuran-1,3-dione (0.81 g, 5.48 mmol) in toluene (25 mL) was added DIPEA (1.1 mL, 6.3 mmol), and the resulting solution was heated at 100° C. for 17 h. The reaction mixture was cooled to room temperature and concentrated to give a residue that was then purified by silica gel chromatography (0-100% EtOAc / hexanes) to give the title compound (89.5%).

[0685] Step C: (S)-2-(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)isoindoline-1,3-dione. To a 50 mL pear-shaped flask charged with (S)—N-(6-chloro-5-(1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)pyridazin-3-yl)pivalamide (1.2 g, 2.9 mmol, Step B), 1,4-dioxane (7.2 mL) was added followed by 6 M HSO (4.8 mL, 28.8 mmol), and the resulting yellow solution was heated at 60° C. for 11 hours. The solution was then cooled to 0° C., and the pH was adjusted to pH 8 by the slow addition of 58.7 mL of saturated aqueous sodium bicarbonate. The aqueous portion of the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give a brown oil. The product was purified by silica gel chromatography (0-100% EtOAc / hexanes) to give the title compound (74.1%) as a white foam.

[0686] Step D: tert-butyl ((R)-1-(6-chloro-7-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. The title compound was prepared by using (S)-2-(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)isoindoline-1,3-dione (Step C) instead of (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one and ((3S,4R)-1-iodo-2-oxo-4-(((R)-1 Prepared as described for Step A of the synthesis of intermediate 41 using tert-butyl (S)-(4-iodo-3-oxo-1-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)butan-2-yl)carbamate instead of tert-butyl (S)-(4-iodo-3-oxo-1-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pentan-3-yl)carbamate to afford the title compound (65%) as a brown oil.

[0687] Step E: tert-butyl ((R)-1-(7-((S)-1-amino-2-methoxyethyl)-6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. To a solution of tert-butyl ((R)-1-(6-chloro-7-((S)-1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (473 mg, 0.756 mmol, Step D) in EtOH (5 mL) was added hydrazine monohydrate (565 μL, 7.56 mmol), and the resulting reddish-brown solution was stirred at room temperature for 4 h. The mixture was concentrated to give a residue, which was then diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). NaCl (solid) was added to the mixture to facilitate separation of the aqueous and organic layers. The organic layer was dried over anhydrous MgSO4, filtered, concentrated and purified by silica gel chromatography (0-5% (2M NH3 / MeOH solution) / DCM) to afford the title compound (95%) as a brown oil.

[0688] Intermediate 49: 2-(1-(1,3-dioxoisoindolin-2-yl)cyclopropyl)acetaldehyde

[0689] [ka]

[0690] Step A. 2-(1-(2-Hydroxyethyl)cyclopropyl)isoindoline-1,3-dione. To a mixture of 2-(1-aminocyclopropyl)ethan-1-ol hydrochloride (3.40 g, 24.7 mmol), ethyl 1,3-dioxoisoindoline-2-carboxylate (6.04 g, 27.6 mmol), and anhydrous THF (60 mL) was added DIPEA (14.4 mL, 82.4 mmol) dropwise over 1 minute under N. The resulting mixture was heated at 75 °C for 2 days. The mixture was diluted with water (100 mL) and extracted with DCM (3 × 100 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness to give a pale yellow oil. The oil was purified by silica gel chromatography (0-30% EtOAc / petroleum ether) to give the title compound (34% yield) as a white solid.

[0691] Step B. 2-(1-(1,3-Dioxoisoindolin-2-yl)cyclopropyl)acetaldehyde. A mixture of 2-(1-(2-hydroxyethyl)cyclopropyl)isoindoline-1,3-dione (100 mg, 0.430 mmol, Step A), Dess-Martin periodinane (367 mg, 0.860 mmol), NaHCO (254 mg, 3.03 mmol), 4 Å molecular sieves (200 mg), and anhydrous DCM (10 mL) was stirred at room temperature for 1 h. The mixture was then filtered and concentrated to dryness to give a pale yellow oil. The oil was purified by silica gel chromatography (0-30% EtOAc / petroleum ether) to give the title compound (61% yield) as a white solid.

[0692] Intermediate 50: 3-(1,3-dioxoisoindolin-2-yl)-4,4,4-trifluorobutanal

[0693] [ka]

[0694] Step A. 2-(1,1,1-Trifluoro-4-hydroxybutan-2-yl)isoindoline-1,3-dione. To a mixture of 3-amino-4,4,4-trifluorobutan-1-ol (5.04 g, 35.2 mmol), ethyl 1,3-dioxoisoindoline-2-carboxylate (8.50 g, 38.8 mmol), and anhydrous THF (100 mL) was added DIPEA (20.3 mL, 116 mmol) under N. The resulting mixture was heated at 75 °C for 40 h. The mixture was concentrated to dryness, then dissolved in DCM (100 mL) and washed with 2 M aqueous HCl (2 × 50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to dryness to give a yellow gum. The gum was first purified by silica gel chromatography (0-50% EtOAc / petroleum ether) and then further purified by preparative HPLC (Welch Xtimate C18, 5 μm, 30 × 150 mm, 31-61% MeCN / water (formic acid)) to give the title compound (31% yield) as a yellow oil.

[0695] Step B. 3-(1,3-Dioxoisoindolin-2-yl)-4,4,4-trifluorobutanal. A mixture of 2-(1,1,1-trifluoro-4-hydroxybutan-2-yl)isoindoline-1,3-dione (500 mg, 1.83 mmol, Step A), NaHCO (769 mg, 9.15 mmol), and anhydrous DCM (15 mL) was cooled to 0 °C in an ice bath, and then Dess-Martin periodinane (1.16 g, 2.75 mmol) was added in one portion, and the resulting mixture was stirred at room temperature for 1 h. The mixture was then treated dropwise with saturated aqueous NaSO (100 mL) over 30 min and then extracted with EtOAc (2 × 50 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness to give a white solid. The solid was purified by silica gel chromatography (20-50% EtOAc / petroleum ether) to afford the title compound (66% yield) as a yellow oil.

[0696] Intermediate 51: (S *)-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexan-6-yl)methanaminium 2,2,2-trifluoroacetate

[0697] [ka]

[0698] Process A:((S * )-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexan-6-yl)methyl)carbamate tert-butyl. The title compound was prepared by replacing ((3S,4R)-1-iodo-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate with ((S * )-1-((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-3-iodo-2-oxopropyl)carbamate tert-butyl ester in a manner similar to Step A of Intermediate 41. The title compound (70% yield) was purified by silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)).

[0699] Process B:((S *)-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexan-6-yl)methyl) tert-butyl carbamate. The title compound was prepared by substituting ((1R,2R)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl) tert-butyl carbamate. * tert-butyl 2-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexan-6-yl)methyl)carbamate (Step A) in a manner similar to Step B of Intermediate 41. The title compound (68% yield) was purified by silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)).

[0700] Process C:(S * )-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexan-6-yl)methanaminium 2,2,2-trifluoroacetate. The title compound was prepared by substituting ((1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate with tert-butyl ((S *tert-butyl 2-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexan-6-yl)methyl)carbamate (Step B) in a manner similar to Step C of Intermediate 41. The title compound (estimated quantitative yield) was used without further purification.

[0701] Intermediate 52: ((R * )-1-((R * )-3,3-difluorocyclopentyl)-3-(dimethyl(oxo)-λ 6 tert-Butyl (-sulfanylidene)-2-oxopropyl)carbamate

[0702] [ka]

[0703] Step A: (S)—N-((E)-(3,3-Difluorocyclopentyl)methylene)-2-methylpropane-2-sulfinamide. The title compound was synthesized in a manner similar to Step D of Intermediate 37 using 3,3-difluorocyclopentane-1-carbaldehyde instead of (R)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanal (43% yield). This material was found to epimerize over time and was used in Step B.

[0704] Step B: (S)—N-(cyano(3,3-difluorocyclopentyl)methyl)-2-methylpropane-2-sulfinamide. The title compound (90% yield) was synthesized in a manner similar to Step E of Intermediate 37, using (S)—N-((E)-(3,3-difluorocyclopentyl)methylene)-2-methylpropane-2-sulfinamide (Step A) instead of (S)-2-methyl-N-((R,E)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propylidene)propane-2-sulfinamide.

[0705] Step C: Carboxy(3,3-difluorocyclopentyl)methanaminium chloride. The title compound was synthesized in a manner similar to Step F of Intermediate 37, using (S)—N-(cyano(3,3-difluorocyclopentyl)methyl)-2-methylpropane-2-sulfinamide (Step B) instead of (S)—N-((1R,2R)-1-cyano-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide, and was used without further purification.

[0706] Step D: 2-((tert-Butoxycarbonyl)amino)-2-(3,3-difluorocyclopentyl)acetic acid. The title compound was synthesized in a manner similar to Step G of Intermediate 37, using carboxy(3,3-difluorocyclopentyl)methanaminium chloride (Step C) instead of O-((R)-1,1,1-trifluoropropan-2-yl)-L-threonine hydrochloride, and was used without further purification.

[0707] Process E:((R * )-1-((R * )-3,3-difluorocyclopentyl)-3-(dimethyl(oxo)-λ 6tert-Butyl (-sulfanylidene)-2-oxopropyl)carbamate. The title compound was synthesized in a manner similar to Step H of Intermediate 37, using 2-((tert-butoxycarbonyl)amino)-2-(3,3-difluorocyclopentyl)acetic acid (Step D) instead of N-(tert-butoxycarbonyl)-O-((R)-1,1,1-trifluoropropan-2-yl)-L-threonine. Epimerization of the product of Step A resulted in the formation of four diastereomers. These diastereomers were first purified by silica gel chromatography (0-100% EtOAc / hexanes) and then by preparative acidic HPLC (YMC-Triart Prep C18 10 μm column, 50 × 250 mm, 10-50% acetonitrile / water (0.225% formic acid)). The four diastereomers were then separated using SFC. These compounds were first separated using (DAICEL CHIRALPAK IG, 10 μm, 50 × 250 mm, 35% EtOH (containing 0.1% 25% aqueous NH3) / CO2) followed by two more separations using (DAICEL CHIRALPAK IG, 10 μm, 50 × 250 mm, 30% MeOH (containing 0.1% 25% aqueous NH3) / CO2) to give the pure title compound in 10% yield after lyophilization. Further analysis of the title compound provided the following data: analytical SFC using (DAICEL CHIRALPAK IG, 3 μm, 5 × 100 mm, 5-40% MeOH (0.05% DEA) / CO2 over 4.5 min), retention time 3.82 min, and optical rotation [α] D 23 =-28.6 (MeOH, c=0.29).

[0708] Intermediate 53: ((R * )-1-((R * )-3,3-Difluorocyclopentyl)-3-iodo-2-oxopropyl)carbamate tert-Butyl

[0709] [ka]

[0710] Process A:((R * )-3-chloro-1-((R * )-3,3-difluorocyclopentyl)-2-oxopropyl)carbamate tert-butyl. The title compound was prepared by the procedure of ((3S,4R)-1-(dimethyl(oxo)-λ 6 -sulfanylidene)-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate instead of tert-butyl ((R * )-1-((R * )-3,3-difluorocyclopentyl)-3-(dimethyl(oxo)-λ 6

[0123] Synthesized in a manner similar to Step A of Intermediate 39 using tert-butyl (-sulfanylidene)-2-oxopropyl)carbamate (Intermediate 52) which was used without further purification (100% yield).

[0711] Process B:((R * )-1-((R * )-3,3-difluorocyclopentyl)-3-iodo-2-oxopropyl)carbamate tert-butyl. The title compound was prepared by the procedure of ((R)-1-chloro-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate instead of tert-butyl ((3S,4R)-1-chloro-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate. * )-3-chloro-1-((R * Synthesized in a manner similar to Step B of Intermediate 39 using tert-butyl 2-oxopropyl)-3,3-difluorocyclopentylcarbamate (Step A) and used without further purification (100% yield).

[0712] Intermediate 54: (R * )-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((R * )-3,3-Difluorocyclopentyl)methanaminium 2,2,2-trifluoroacetate

[0713] [ka]

[0714] Process A:((R * )-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((R * )-3,3-difluorocyclopentyl)methyl)carbamate tert-butyl. The title compound was prepared by the procedure of ((R * )-1-((R * (3,3-Difluorocyclopentyl)-3-iodo-2-oxopropyl)carbamate (Intermediate 53) was used in a manner similar to Step A of Intermediate 41. The title compound (61% yield) was purified by silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)).

[0715] Process B:((R * )-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((R * )-3,3-difluorocyclopentyl)methyl) tert-butyl)carbamate. The title compound was prepared by the procedure of ((R )-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate instead of tert-butyl ((R *)-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((R * tert-Butyl 3,3-difluorocyclopentyl)methyl)carbamate (Step A) was used in a manner similar to Step B of Intermediate 41. The title compound (>99% yield) was purified by silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)).

[0716] Process C:(R * )-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((R * )-3,3-difluorocyclopentyl)methanaminium 2,2,2-trifluoroacetate. The title compound was prepared by substituting ((1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate with tert-butyl ((R * )-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)((R * Synthesized in a manner similar to Step C of Intermediate 41 using tert-butyl 3,3-difluorocyclopentyl)methyl)carbamate (Step B) and used without further purification.

[0717] Intermediate 55: 1,3-dioxoisoindolin-2-yl 2-cyclopropoxypropanoate

[0718] [ka]

[0719] Step A: 2-Cyclopropoxypropanoic acid. The title compound was synthesized in a manner similar to Step A of Intermediate 37, using cyclopropanol instead of (R)-1,1,1-trifluoropropan-2-ol and 2-bromopropanoic acid instead of (S)-2-bromopropanoic acid, and was used without further purification.

[0720] Step B: 1,3-Dioxoisoindolin-2-yl 2-cyclopropoxypropanoate. 2-Cyclopropoxypropanoic acid (3.2 g, 25 mmol, Step A), DMAP (310 mg, 2.50 mmol), and 2-hydroxyisoindoline-1,3-dione (6.3 g, 37 mmol) were dissolved in DCM (90 mL) at 0° C. Separately, DCC (5.7 g, 27 mmol) was dissolved in DCM (35 mL), and then this DCC solution was added dropwise to the reaction mixture. The reaction was then warmed to room temperature and allowed to stir overnight. The reaction mixture was then filtered through diatomaceous earth (e.g., Celite®), concentrated to dryness, and purified by silica gel chromatography (0-70% EtOAc / hexanes) to provide the title compound in 65% yield.

[0721] Intermediate 56: (S)-N-((E)-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)methylene)-2,4,6-trimethylbenzenesulfinamide

[0722] [ka]

[0723] Step A: (S)-6-chloro-7-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazine-2-carboxylate. (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (4.0 g, 12 mmol, Intermediate 35) was dissolved in EtOH (83 mL). 4 Å molecular sieves (5 g) and ethyl bromopyruvate (3.5 mL, 25 mmol) were added sequentially, and the resulting reaction mixture was heated to 70° C. overnight. The reaction mixture was then filtered through diatomaceous earth (e.g., Celite®) and washed with EtOH. The solution was then partitioned between DCM (50 mL) and saturated aqueous NaHCO (80 mL) and aqueous NaSO (40 mL, 0.5 M). The aqueous layer was further extracted with DCM (4 × 30 mL). The combined organic layers were dried over anhydrous NaSO, filtered, concentrated to dryness, and purified by silica gel chromatography (15-90% acetone / hexanes (0.1% TEA)) to give the title compound as a tan foam in 78% yield.

[0724] Step B: (S)-7-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazine-2-carboxylate. Ethyl (S)-6-chloro-7-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazine-2-carboxylate (4.0 g, 9.7 mmol, Step A), 10% Pd / C (1.2 g, 9.7 mmol), and 28% NHOH (2.0 mL, 29 mmol) were added sequentially to a Parr shaker containing MeOH (195 mL). The vessel was then pressurized to 20 psi of H and shaken for approximately 1 hour. The reaction vessel was then depressurized, and the reaction mixture was filtered and concentrated to dryness. The residue was partitioned between EtOAc (40 mL) and saturated aqueous NaHCO (40 mL). The aqueous layer was further extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound in 90% yield, which was used without further purification.

[0725] Step C: (S)-7-(1-(5,5-Difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazine-2-carbaldehyde. Ethyl (S)-7-(1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazine-2-carboxylate (3.4 g, 8.8 mmol, Step B) was dissolved in THF (88 mL) and the reaction mixture was cooled to −78° C. Then, DIBAL solution (24 mL, 24 mmol, 1 M in DCM) was added dropwise over 5 minutes. The reaction mixture was allowed to stir at −78° C. for 1.5 hours and then quenched with Rochelle's salt (10 g), saturated aqueous Rochelle's salt solution (25 mL), and EtOAc (75 mL). The solution was allowed to warm to room temperature and stirred overnight. The solution was then diluted with EtOAc (75 mL), brine (30 mL), and 0.1 M aqueous HCl (40 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (4 × 40 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to provide the title compound in 99% yield, which was used without further purification.

[0726] Step D: (S)—N-((E)-(7-((S)-1-(5,5-Difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)methylene)-2,4,6-trimethylbenzenesulfinamide. (S)-7-(1-(5,5-Difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazine-2-carbaldehyde (2.9 g, 8.7 mmol, Step C) and CsCO (20 g, 61 mmol) were added to DCM (115 mL). Then, (S)-2,4,6-trimethylbenzenesulfinamide (1.7 g, 9.5 mmol) was added, and the reaction was allowed to stir at room temperature for 4 hours. The reaction was filtered and washed with DCM. The solution was concentrated to dryness and then triturated with hexane (45 mL) and DCM (16 mL). The cloudy solution was filtered and the solid was dried to give the title compound in 92% yield.

[0727] Intermediate 57: 1-((1S)-1-(2-((1R * )-1-amino-2-cyclopropoxypropyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0728] [ka]

[0729] Process A:(S)-N-((1R *)-2-Cyclopropoxy-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)propyl)-2,4,6-trimethylbenzenesulfinamide. (S)—N-((E)-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)methylene)-2,4,6-trimethylbenzenesulfinamide (160 mg, 0.32 mmol, Intermediate 56) was dissolved in DMSO (4.9 mL), followed by the sequential addition of DIPEA (0.14 mL, 0.79 mmol), diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (160 mg, 0.63 mmol), and 1,3-dioxoisoindolin-2-yl 2-cyclopropoxypropanoate (180 mg, 0.63 mmol, Intermediate 55). The reaction mixture was sparged with N for 15 minutes and then irradiated with 450 nm light (40% LED intensity, blown at maximum rpm, stirred at 1000 rpm) for 3 hours. DIPEA (30 μL, 0.16 mmol), diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (32 mg, 0.13 mmol), and 1,3-dioxoisoindolin-2-yl 2-cyclopropoxypropanoate (34 mg, 0.13 mmol) were then added. The reaction mixture was sparged again for 5 minutes and irradiated for an additional 30 minutes with 450 nm light (40% LED intensity, blown at maximum rpm, stirred at 1000 rpm). The reaction mixture was then diluted with brine (30 mL), saturated aqueous NaHCO (15 mL), water (15 mL), and EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (4 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness, and the residue was then purified by silica gel chromatography (0-100% (25% EtOH and 0.1% TEA in EtOAc) / EtOAc) to give the title compound in 52% yield.

[0730] Process B: 1-((1S)-1-(2-((1R) *)-1-amino-2-cyclopropoxypropyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. The title compound was prepared by the procedure of ((R)-1-(7-((S * )-1-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate instead of tert-butyl (S)-N-((1R * )-2-cyclopropoxy-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)propyl)-2,4,6-trimethylbenzenesulfinamide (Step A) was synthesized in a manner similar to Intermediate 9 and used without further purification (100% yield).

[0731] Intermediate 58: (S)-1-(7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentan-1-aminium 2,2,2-trifluoroacetate

[0732] [ka]

[0733] Step A: tert-butyl ((S)-1-(6-chloro-7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)carbamate. (S)-tert-Butyl (7,7,7-trifluoro-1-iodo-6,6-dimethyl-2-oxoheptan-3-yl)carbamate (150 mg, 0.33 mmol, Intermediate 46) was added to a solution of (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-cyclopropoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (77 mg, 0.22 mmol, Intermediate 36) and dibasic sodium phosphate (41 mg, 0.29 mmol) in NMP (0.16 mL) and the reaction mixture was heated to 40° C. for 18 hours. An additional aliquot of (S)-(7,7,7-trifluoro-1-iodo-6,6-dimethyl-2-oxoheptan-3-yl)carbamate (100 mg, 0.22 mmol, Intermediate 46) and dibasic sodium phosphate (40 mg, 0.28 mmol) was then added, and the mixture was heated at 40° C. for an additional 8 hours. The reaction mixture was then poured into water and extracted with EtOAc (3×). The combined organic layers were washed twice with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)) to provide the title compound in 99% yield.

[0734] Step B: ((S)-1-(7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)carbamate tert-butyl. The title compound was synthesized in a manner similar to Step B of Intermediate 41 using tert-butyl ((S)-1-(6-chloro-7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)carbamate (Step A) instead of tert-butyl ((1R,2R)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate. This material was purified by silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)) to afford the title compound in 55% yield.

[0735] Step C: (S)-1-(7-((S)-2-cyclopropoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentan-1-aminium 2,2,2-trifluoroacetate. The title compound was prepared by the addition of ((1R,2R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate instead of tert-butyl ((S)-1-(7-((S)-2 tert-Butyl-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)carbamate (Step B) in a manner similar to Step C of Intermediate 41, which was used without further purification (100% yield).

[0736] Intermediate 59: Tributyl(isopropoxymethyl)stannane

[0737] [ka] Sodium hydride (250 mg, 6.25 mmol, 60% dispersion in mineral oil) was dissolved in DMF (20 mL) under dry conditions and cooled to 0 °C. Propan-2-ol (478 μL, 6.25 mmol) was added dropwise and stirred for 5 min, followed by tributyl(iodomethyl)stannane (1.66 mL, 5.00 mmol). The ice bath was removed, and after stirring for 1 h, the reaction was quenched with HO (15 mL), diluted with 5% aqueous LiCl (10 mL), and extracted with DCM (2 × 20 mL). The combined organic layers were washed with 5% aqueous LiCl, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (10% EtOAc / hexanes) to give the title compound in 95% yield.

[0738] Intermediate 60: Tributyl(cyclobutoxymethyl)stannane

[0739] [ka] The title compound (100% yield) was prepared as described for the synthesis of intermediate 59 using cyclobutanol instead of propan-2-ol.

[0740] Intermediate 61:1-((S * )-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-cyclobutoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0741] [ka]

[0742] Process A:((S)-(7-((S * tert-Butyl)-1-(((R)-tert-butylsulfinyl)amino)-2-cyclobutoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound (50% yield) was synthesized in a manner similar to Step A of Intermediate 3, using tributyl(cyclobutoxymethyl)stannane (Intermediate 60) instead of tributyl(methoxymethyl)stannane.

[0743] Process B:((S)-(7-((S) * )-1-amino-2-cyclobutoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate tert-butyl. The title compound (94% yield) was obtained by the procedure of ((R)-1-(7-((S *)-1-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate tert-butyl ((S)-(7-((S * Prepared as described for the synthesis of intermediate 9 using tert-butyl 2-cyclobutoxyethyl)-1-(((R)-tert-butylsulfinyl)amino)-2-cyclobutoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step A).

[0744] Process C:((S)-(7-((S * )-2-cyclobutoxy-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate tert-butyl. The title compound (78% yield) was obtained by reacting ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate with tert-butyl ester. * Prepared as described for Step A of the synthesis of Intermediate 2 using tert-butyl)-1-amino-2-cyclobutoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step B).

[0745] Process D:((S)-(7-((S *)-1-((3-amino-2,2-difluoropropyl)amino)-2-cyclobutoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate tert-butyl. The title compound (90% yield) was obtained by replacing ((S)-(7-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate with ((S)-(7-((S * Prepared as described for Step B of the synthesis of Intermediate 2 using tert-butyl 2-cyclobutoxy-1-((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step C).

[0746] Process E:((S)-(7-((S * )-2-cyclobutoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate tert-butyl. The title compound (66% yield) was obtained by reacting ((S)-(7-((R)-((3-amino-2,2-difluoropropyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate with tert-butyl ester. * Prepared as described for step C of the synthesis of intermediate 2 using tert-butyl 1-((3-amino-2,2-difluoropropyl)amino)-2-cyclobutoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (step D).

[0747] Process F:1-((S *)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-cyclobutoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. The title compound was prepared by the procedure of ((S)-(7-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate instead of tert-butyl ((S)-(7-((S * Prepared as described for Step D of the synthesis of Intermediate 2 using tert-butyl 2-cyclobutoxy-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step E) and adding DCM (2 mL) as a co-solvent, and the residue was used without further purification (82% yield).

[0748] Intermediate 62:1-((S * )-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2-isopropoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0749] [ka] The title compound (27% yield) was prepared as described for the synthesis of Intermediate 61, using tributyl(isopropoxymethyl)stannane (Intermediate 59) instead of tributyl(cyclobutoxymethyl)stannane.

[0750] Intermediate 63:1-((R * )-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(tetrahydro-2H-pyran-4-yl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0751] [ka]

[0752] Process A:((S)-(7-((R * tert-Butyl ((S)-(7-((E)-(((S)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. A solution of tert-butyl ((S)-(7-((E)-(((S)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (3.00 g, 6.03 mmol) in CHCl (60 mL) was cooled to −78° C., followed by the dropwise addition of tetrahydropyran-4-ylmagnesium bromide (25 mL, 0.5 M in THF, 13 mmol). The reaction was stirred for 20 minutes and then warmed to 0° C. The reaction was stirred at this temperature for 30 minutes, after which an additional portion of tetrahydropyran-4-ylmagnesium bromide (12 mL, 0.5 M THF solution, 6.0 mmol) was added. The reaction was stirred at 0 °C for 1 hour, after which an additional portion of tetrahydropyran-4-ylmagnesium bromide (6.0 mL, 0.5 M THF solution, 3.0 mmol) was added. The reaction was stirred at 0 °C for 1 hour, after which it was quenched with acetic acid (1.4 mL, 24 mmol), diluted with saturated aqueous NaHCO3, and the layers separated. The aqueous phase was extracted with CHCl2, after which the combined organic layers were washed with brine, dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure. The resulting two diastereoisomers were purified and separated by silica gel chromatography (30-60% acetone / hexanes). The major diastereomer (second eluting peak) was further purified by silica gel chromatography (50-60% acetone / hexane (containing 0.1% TEA)) (21% yield) to give R * designated as isomers.

[0753] Process B:((S)-(7-((R* )-amino(tetrahydro-2H-pyran-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate tert-butyl. The title compound (86% yield) was obtained by the procedure of ((R)-1-(7-((S * )-1-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate instead of tert-butyl ((S)-(7-((R * Prepared in a manner similar to Intermediate 9 using tert-butyl 2H-pyran-4-yl)methylimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step A).

[0754] Process C:((S)-(7-((R * )-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)(tetrahydro-2H-pyran-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl) tert-butylcarbamate. The title compound was prepared by the procedure of ((R)-1-(7-((S * )-1-amino-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate tert-butyl ester * Prepared in a similar manner to Intermediate 10 using tert-butyl 2H-amino(tetrahydro-2H-pyran-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step B). Purification by silica gel chromatography (20-100% (10% MeOH / EtOAc) / (0.1% TEA / hexanes)) afforded the title compound in 29% yield.

[0755] Process D:1-((R * )-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(tetrahydro-2H-pyran-4-yl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. ((S)-(7-((R * To a solution of tert-butyl (4,4-difluorocyclohexyl)methyl)-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)(tetrahydro-2H-pyran-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (0.21 g, 0.32 mmol, Step C) in CHCl (0.2 mL) was added TFA (1.0 mL, 13 mmol). The reaction mixture was stirred at room temperature for 10 minutes, then diluted with HO, and NaCO was added until the pH of the mixture reached pH 10. The mixture was extracted with 4:1 CHCl:IPA, then the combined organics were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to provide the title compound in 57% yield.

[0756] Intermediate 64: 1,3-dioxoisoindolin-2-yl 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propanoate

[0757] [ka]

[0758] Step A: 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propanoic acid. The title compound was synthesized in a manner similar to Step A of Intermediate 37, using 1,1,1-trifluoro-2-methylpropan-2-ol instead of (R)-1,1,1-trifluoropropan-2-ol and 2-bromopropanoic acid instead of (S)-2-bromopropanoic acid, and was used without further purification.

[0759] Step B: 1,3-dioxoisoindolin-2-yl 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propanoic acid. The title compound (18% yield) was synthesized in a manner similar to Step B of Intermediate 55, using 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propanoic acid (Step A) instead of 2-cyclopropoxypropanoic acid.

[0760] Intermediate 65: 1-((1S)-1-(2-((1R * )-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0761] [ka]

[0762] Process A:(S)-N-((1R * )-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propyl)-2,4,6-trimethylbenzenesulfinamide. The title compound (45% yield) was synthesized in a manner similar to Step A of Intermediate 57, using 1,3-dioxoisoindolin-2-yl 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propanoate (Intermediate 64) instead of 1,3-dioxoisoindolin-2-yl 2-cyclopropoxypropanoate.

[0763] Process B: 1-((1S)-1-(2-((1R) *)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. The title compound was prepared by the procedure of ((R)-1-(7-((S * )-1-(((R)-tert-butylsulfinyl)amino)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate instead of tert-butyl (S)-N-((1R * )-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propyl)-2,4,6-trimethylbenzenesulfinamide (Step A) was synthesized in a similar manner to Intermediate 9 and used without further purification (100% yield).

[0764] Intermediate 66: 1-((R)-(2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)(cyclopropyl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0765] [ka]

[0766] Step A: (S,E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide. To a mixture of cyclopropanecarboxaldehyde (23.7 mL, 317.7 mmol) and (S)-2-methylpropane-2-sulfinamide (35 g, 289 mmol) in DCM (271 mL) was added CuSO (138 g, 866 mmol) and PPTS (3.63 g, 14.4 mmol), and the resulting mixture was stirred at room temperature for 40 hours. Additional cyclopropanecarboxaldehyde (2.15 mL, 28.9 mmol) and CuSO (23 g, 140 mmol) were then added. The mixture was stirred at room temperature for 2.5 days, then filtered through diatomaceous earth (e.g., Celite®), and the filtrate was concentrated under reduced pressure. The concentrate was filtered through a silica gel pad and rinsed with 40% EtOAc / hexanes. The filtrate was concentrated to dryness to give the title compound (86% yield) as a pale yellow oil.

[0767] Step B: N-(5-((R)-(((S)-tert-Butylsulfinyl)amino)(cyclopropyl)methyl)-6-chloropyridazin-3-yl)pivalamide. To a solution of 2,2,6,6-tetramethylpiperidinylmagnesium chloride-lithium chloride complex in THF / toluene (75 mL, 61 mmol, 0.82 M) was added a solution of N-(6-chloropyridazin-3-yl)pivalamide (5.00 g, 23.4 mmol, Intermediate 32, Step A) in THF (50 mL) dropwise via addition funnel over 20 minutes at −40° C. An additional aliquot of THF (10 mL) was used to rinse the residue in the addition funnel into the reaction mixture. The resulting solution was stirred at −40° C. for 3 hours, after which (S,E)—N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide (5.12 g, 28.1 mmol, Step A) was added. The solution was removed from the cold bath and allowed to warm to room temperature. After 1 hour, additional (S,E)—N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide (1.28 g, 7.02 mmol, Step A) was added, and the mixture was stirred at room temperature overnight. Saturated aqueous NH4Cl was then added, and the mixture was extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (20-50% acetone / hexanes) to give the title compound (65% yield) as a pale yellow foam.

[0768] Step C: (R)-N-(5-(amino(cyclopropyl)methyl)-6-chloropyridazin-3-yl)pivalamide. To a mixture of N-(5-((R)-(((S)-tert-butylsulfinyl)amino)(cyclopropyl)methyl)-6-chloropyridazin-3-yl)pivalamide (6.00 g, 15.5 mmol, Step B) in EtOAc (77.5 mL) was added 4 M HCl / 1,4-dioxane solution (15.5 mL, 62 mmol), and the resulting mixture was stirred at room temperature for 3 days. The mixture was then poured into water (200 mL) and diluted with hexane (150 mL). The layers were separated, and the organic layer was extracted with 0.05 M aqueous HCl (50 mL). The aqueous layers were combined and washed with hexane (50 mL). The aqueous layer was then poured into a flask with EtOAc (100 mL), and the pH of the solution was adjusted to pH 10 by the addition of 3 M aqueous NaOH. The layers were separated and the aqueous layer was further extracted with EtOAc (4 x 50 mL). The EtOAc layers were combined, dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the title compound (86% yield) as a foam.

[0769] Step D: (R)—N-(6-chloro-5-(cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)pyridazin-3-yl)pivalamide. A mixture of (R)—N-(5-(amino(cyclopropyl)methyl)-6-chloropyridazin-3-yl)pivalamide (2.0 g, 7.1 mmol, Step C), 3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl trifluoromethanesulfonate (4.22 g, 11.3 mmol), DIPEA (1.85 mL, 10.6 mmol), and ACN (24 mL) was heated at 55° C. for 2.5 days. The mixture was cooled to room temperature and concentrated to dryness. The residue was purified by silica gel chromatography (10-50% acetone / hexanes (0.1% TEA)) to afford the title compound (78% yield) as a white solid.

[0770] Step E: (R)-2-(3-(((6-Amino-3-chloropyridazin-4-yl)(cyclopropyl)methyl)amino)-2,2-difluoropropyl)isoindoline-1,3-dione. To a solution of (R)-N-(6-chloro-5-(cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)pyridazin-3-yl)pivalamide (1 g, 2 mmol, Step D) in MeOH (15 mL) was added H2SO4 (15 mL, 45 mmol, 3 M aqueous solution), and the resulting solution was heated at 55 °C for 8 h. The mixture was cooled to room temperature and diluted with half-saturated brine (50 mL) and EtOAc, after which the pH of the mixture was adjusted to pH 12 by the addition of 3 M aqueous NaOH. The layers were separated, and the aqueous layer was further extracted with EtOAc (50 mL), followed by DCM (2 x 30 mL). The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to dryness to give the title compound (68% yield).

[0771] Process F:(R)-N 1 -((6-amino-3-chloropyridazin-4-yl)(cyclopropyl)methyl)-2,2-difluoropropane-1,3-diamine. The title compound was prepared as described for Step B of Intermediate 2 using (R)-2-(3-(((6-amino-3-chloropyridazin-4-yl)(cyclopropyl)methyl)amino)-2,2-difluoropropyl)isoindoline-1,3-dione (Step E) instead of tert-butyl ((S)-(7-((R)-cyclopropyl((3-(1,3-dioxoisoindolin-2-yl)-2,2-difluoropropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate and used without further purification.

[0772] Step G: (R)-1-((6-amino-3-chloropyridazin-4-yl)(cyclopropyl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. The title compound (69% yield) was prepared by reacting (R)-N-(7-((S)-1-((3-amino-2,2-difluoropropyl)amino)-2-cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate with tert-butyl ester. 1 Prepared as described for Intermediate 15, Step C using -((6-amino-3-chloropyridazin-4-yl)(cyclopropyl)methyl)-2,2-difluoropropane-1,3-diamine (Step F).

[0773] Step H: tert-butyl ((R)-1-(6-chloro-7-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. The title compound was prepared as described for Step A of Intermediate 41, using (R)-1-((6-amino-3-chloropyridazin-4-yl)(cyclopropyl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (Step G) instead of (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one and using tert-butyl (S)-(4-iodo-3-oxo-1-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)butan-2-yl)carbamate instead of tert-butyl ((3S,4R)-1-iodo-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate. Additionally, the reaction mixture was heated at 50° C. for 48 hours instead of 16 hours and purified by silica gel chromatography (5-60% acetone / hexanes (0.1% TEA)) to give the title compound in 79% yield.

[0774] Step I: tert-Butyl ((R)-1-(7-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. To a Parr shaker bottle was added 10% Pd / C (469 mg, 3.83 mmol) and MeOH (10 mL). A solution of tert-butyl ((R)-1-(6-chloro-7-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (385 mg, 0.63 mmol, Step H) in MeOH (20 mL) was then added, and the bottle was placed under 50 psi of H on a Parr shaker for 17 hours. The bottle was sparged with air and filtered through diatomaceous earth (e.g., Celite®), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-50% acetone / hexanes (0.1% TEA)) to provide the title compound (5% yield) as a pale yellow oil.

[0775] Step J: 1-((R)-(2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)(cyclopropyl)methyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. The title compound (100% yield) was prepared as described in Step C of Intermediate 20 using tert-butyl ((R)-1-(7-((R)-cyclopropyl(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (Step I) instead of tert-butyl (S)-((7-((5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.

[0776] Intermediate 67: 1-((R)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0777] [ka]

[0778] Step A: tert-Butyl ((S)-(6-chloro-7-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. An oven-dried vial was charged with (R)-1-(1-(6-amino-3-chloropyridazin-4-yl)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (79 mg, 0.27 mmol, Intermediate 84), activated 4 Å molecular sieves, and DMA (1.2 mL). A separate solution of tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-3-iodo-2-oxopropyl)carbamate (451 mg, 1.08 mmol) in DMA (6 mL) was added, and the reaction mixture was heated to 50° C. under a N atmosphere for 2.5 days. An additional aliquot of a solution of tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-3-iodo-2-oxopropyl)carbamate (451 mg, 1.08 mmol) in DMA (3 mL) was then added, and the reaction mixture was heated at 50° C. for 1 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc, filtered, and the collected solid was rinsed with EtOAc and DCM. To the filtrate was added one-quarter saturated brine (50 mL), and the layers were separated. The aqueous layer was further extracted with EtOAc (20 mL), and then the organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (5-60% acetone / hexane (0.1% TEA)) to give the title compound (100% yield).

[0779] Step B: 1-((R)-1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one. To a Parr shaker bottle was added 10% Pd / C (250 mg, 2.04 mmol) and MeOH (10 mL). A solution of tert-butyl ((S)-(6-chloro-7-((R)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (189 mg, 0.34 mmol, Step A) in MeOH (15 mL) was then added, followed by NHOH (0.28 mL, 2.12 mmol, 28-30% aqueous solution), and the bottle was placed under 50 psi of H on a Parr shaker for 3.5 h. The bottle was sparged with air and concentrated to dryness. The residue was dissolved in DCM (6 mL) and cooled to 0 °C in an ice bath, after which TFA (2 mL, 26 mmol) was added. The resulting mixture was stirred at room temperature for 75 minutes and then concentrated to dryness to give the title compound (99% yield), which was used without further purification.

[0780] Intermediate 68: 1-((S)-1-(2-((R)-1-amino-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one

[0781] [ka]

[0782] Step A: tert-butyl ((R)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. The title compound (50% yield) was prepared as described in Step A of Intermediate 67, using (S)-1-(1-(6-amino-3-chloropyridazin-4-yl)-2-methoxyethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one (Intermediate 35) instead of (R)-1-(1-(6-amino-3-chloropyridazin-4-yl)ethyl)-5,5-difluorotetrahydropyrimidin-2(1H)-one and using tert-butyl (S)-(4-iodo-3-oxo-1-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)butan-2-yl)carbamate instead of tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-3-iodo-2-oxopropyl)carbamate.

[0783] Step B: tert-butyl ((R)-1-(7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate. A vial was charged with tert-butyl ((R)-1-(6-chloro-7-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate (127 mg, 0.21 mmol, Step A), EtOH (20 mL), Pd / C (63 mg, 0.52 mmol, 10 wt% Pd), and ammonium formate (130 mg, 2.07 mmol). The vial was heated to 80° C. and stirred for 6 hours, then at room temperature overnight. The reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), and the solid was washed with EtOH. The combined organic layers ...

Claims

1. Formula (I): 【Chemical 1】 [In the formula, R １ but, 【Chemistry 2】 and R １ａ independently for each occurrence, -C （１～３） Alkyl or -C （３～５） Cycloalkyl (wherein the —C （１～３） alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when m1 is 2, two geminal R １ａ The groups, together with the carbon atoms to which they are attached, form a spiro C （３～５） forming a cycloalkyl, R １ｂ each occurrence independently represents halo or -C （１～３） alkyl (wherein the -C （１～３） alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R １ｂ The groups, together with the carbon atoms to which they are attached, form a fused C （３～７） Cycloalkyl (wherein the C （３～７） cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms, n is 1 or 2; m1, m2, and m3 are independently 0, 1, or 2; R ２ But H, -C （１～３） Alkyl, -C （３～５） cycloalkyl, —C （１～３） Alkyl-O-C （１～３） Alkyl, -C （１～３） Alkyl-O-C （３～５） cycloalkyl, or 4- to 6-membered heterocyclyl (wherein the —C （１～３） alkyl, the aforementioned -C （３～５） cycloalkyl, the aforementioned —C （１～３） Alkyl-O-C （１～３） alkyl, and the —C （１～３） Alkyl-O-C （３～５） The cycloalkyl group may be unsubstituted or may contain 1 to 6 R ２ａ substituted with a group; R ２ａ is independently at each occurrence fluorine or —CN; R ３ But, -C （１～１０） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, -C （１～６） Alkyl-O-C （３～５） cycloalkyl, —C （１～６） Alkyl-O-C （３～５） Cycloalkyl-C （１～３） Alkyl, -C （３～８） cycloalkyl, or -C （１～３） Alkyl-(C （３～５） cycloalkyl) １～２ (each unsubstituted or substituted with 1 to 6 fluorine atoms); R ４ is unsubstituted or has 1 to 2 R ４ａ is a 5-membered heteroaryl substituted with a group; R ４ａ But, halo, -C （１～６） Alkyl, —O—C （１～６） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, or -C （０～２） Alkyl-C （３～６） Cycloalkyl (wherein the —C （１～６） alkyl, the aforementioned —O—C （１～６） alkyl, the aforementioned -C （１～６） Alkyl-O-C （１～６） alkyl, and the —C （０～２） Alkyl-C （３～６） Cycloalkyl is unsubstituted or substituted with fluorine, —CH ３ , -CD ３ , -CD ２ CD ３ , -CH ２ F, -CHF ２ , and -CF ３ or a pharmaceutically acceptable salt thereof.

2. R １ but, 【Chemistry 3】 and R １ａ independently for each occurrence, -C （１～３） Alkyl or -C （３～５） Cycloalkyl (wherein the —C （１～３） alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when m1 is 2, two geminal R １ａ The groups, together with the carbon atoms to which they are attached, form a spiro C （３～５） forming a cycloalkyl, R １ｂ each occurrence independently represents halo or -C （１～３） alkyl (wherein the -C （１～３） alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R １ｂ The groups, together with the carbon atoms to which they are attached, form a fused C （３～７） Cycloalkyl (wherein the C （３～７） cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; n is 1 or 2; m1, m2, and m3 are independently 0, 1, or 2; R ２ But H, -C （１～３） Alkyl, -C （３～５） cycloalkyl, —C （１～３） Alkyl-O-C （１～３） Alkyl, -C （１～３） Alkyl-O-C （３～５） cycloalkyl, or 4- to 6-membered heterocyclyl (wherein the —C （１～３） Alkyl and the -C （３～５） Cycloalkyl is unsubstituted or has 1 to 6 R ２ａ substituted with a group; R ２ａ is independently at each occurrence fluorine or —CN; R ３ But, -C （１～６） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, -C （１～６） Alkyl-O-C （３～５） cycloalkyl, —C （１～６） Alkyl-O-C （３～５） Cycloalkyl-C （１～３） Alkyl, -C （３～８） cycloalkyl, or —CH(C （３～５） cycloalkyl) ２ (each unsubstituted or substituted with 1 to 6 fluorine atoms); R ４ is unsubstituted or has 1 to 2 R ４ａ is a 5-membered heteroaryl substituted with a group; R ４ａ But, halo, -C （１～６） Alkyl, —O—C （１～６） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, or -C （０～２） Alkyl-C （３～６） Cycloalkyl (wherein the —C （１～６） alkyl, the aforementioned —O—C （１～６） alkyl, the aforementioned -C （１～６） Alkyl-O-C （１～６） alkyl, and the —C （０～２） Alkyl-C （３～６） Cycloalkyl is unsubstituted or substituted with fluorine, —CH ３ , -CD ３ , -CD ２ CD ３ , -CH ２ F, -CHF ２ , and -CF ３ 10. The compound of claim 1, wherein the compound is substituted with 1 to 6 substituents independently selected from:

3. R １ but, 【Chemistry 4】 and R １ａ independently for each occurrence, -C （１～３） Alkyl or -C （３～５） Cycloalkyl (wherein the —C （１～３） alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; R １ｂ each occurrence independently represents halo or -C （１～３） alkyl (wherein the -C （１～３） alkyl is unsubstituted or substituted with 1 to 5 fluorine atoms), or when n is 2, two R １ｂ The groups, together with the carbon atoms to which they are attached, form a fused C （３～７） Cycloalkyl (wherein the C （３～７） cycloalkyl is unsubstituted or substituted with 1 to 5 fluorine atoms; n is 1 or 2; m1, m2, and m3 are independently 0, 1, or 2; R ２ But H, -C （１～３） Alkyl, -C （３～５） cycloalkyl, —C （１～３） Alkyl-O-C （１～３） Alkyl, or -C （１～３） Alkyl-O-C （３～５） is cycloalkyl, R ３ But, -C （１～６） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, -C （１～６） Alkyl-O-C （３～５） cycloalkyl, or -C （３～８） cycloalkyl, each of which is unsubstituted or substituted with 1 to 6 fluorine atoms; R ４ is unsubstituted or has 1 to 2 R ４ａ is a 5-membered heteroaryl substituted with a group; R ４ａ But, halo, -C （１～６） Alkyl, —O—C （１～６） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, or -C （０～２） Alkyl-C （３～６） Cycloalkyl (wherein the —C （１～６） alkyl, the aforementioned —O—C （１～６） alkyl, the aforementioned -C （１～６） Alkyl-O-C （１～６） alkyl, and the —C （０～２） Alkyl-C （３～６） Cycloalkyl is unsubstituted or substituted with fluorine, —CH ３ , -CD ３ , -CD ２ CD ３ , -CH ２ F, -CHF ２ , and -CF ３ 10. The compound of claim 1, wherein the compound is substituted with 1 to 6 substituents independently selected from:

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

5. R ２ But H, -C （３～５） cycloalkyl, —C （１～３） Alkyl-O-C （１～３） Alkyl, or -C （１～３） Alkyl-O-C （３～５） 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

6. R ３ But, -C （１～６） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, or -C （１～６） Alkyl-O-C （３～５） 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is cycloalkyl, each unsubstituted or substituted with 1 to 6 fluorine atoms.

7. R ３ but, 【Chemistry 6】 2. The compound of claim 1, wherein:

8. 2. The compound of claim 1, which is a compound of formula Id-1, or a pharmaceutically acceptable salt thereof. 【Chemistry 7】

9. R ４ is pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, or 1,2,5-oxadiazolyl (each of which is unsubstituted or has one to two R ４ａ 2. The compound of claim 1, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof.

10. R ４ａ But, -C （１～４） Alkyl, —O—C （１～４） Alkyl, -C （１～４） Alkyl-O-C （１～４） Alkyl, or -C （０～２） Alkyl-C （３～４） Cycloalkyl (wherein the —C （１～４） alkyl, the aforementioned —O—C （１～４） alkyl, the aforementioned -C （１～４） Alkyl-O-C （１～４） alkyl, and the —C （０～２） Alkyl-C （３～４） Cycloalkyl is unsubstituted or substituted with fluorine, —CH ３ , -CD ３ , -CD ２ CD ３ , -CH ２ F, -CHF ２ , and -CF ３ 10. The compound of claim 1, wherein the compound is substituted with 1 to 6 substituents independently selected from:

11. R ４ but, 【Chemistry 8】 2. The compound of claim 1, wherein:

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

13. 【Catalog 11】 10. The compound of claim 1, having a structure selected from the group consisting of:

14.

12. 【Chemistry 13】 10. The compound of claim 1, having a structure selected from the group consisting of:

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. 16. The pharmaceutical composition of claim 15, or a pharmaceutically acceptable salt thereof, which is administered orally.

17. 17. The pharmaceutical composition of claim 16, or a pharmaceutically acceptable salt thereof, administered as a tablet or capsule.

18. 15. A process for making a pharmaceutical composition, comprising combining a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A.

20. 20. The pharmaceutical composition of claim 19, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

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